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Placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment at 18 months: effect modification by maternal vitamin D status

BMC Medicine volume 23, Article number: 252 (2025) Cite this article

Abstract

Background

Epidemiological studies that have simultaneously explored the effects of placental and cord blood inflammatory cytokine levels on neurodevelopment in offspring, as well as the role of maternal vitamin D in these associations, are lacking. To investigate the associations of placental and cord blood inflammatory cytokine levels with neurodevelopment in 18-month-old children, and the potential modification effect by maternal vitamin D.

Methods

Based on the Ma’anshan birth cohort, the current study involved 1241 mother–child pairs. The placental inflammatory cytokine mRNA expression levels, cord serum inflammatory cytokine concentrations, and maternal serum vitamin D concentrations were determined. Children’s neurodevelopmental outcomes were defined as the Chinese version of the Ages and Stages Questionnaire (Third Edition) subdomain scores below the established cutoff scores. Generalized linear models were utilized to assess the effects of placental and cord serum inflammatory cytokines on neurodevelopmental outcomes and to examine the modification effects of maternal vitamin D.

Results

After adjusting for confounders, each one-unit increase in placental IL-6 (OR = 1.30, 95% CI: 1.09, 1.55, P-FDR = 0.024), IL-8 (OR = 1.25, 95% CI: 1.05, 1.49, P-FDR = 0.036), and IFN-γ level in the cord serum (OR = 1.74, 95% CI: 1.16, 2.61, P-FDR = 0.042) was associated with an increased risk of fine motor delay. Elevated levels of placental TNF-α (OR = 1.38, 95% CI: 1.12, 1.69, P-FDR = 0.012), IL-6 (OR = 1.29, 95% CI: 1.04, 1.61, P-FDR = 0.042), and IL-8 (OR = 1.31, 95% CI: 1.06, 1.62, P-FDR = 0.036) were associated with an increased risk of personal-social delay. Stratified analyses showed that lower maternal vitamin D levels (< 20 ng/mL) moderated the associations between inflammatory markers and delays in fine motor, gross motor, and personal-social subdomains.

Conclusions

Elevated levels of specific inflammatory cytokines in the placenta and umbilical cord blood were associated with developmental delays on a parental-reported screening tool. Maternal vitamin D status can modify the adverse effects of the intrauterine pro-inflammatory milieu on the neurodevelopment of children.

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Background

The period from early pregnancy until childbirth is a critical window for fetal brain and neural development [1, 2]. During this delicate and complex stage, healthy neurodevelopmental processes can provide a solid foundation for the subsequent positive growth and development of individuals. Moreover, multiple prenatal factors can also lead to deviations from the typical trajectories of neurodevelopment [3], which may correspondingly result in a variety of adverse outcomes later in life, such as childhood neurodevelopmental delay [4], behavior and mental health outcomes [5], impaired academic performance [6], and low socioeconomic status [7].

The maternal immune activation (MIA)-induced inflammatory perturbations in utero are considered important risk factors for abnormalities in fetal neurodevelopment. Among the multiple inflammatory biomarkers, cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-6 (IL-6) are the most frequently measured indicators of the inflammatory response [2, 8]. As key hubs for the exchange of nutrients and various metabolites at the mother-fetus interface, the placenta and umbilical cord play pivotal roles in the association between MIA and fetal neurodevelopment [9, 10]. MIA-induced inflammatory cytokines can either trigger a placental inflammatory response directly [11] or enter the fetus via the vertical transfer pathway through the umbilical cord [12], both of which can disrupt the precise balance between inflammatory cytokines in the maternal–fetal circulation and elicit a long-lasting effect on fetal neurodevelopmental processes via direct (e.g., inflammatory perturbations in the fetal brain) [2] or indirect pathways (e.g., altered placental secretion and metabolic function) [13].

Previous epidemiologic studies have reported the effects of inflammatory cytokine levels in the placenta or cord blood on multiple neurodevelopmental outcomes in offspring. Data from the Boston Birth Cohort revealed that placental histological chorioamnionitis (based on data from pathological reports) is a risk factor for offspring neurodevelopmental disorders (e.g., attention-deficit/hyperactivity disorder and autism spectrum disorder) [14]. In the Ma’anshan birth cohort (MABC), our team noted that placental inflammation (TNF-α, IFN-γ, C-reactive protein, IL-1β, IL-6, IL-8, IL-4, and IL-10) is associated with cognitive performance and behavioral problems in preschool children [15, 16]. Furthermore, a longitudinal study suggested that the levels of inflammatory cytokines (TNF-α, IFN-γ, and IL-12p70) in umbilical cord blood are associated with verbal and performance intelligence quotients in children (including preterm birth and small-for-gestational-age children) [17]. Wang et al. reported that higher high-sensitivity C-reactive protein levels in the cord blood of children increase the risk of neurodevelopmental delay [10]. However, previous studies have selected only a single biospecimen (either the placenta or umbilical cord blood) for the measurement of inflammatory cytokine levels, and the types of detected cytokines in different biospecimens have varied, thus underestimating the true impact of the intrauterine immune environment on offspring neurodevelopment. When considering that a consistent inflammatory cytokine profile in the placenta and cord blood can provide a complete picture of the fetal immune environment compared with a single biospecimen, there is an urgent need to simultaneously explore the effects of placental and cord blood inflammatory cytokine levels on neurodevelopment in offspring.

The development of safe, cost-effective, and highly feasible interventions for neurodevelopmental impairments in children has been an ongoing priority in public health. Recently, increasing evidence from prospective birth cohort studies has indicated that appropriate maternal vitamin D levels can attenuate the negative effects of prenatal immune function-related adverse environmental exposure on the neurodevelopmental process of the fetus [18,19,20]. As an essential nutrient for maintaining normal pregnancy, the level of vitamin D in pregnant women not only influences fetal neurodevelopment [21] but also affects the intensity of maternal and fetal inflammatory responses by regulating the differentiation, maturation, and function of immune cells (such as natural killer cells, macrophages, dendritic cells, B lymphocytes, and T lymphocytes) [22]. Therefore, it is important to elucidate whether maternal serum vitamin D status can modify the increased risk of neurodevelopmental delay in offspring due to exposure to an adverse intrauterine immune environment.

Based on data from the MABC, we aimed to evaluate the associations between placental and cord blood inflammatory cytokine levels and neurodevelopment in 18-month-old children, as well as the potential modification effect by maternal vitamin D.

Methods

Study population

In Ma’anshan city, China, 3474 pregnant women were recruited for the MABC (2013–2014). With informed consent obtained from the participants, the MABC collected demographic and medically relevant information (No. 20131195). Among the population, 3273 mothers with singleton live births were followed [23]. Placenta and cord blood samples were collected after delivery by obstetricians, and neurodevelopment assessments of the children were conducted at 18 months of age. After excluding 1943 mother–child pairs without placenta and cord blood samples and 89 children without information on neurodevelopment assessments at 18 months, a total of 1241 mother–child pairs were included in our study (Additional file 1: Fig. S1).

Placental inflammatory cytokine mRNA expression assay

Placental tissues were collected within half an hour of delivery. After rinsing with normal saline, we removed an intact placental lobule (which was free of maternal decidua, calcification, and fascia) vertically from the full-thickness placenta at a periumbilical position of 5 cm. The extracted placental lobule was subsequently longitudinally sectioned into tissue pieces measuring less than or equal to 0.5 cm in size; these pieces were treated with RNAlater and stored at − 80 °C for measurement. The expression of placental tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-6, IL-8, and IL-10 mRNA were determined by real-time quantitative polymerase chain reaction (RT-qPCR). The oligonucleotide sequences that were utilized in RT-qPCR are shown in Additional file 1: Table S1. To normalize all of the RT-qPCR data, 18S rRNA was selected as the endogenous reference RNA. The delta cycle threshold (ΔCt) was calculated to represent the difference between the target mRNA and the normalized RNA, and the ΔCt was calculated as the Ct mRNA minus Ct normalized mRNA. The detailed procedures have been previously described [15].

Cord serum inflammatory cytokine measurement

Umbilical cord blood samples were collected after delivery, and the serum samples were separated and stored at − 80 °C. The method that was used to measure inflammatory cytokines in cord serum has been reported elsewhere [24]. The detection rates of TNF-α, IFN-γ, IL-1β, IL-6, IL-8, and IL-10 were 99.99%, 96.13%, 94.76%, 100%, 100%, and 100%, respectively. The limits of detection (LODs) for TNF-α, IFN-γ, IL-1β, IL-6, IL-8, and IL-10 were 0.16, 0.48, 0.14, 0.11, 0.13, and 0.56 (pg/mL), respectively. The concentrations of inflammatory cytokines in cord serum below the LODs were replaced by the LODs divided by the square root of 2 for further analyses.

Maternal serum 25-hydroxyvitamin D (25(OH)D) measurement

Maternal blood samples from the three trimesters were collected and stored at − 80 °C until measurement. Maternal serum total 25(OH)D was determined via a Diasorin kit (DiaSorin Inc, Stillwater, MN, USA) by well-trained experimenters [25]. The intra- and inter-coefficients of variation were less than 10%. In our study, the maternal serum 25(OH)D concentrations were 18.34 ± 8.34 ng/mL, 21.38 ± 9.47 ng/mL, and 19.08 ± 9.63 ng/mL during the first, second, and third trimester, respectively. The average serum 25(OH)D concentrations of the three trimesters were calculated and divided into two groups (“deficiency, < 20 ng/mL” and “non-deficiency, ≥ 20 ng/mL”) to reflect maternal vitamin D status during pregnancy [18, 26].

Assessment of child neurodevelopment

In MABC, neurodevelopment in 18-month-old children was assessed via the Chinese version of the Ages and Stages Questionnaire, Third Edition (ASQ-3). The ASQ-3 is an affordable, cost-effective, and validated instrument that effectively screens for potential early neurodevelopmental delays in Chinese children [27]. The ASQ-3 consists of the following five domains: communication, gross motor, fine motor, problem solving, and personal-social. Each dimension consists of six items with three options, including “yes,” “sometimes,” and “not yet,” scoring 10, 5, and 0, respectively. The total score for each domain ranges from 0 to 60 points. In the current study, under the supervision and guidance of a professional pediatric psychologist, parents completed the ASQ-3 via face-to-face or phone interviews. A child’s score below the cutoff scores (the mean score minus 2 standard deviations) in one of the domains was considered to indicate developmental delay in that domain [28].

Covariates

In the MABC, maternal age, pre-pregnancy body mass index (BMI), family monthly income, maternal smoking and drinking statuses, maternal fever, maternal infection or inflammation conditions, maternal folic acid supplementation during pregnancy, birth weight, the child’s main caregiver, breastfeeding duration, and child age at neurodevelopmental testing were collected via structured questionnaires or medical records. The Pregnancy-Related Anxiety Questionnaire was employed to assess maternal pregnancy-related anxiety [29]. Placental efficiency was calculated as birth weight divided by placental weight [30]. Information on delivery mode, gestational age, and child sex was obtained from clinical medical records.

Statistical analysis

Student’s t-test or the chi-square test was employed to compare characteristics between the included and source populations. The distributions of placental inflammatory cytokine mRNA expression levels, cord serum inflammatory cytokine concentrations, and ASQ domain-specific scores are presented as selected percentile values, and the neurodevelopmental delay of each domain is expressed as frequencies with percentages. The correlations between different placental and cord serum inflammatory cytokines were assessed via Spearman’s rank correlation coefficient. Due to the skewed distribution of the placental and cord serum inflammatory cytokine levels, natural logarithm-transformed (ln-transformed) values were calculated for further analyses.

Restricted cubic splines (RCS) were performed to explore the nonlinear associations between placental and cord serum inflammatory cytokines and children’s developmental delay in each domain. In the RCS model, statistical significance was defined as a p value less than 0.05. Generalized linear models were utilized to estimate the associations between placental and cord serum inflammatory cytokines and suspected developmental delay in each domain, based on the ASQ-3 cutoff scores. The odds ratios (ORs) and their 95% confidence intervals (CIs) were used as indicators of the strength of these associations. In adjusted models, potential confounders were identified based on a directed acyclic graph (Additional file 1: Fig. S2), which included maternal age, pre-pregnancy BMI, delivery mode, family monthly income, smoking and drinking during pregnancy, maternal fever during pregnancy, maternal infection or inflammation conditions during pregnancy, maternal pregnancy-related anxiety, placental efficiency, gestational age, children sex, and children’s age at neurodevelopmental testing. False discovery rate (FDR) corrected p values were calculated for multiple tests [31], and FDR corrected p values < 0.10 were considered to be statistically significant [32].

Stratified analyses were conducted to evaluate the influence of maternal vitamin D status on the associations between placental and cord serum inflammatory cytokines and developmental delay in each domain. We tested for maternal 25(OH)D status differences by adding a multiplicative interaction term (maternal 25(OH)D status × inflammatory cytokines) to the multivariable logistic regression models. Furthermore, these associations were also examined after stratification by trimester. In addition, analyses stratified by the sex of the children were conducted based on the sex-specific effects of inflammatory cytokines [16], and interaction terms (child sex × inflammatory cytokines) were added to the models. We also tested whether delivery mode affected the associations between placental and cord serum inflammatory cytokines and developmental delay in children. The multiplicative interaction term p values < 0.10 were considered to be statistically significant [33].

Three sensitivity analyses were conducted to test the robustness of the results. First, to investigate the effects of placental and cord serum inflammatory cytokines on neurodevelopment in full-term birth children, we excluded 39 preterm birth children. Second, we excluded 19 infants with low birth weights. Third, we further controlled for maternal folic acid supplementation during pregnancy, children main caregivers, and breastfeeding duration.

All of the analyses were performed via SPSS (version 23.0) and R (version 4.3.1). RCS was implemented in R via the “rcssci” package.

Results

Characteristics of participants

The characteristics of the participants are shown in Table 1 and Additional file 1: Table S2. The maternal age and pre-pregnancy BMI were 26.63 ± 3.55 years and 20.59 ± 2.88 kg/m2, respectively. A total of 42.0% of the households had a per capita monthly income between 2500 and 4000 Chinese yuan (CNY). During pregnancy, the vast majority of mothers took folic acid supplements (91.2%), did not smoke or drink alcohol (91.0%), did not have a fever (87.7%), and were not in a state of infection or inflammation (91.9%). More than half of the pregnant women did not experience anxiety during pregnancy (52.6%), and the average serum 25(OH)D concentration was less than 20 ng/mL (58.7%). In addition, placental weight, placental efficiency, birth weight, gestational age, and children’s age at neurodevelopmental testing were 571.96 ± 162.77 g, 6.39 ± 2.87, 3382.68 ± 429.32 g, 39.14 ± 1.27 weeks, and 18.16 ± 0.60 months, respectively. More than half of the children were boys (50.7%), were delivered by cesarean Sect. (55.1%), or were breastfed for more than 4 months (56.8%); additionally, their primary caregivers were parents and grandparents (73.2%).

Table 1 Demographic characteristics of the participants [mean ± SD or n (%)]
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Distribution of placental and cord serum inflammatory cytokines and children’s neurodevelopment

With respect to placental inflammatory cytokines, the median values of the mRNA expression levels (ΔCt) for TNF-α, IFN-γ, IL-1β, IL-6, IL-8, and IL-10 were 6.09, 3.44, 2.77, 2.90, 2.05, and 2.79, respectively. In the umbilical cord serum, the median concentrations (pg/mL) of TNF-α, IFN-γ, IL-1β, IL-6, IL-8, and IL-10 were 12.81, 1.40, 0.46, 1.82, 6.91, and 7.25, respectively (Table 2). The correlations between placental and cord serum inflammatory cytokines are shown in Fig. 1. In addition, the prevalence of each domain-specific neurodevelopment delay in children is displayed in Table 3, including communication (4.8%), gross motor (3.6%), fine motor (5.9%), problem solving (4.3%), and personal-social (3.9%).

Table 2 Distribution of placental inflammatory cytokine mRNA expression and cord serum inflammatory cytokine concentrations (n = 1241)
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Fig. 1
figure 1

Spearman correlation coefficients between placental and cord serum inflammatory cytokines. Abbreviations: C, cord serum; P, placenta. Note: *p value < 0.05, **p value < 0.01, ***p value < 0.001

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Table 3 Distribution of children’s neurodevelopmental assessments (n = 1241)
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Associations between placental and cord serum inflammatory cytokines and children’s neurodevelopment

Figure 2 shows the associations between placental and cord serum inflammatory cytokine levels and the children’s domain-specific neurodevelopment delay. Each one-unit increase in placental IL-6 (OR = 1.30, 95% CI: 1.09, 1.55, P-FDR = 0.024) and IL-8 (OR = 1.25, 95% CI: 1.05, 1.49, P-FDR = 0.036) was associated with an increased risk of fine motor delay. Furthermore, the IFN-γ level in the cord serum was positively associated with an increased risk of fine motor delay (OR = 1.74, 95% CI: 1.16, 2.61, P-FDR = 0.042). Each one-unit increase in placental TNF-α (OR = 1.38, 95% CI: 1.12, 1.69, P-FDR = 0.012), IL-6 (OR = 1.29, 95% CI: 1.04, 1.61, P-FDR = 0.042), and IL-8 (OR = 1.31, 95% CI: 1.06, 1.62, P-FDR = 0.036) was associated with an increased risk of personal-social delay. Additionally, the RCS results suggested that there were no nonlinear associations between placental (Additional file 1: Fig. S3) or cord serum (Additional file 1: Fig. S4) inflammatory cytokines and neurodevelopmental delay in children (all nonlinear p values > 0.05). Based on sex-stratified analyses (Additional file 1: Table S3), we observed a positive association between placental IFN-γ and gross motor delay in boys (OR = 1.35, 95% CI: 1.10, 1.66, P-FDR = 0.018, P-interaction = 0.002). Furthermore, we did not observe significant differences in the associations between placental and cord serum inflammatory cytokines and children’s neurodevelopmental delay stratified by delivery mode (Additional file 1: Table S4).

Fig. 2
figure 2

The associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopmental delay. Models adjusted for maternal age, pre-pregnancy BMI, delivery mode, family monthly income per capita, smoking and drinking during pregnancy, maternal fever during pregnancy, maternal infection or inflammation conditions during pregnancy, maternal pregnancy-related anxiety, placental efficiency, gestational age, children sex, and children’s age at neurodevelopmental testing

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The modification effects of maternal vitamin D status on the associations between placental and cord serum inflammatory cytokines and children’s neurodevelopment

The modification effects of maternal vitamin D status are shown in Fig. 3. Lower maternal serum vitamin D levels (< 20 ng/mL) aggravated cord serum IFN-γ-associated risks of gross motor delay (OR = 2.44, 95% CI: 1.23, 4.86, P-FDR = 0.066, P-interaction = 0.071). Placental TNF-α (OR = 1.30, 95% CI: 1.04, 1.63, P-FDR = 0.046, P-interaction = 0.032) and IL-6 (OR = 1.60, 95% CI: 1.24, 2.07, P-FDR ≤ 0.001, P-interaction = 0.040), as well as cord serum TNF-α (OR = 1.94, 95% CI: 1.05, 3.60, P-FDR = 0.052, P-interaction = 0.009), IL-1β (OR = 1.71, 95% CI: 1.02, 2.88, P-FDR = 0.052, P-interaction = 0.095), IL-6 (OR = 1.41, 95% CI: 1.06, 1.86, P-FDR = 0.052, P-interaction = 0.003), IL-8 (OR = 1.56, 95% CI: 1.03, 2.39, P-FDR = 0.052, P-interaction = 0.005), and IL-10 (OR = 1.56, 95% CI: 0.95, 2.56, P-FDR = 0.079, P-interaction = 0.042), were all found to have stronger adverse associations with fine motor delay in the maternal vitamin D deficiency group. Moreover, higher levels of maternal serum vitamin D (≥ 20 ng/mL) attenuated the risk of fine motor delay induced by cord serum IL-6 (OR = 0.61, 95% CI: 0.38, 0.96, P-FDR = 0.093, P-interaction = 0.003) and IL-8 (OR = 0.57, 95% CI: 0.35, 0.91, P-FDR = 0.093, P-interaction = 0.005). Moreover, in the vitamin D deficiency group, each one-unit increase in placental TNF-α was positively associated with personal-social delay (OR = 1.68, 95% CI: 1.28, 2.24, P-FDR = 0.006, P-interaction = 0.043). Additionally, maternal serum vitamin D levels less than 20 ng/mL during the first trimester could aggravate the risk of fine motor delay induced by placental TNF-α (OR = 1.29, 95% CI: 1.05, 1.60, P-FDR = 0.032, P-interaction = 0.011) and IL-8 (OR = 1.42, 95% CI: 1.14, 1.76, P-FDR = 0.006, P-interaction = 0.062) (Additional file 1: Tables S5–S8).

Fig. 3
figure 3

The associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopmental delay stratified by maternal vitamin D status. Models adjusted for maternal age, pre-pregnancy BMI, delivery mode, family monthly income per capita, smoking and drinking during pregnancy, maternal fever during pregnancy, maternal infection or inflammation conditions during pregnancy, maternal pregnancy-related anxiety, placental efficiency, gestational age, children sex, and children’s age at neurodevelopmental testing

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Sensitivity analyses

In sensitivity analyses that excluded preterm birth children (Additional file 1: Table S9) and low birth weight children (Additional file 1: Table S10), the associations between placental and cord serum inflammatory cytokines and the children’s domain-specific neurodevelopmental delay were similar to those in the main analyses. After additionally adjusting for maternal folic acid supplementation during pregnancy, children’s main caregivers, and breastfeeding duration, those associations did not substantially change (Additional file 1: Table S11).

Discussion

In this birth cohort study, we found that elevated levels of specific inflammatory cytokines in placental (TNF-α, IL-6, and IL-8) and cord blood (IFN-γ) samples were associated with an increased risk of domain-specific neurodevelopmental delay in 18-month-old children. Maternal serum vitamin D levels less than 20 ng/mL intensified the associations between placental and cord serum inflammatory markers and delays in fine motor, gross motor, and personal-social subdomains.

As an important component of the maternal–fetal interface, the placenta occupies a unique immunoecological niche and can maintain the immune homeostatic environment that is necessary for the normal course of pregnancy via complex immunoregulatory mechanisms [34]. The concept of the “placenta-brain axis” has been proposed to closely link the placenta and fetal central nervous system [35]. However, when immune homeostasis dominated by the placenta is dysregulated, it may adversely affect fetal neurodevelopment. A retrospective cohort study revealed that placental inflammatory villitis is a dominant risk factor for neonatal encephalopathy and subsequent adverse neurodevelopmental outcomes [36]. A case–control study revealed that placental inflammation increases the risk of neuropsychiatric disorders in children [37]. Our team previously reported the detrimental effects of elevated placental inflammatory cytokine levels on the preschoolers’ behavioral and cognitive development [15, 16]. Similarly, the current study revealed that elevated placental TNF-a, IL-6, and IL-8 levels can lead to fine motor and personal-social development delays in toddlers. In summary, the pro-inflammatory milieu of the placenta may cause both short- and long-term adverse effects on offspring neurodevelopment. The potential mechanisms by which placental inflammation regulates fetal neurodevelopment are complex and diverse. For example, placental inflammation can cause insufficient placental development and impaired barrier function [38], induce placental endocrine changes [13, 39], affect placental metabolic function [40], and change the expression levels of genes related to fetal neurodevelopment in the placenta [13]. Furthermore, placental inflammation can influence the intensity of the fetal immune response [41], which can also activate inflammatory signaling pathways [42] and oxidative stress [43] in the fetal brain.

In the present study, we observed that elevated placental IFN-γ levels increased the risk of fine motor delay in boys. Consistent with our findings, previous studies have also suggested the sexually dimorphic effects of placental inflammation on offspring neurodevelopment. In a case–control study, Straughen et al. reported a stronger association between placental inflammation and autism spectrum disorder in boys [44]. The results from the MABC suggest that the adverse effects of placental inflammation on the attention-deficit/hyperactivity disorder symptoms and cognitive performance of boys are more pronounced [15, 29]. Sex-specific mechanisms of placental regulation of fetal neurodevelopment have been progressively identified and intensively explored. When additional immune challenges occur in the placenta, males are exposed to greater health risks because of their greater inflammatory tone [45]. In terms of endocrine action, substance transport, and other functions, the male placenta exhibits greater immune-related vulnerability [46]. Furthermore, placental inflammation increases Toll-like receptor 4 signaling in male fetal macrophages, which leads to excessive microglial phagocytosis of serotonin neurons in the dorsal septal nucleus of the developing septum and decreases serotonin bioavailability in the fetal brain [47].

The umbilical cord is the only conduit for substance exchange between the mother and the fetus. The cytokines in umbilical cord blood are able to enter the fetus through the fetal circulation pathway, which can reflect the level of fetal inflammation to a certain extent [48], and directly participate in the regulation of fetal neurological development [49]. A prospective cohort study indicated that high levels of various inflammatory cytokines in umbilical cord serum were associated with cerebral palsy in children at 5 years of age [50]. Based on non-invasive fetal magnetoencephalography, Mercado et al. reported that cord-blood inflammatory markers were strongly associated with fetal brain activity [49]. In addition, a study in Bangladesh noted that high levels of CRP and IL-6 in cord serum were associated with an elevated risk of fine motor delay in offspring [51]. Similarly, our findings revealed that elevated cord serum IFN-γ levels increased the risk of children’s fine motor delay. The underlying mechanism linking cord serum IFN-γ levels and neurodevelopmental delay in children may involve microglial cell activation in the fetal brain. Microglia, which originate from the yolk sac, are macrophages that reside in the brain and exhibit remarkable functional diversity in regulating neurogenesis, synaptic development and refinement, myelination, and synaptic transmission during various stages of brain development [52]. As a fundamental mediator of microglial cell activation, IFN-γ is able to program microglia to an activated phenotype [53], thus leading to morphological and functional changes that impair normal brain developmental processes, thereby increasing susceptibility to neurodevelopmental delays in childhood [54].

Based on stratified analysis of maternal vitamin D levels, we found that maternal vitamin D deficiency may exacerbate the effects of an adverse intrauterine immune environment on the risk of childhood neurodevelopmental delays. Similarly, Wang et al. reported that adequate vitamin D in cord blood, which is strongly correlated with maternal vitamin D levels, attenuated the damaging effects of fetal immune activation on neurodevelopment in children [10]. In both regional birth cohorts, the modifying role of maternal vitamin D status in the associations of prenatal immune-related adverse environmental exposures with offspring neurodevelopment was identified [18, 19]. The immunomodulatory role of vitamin D at the maternal–fetal interface has gradually attracted increasing attention. Low levels of vitamin D during pregnancy may induce maternal and placental inflammation via multiple immunomodulatory pathways (e.g., innate immunity and adaptive immunity pathways) [55, 56], thus leading to fetal exposure to an imbalanced intrauterine immune environment. By interacting with the vitamin D receptor on immune cells, 1,25(OH)2D3 (which is the main activated form of vitamin D) is able to inhibit the activation of the nuclear factor-kappa B signaling pathway, which correspondingly reduces the expression of inflammatory cytokines [57, 58]. Additionally, vitamin D status during pregnancy may modulate the maternal immune system by modifying the gut microbiota, which correspondingly affects the intrauterine inflammatory milieu and fetal neurodevelopment [59,60,61]. Furthermore, placental function, which is an important determinant of fetal neurodevelopment, is closely related to maternal vitamin D status [62]. Moreover, maternal serum 25(OH)D can enter the fetus through the placenta and influence the fetal neurodevelopmental process by participating in the differentiation of brain neuronal cells, neurotransmitter synthesis, antioxidant activity, and cytokine regulation [63, 64]. In summary, moderate vitamin D supplementation during pregnancy might be a potential mitigation strategy for impaired neurodevelopment in children associated with an adverse prenatal inflammatory environment. Future large-sample interventional studies in representative populations are needed to clarify the actual benefits of vitamin D supplementation during pregnancy on maternal and child health.

Using a prospective birth cohort, we measured inflammatory cytokine levels in both placenta and cord blood, which enabled a more comprehensive exploration of the actual effects of the prenatal intrauterine immune environment on the neural development of offspring. In addition, our findings suggest that maternal vitamin D supplementation during pregnancy attenuates the neurodevelopmental damage caused by the intrauterine pro-inflammatory milieu in offspring, which may facilitate subsequent interventional and translational studies related to vitamin D supplementation during pregnancy. However, several limitations must be noted. First, given the wide variety of inflammatory cytokines, our selection of only six biomarkers may have underestimated the impact of intrauterine immune activation on child neurodevelopment. Second, we did not assess the levels of inflammatory cytokines in the amniotic fluid or fetal brain tissue, nor did we measure the inflammatory state of the children after birth. Third, maternal serum inflammatory cytokine levels during pregnancy were not included in the current study. As a complement, we included factors associated with maternal immune activation, such as smoking and drinking during pregnancy, maternal fever, maternal infection or inflammation conditions, and maternal pregnancy-related anxiety, as covariates in the models. Fourth, we did not measure the vitamin D concentration in fetal cord blood. Fifth, neurodevelopmental assessments at a single age are not fully representative of neurological status throughout childhood. Subsequent studies are needed to further analyze the impacts of maternal–fetal immunity activities on neurodevelopmental outcomes at multiple time points and neurodevelopmental trajectories in offspring. Reporting bias may affect the accuracy of neurodevelopmental measurement in children. Furthermore, the ASQ is a screening measure and not a diagnostic assessment of development delays. Finally, the current study was conducted in Ma’anshan city, which is regionally representative. Future studies need to be conducted in different regions and ethnic groups to validate our findings.

Conclusions

Our findings suggest that a prenatal intrauterine pro-inflammatory milieu increases the risk of neurodevelopment delay in young children. The detrimental relationships between placental and cord serum inflammatory cytokine levels and domain-specific neurodevelopment delays in children were amplified with maternal vitamin D deficiency.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

MABC:

The Ma’anshan birth cohort

RT-qPCR:

Real-time quantitative polymerase chain reaction

MIA:

Maternal immune activation

IL:

Interleukin

TNF-α:

Tumor necrosis factor-α

IFN-γ:

Interferon-γ

LODs:

Limits of detection

ASQ-3:

The Ages and Stages Questionnaire, Third Edition

BMI:

Body mass index

SD:

Standard deviation

ORs:

Odds ratios

CIs:

Confidence intervals

RCS:

Restricted cubic splines

FDR:

False discovery rate

References

  1. Vuong HE, Pronovost GN, Williams DW, Coley EJL, Siegler EL, Qiu A, et al. The maternal microbiome modulates fetal neurodevelopment in mice. Nature. 2020;586(7828):281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Han VX, Patel S, Jones HF, Dale RC. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders. Nat Rev Neurol. 2021;17(9):564–79.

    Article  PubMed  Google Scholar 

  3. Al-Haddad BJS, Oler E, Armistead B, Elsayed NA, Weinberger DR, Bernier R, et al. The fetal origins of mental illness. Am J Obstet Gynecol. 2019;221(6):549–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang H, Yin W, Ma S, Wang P, Zhang L, Li P, et al. Prenatal environmental adversity and childneurodevelopmental delay: the role of maternal low-grade systemic inflammation and maternal anti-inflammatory diet. Eur Child Adolesc Psychiatry. 2023;33(6):1771–81.

    Article  PubMed  Google Scholar 

  5. Van den Bergh BRH, van den Heuvel MI, Lahti M, Braeken M, de Rooij SR, Entringer S, et al. Prenatal developmental origins of behavior and mental health: the influence of maternal stress in pregnancy. Neurosci Biobehav Rev. 2020;117:26–64.

    Article  PubMed  Google Scholar 

  6. Hair NL, Hanson JL, Wolfe BL, Pollak SD. Association of child poverty, brain development, and academic achievement. JAMA Pediatr. 2015;169(9):822–9.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Rakesh D, Whittle S, Sheridan MA, McLaughlin KA. Childhood socioeconomic status and the pace of structural neurodevelopment: accelerated, delayed, or simply different? Trends Cogn Sci. 2023;27(9):833–51.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kathuria A, Lopez-Lengowski K, Roffman JL, Karmacharya R. Distinct effects of interleukin-6 and interferon-γ on differentiating human cortical neurons. Brain Behav Immun. 2022;103:97–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Goldstein JA, Gallagher K, Beck C, Kumar R, Gernand AD. Maternal-fetal inflammation in the placenta and the developmental origins of health and disease. Front Immunol. 2020;11: 531543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang P, Wu L, Yin WJ, Tao RX, Zhang Y, Li PP, et al. Associations of cord blood meta-inflammation and vitamin D with neurodevelopmental delay: a prospective birth cohort study in China. Front Immunol. 2022;13:1078340.

    Article  CAS  PubMed  Google Scholar 

  11. Zhu MJ, Du M, Nathanielsz PW, Ford SP. Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in the mid-gestation sheep placenta. Placenta. 2010;31(5):387–91.

    Article  CAS  PubMed  Google Scholar 

  12. Albrecht M, Pagenkemper M, Wiessner C, Spohn M, Lütgehetmann M, Jacobsen H, et al. Infant immunity against viral infections is advanced by the placenta-dependent vertical transfer of maternal antibodies. Vaccine. 2022;40(11):1563–71.

    Article  CAS  PubMed  Google Scholar 

  13. Núñez Estevez KJ, Rondón-Ortiz AN, Nguyen JQT, Kentner AC. Environmental influences on placental programming and offspring outcomes following maternal immune activation. Brain Behav Immun. 2020;83:44–55.

    Article  PubMed  Google Scholar 

  14. Raghavan R, Helfrich BB, Cerda SR, Ji Y, Burd I, Wang G, et al. Preterm birth subtypes, placental pathology findings, and risk of neurodevelopmental disabilities during childhood. Placenta. 2019;83:17–25.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zhou J, Tong J, Ru X, Teng Y, Geng M, Yan S, et al. Placental inflammatory cytokines mRNA expression and preschool children’s cognitive performance: a birth cohort study in China. BMC Med. 2023;21(1):449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhou J, Teng Y, Zhang F, Ru X, Li P, Wang J, et al. Sex-specific association between placental inflammatory cytokine mRNA expression and preschoolers’ behavioral development: the Ma’anshan birth cohort study. Brain Behav Immun. 2022;104:110–21.

    Article  CAS  PubMed  Google Scholar 

  17. von Ehrenstein OS, Neta GI, Andrews W, Goldenberg R, Goepfert A, Zhang J. Child intellectual development in relation to cytokine levels in umbilical cord blood. Am J Epidemiol. 2012;175(11):1191–9.

    Article  Google Scholar 

  18. Lu M, Gan H, Zhou Q, Han F, Wang X, Zhang F, et al. Trimester-specific effect of maternal co-exposure to organophosphate esters and phthalates on preschooler cognitive development: the moderating role of gestational vitamin D status. Environ Res. 2024;251(Pt 1): 118536.

    Article  CAS  PubMed  Google Scholar 

  19. Gao Y, Zhang Y, Luo J, Mao D, Lei X, Liu C, et al. Effect modification by maternal vitamin D status in the association between prenatal exposure to per- and polyfluoroalkyl substances and neurodevelopment in 2-year-old children. Environ Int. 2024;185: 108563.

    Article  CAS  PubMed  Google Scholar 

  20. Liu Z, Lu Y, Zhong K, Wang C, Xu X. The associations between endocrine disrupting chemicals and markers of inflammation and immune responses: a systematic review and meta-analysis. Ecotoxicol Environ Saf. 2022;234: 113382.

    Article  CAS  PubMed  Google Scholar 

  21. Lisi G, Ribolsi M, Siracusano A, Niolu C. Maternal vitamin D and its role in determining fetal origins of mental health. Curr Pharm Des. 2020;26(21):2497–509.

    Article  CAS  PubMed  Google Scholar 

  22. Tamblyn JA, Hewison M, Wagner CL, Bulmer JN, Kilby MD. Immunological role of vitamin D at the maternal-fetal interface. J Endocrinol. 2015;224(3):R107–21.

    Article  CAS  PubMed  Google Scholar 

  23. Huang K, Tong J, Tao S, Wu X, Yan S, Gao G, et al. Cohort profile: the Ma’anshan birth cohort (MABC) study. Int J Epidemiol. 2024;53(6):dyae142.

    Article  PubMed  Google Scholar 

  24. Wang X, Tong J, Liang C, Wang X, Ma Y, Tao S, et al. Trimester-specific effects of maternal exposure to single and mixed metals on cord serum inflammatory cytokines levels: a prospective birth cohort study. Sci Total Environ. 2023;895: 165086.

    Article  CAS  PubMed  Google Scholar 

  25. Gao H, Tong J, Zhu BB, Chen Y, Ye AX, Huang K, et al. Lag associations of gestational phthalate exposure with maternal serum vitamin D levels: repeated measure analysis. Chemosphere. 2022;299: 134319.

    Article  CAS  PubMed  Google Scholar 

  26. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–30.

    Article  CAS  PubMed  Google Scholar 

  27. Xie H, Clifford J, Squires J, Chen CY, Bian X, Yu Q. Adapting and validating a developmental assessment for Chinese infants and toddlers: the ages & stages questionnaires: inventory. Infant Behav Dev. 2017;49:281–95.

    Article  PubMed  Google Scholar 

  28. Wei Q, Zou J, Ma X, Xiao X, Zhang Y, Shi H. Prospective associations between various prenatal exposures to maternal psychological stress and neurodevelopment in children within 24 months after birth. J Affect Disord. 2023;327:101–10.

    Article  PubMed  Google Scholar 

  29. Shao S, Wang J, Huang K, Wang S, Liu H, Wan S, et al. Prenatal pregnancy-related anxiety predicts boys’ ADHD symptoms via placental C-reactive protein. Psychoneuroendocrinology. 2020;120: 104797.

    Article  CAS  PubMed  Google Scholar 

  30. Gao H, Geng ML, Huang K, Zhu BB, Zhang C, Gan H, et al. Relationship of individual and mixed prenatal phthalate exposure with placental structure and efficiency in the prospective Ma’anshan Birth Cohort Study. Sci Total Environ. 2022;838(Pt 3): 156498.

    Article  CAS  PubMed  Google Scholar 

  31. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Statist Soc Ser B. 1995;57(1):289–300.

    Article  Google Scholar 

  32. Lei X, Zhang Y, Wang Z, Lu Z, Pan C, Zhang S, et al. Effects of prenatal exposure to PM(2.5) and its composition on cognitive and motor functions in children at 12 months of age: the Shanghai birth cohort study. Environ Int. 2022;170: 107597.

    Article  CAS  PubMed  Google Scholar 

  33. Greenland S, Senn SJ, Rothman KJ, Carlin JB, Poole C, Goodman SN, et al. Statistical tests, p values, confidence intervals, and power: a guide to misinterpretations. Eur J Epidemiol. 2016;31(4):337–50.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ander SE, Diamond MS, Coyne CB. Immune responses at the maternal-fetal interface. Sci Immunol. 2019;4(31):eaat6114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rosenfeld CS. The placenta-brain-axis. J Neurosci Res. 2021;99(1):271–83.

    Article  CAS  PubMed  Google Scholar 

  36. Mir IN, Johnson-Welch SF, Nelson DB, Brown LS, Rosenfeld CR, Chalak LF. Placental pathology is associated with severity of neonatal encephalopathy and adverse developmental outcomes following hypothermia. Am J Obstet Gynecol. 2015;213(6):849.e1-8497.

    Article  PubMed  Google Scholar 

  37. Gibson B, Goodfriend E, Zhong Y, Melhem NM. Fetal inflammatory response and risk for psychiatric disorders. Transl Psychiatry. 2023;13(1):224.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ward EJ, Bert S, Fanti S, Malone KM, Maughan RT, Gkantsinikoudi C, et al. Placental inflammation leads to abnormal embryonic heart development. Circulation. 2023;147(12):956–72.

    Article  CAS  PubMed  Google Scholar 

  39. Straley ME, Togher KL, Nolan AM, Kenny LC, O’Keeffe GW. LPS alters placental inflammatory and endocrine mediators and inhibits fetal neurite growth in affected offspring during late gestation. Placenta. 2014;35(8):533–8.

    Article  CAS  PubMed  Google Scholar 

  40. Lien YC, Zhang Z, Barila G, Green-Brown A, Elovitz MA, Simmons RA. Intrauterine inflammation alters the transcriptome and metabolome in placenta. Front Physiol. 2020;11: 592689.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Stinson LF, Payne MS, Keelan JA. Placental and intra-amniotic inflammation are associated with altered fetal immune responses at birth. Placenta. 2019;85:15–23.

    Article  CAS  PubMed  Google Scholar 

  42. Yellowhair TR, Noor S, Maxwell JR, Anstine CV, Oppong AY, Robinson S, et al. Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis. Exp Neurol. 2018;301(Pt B):110–9.

    Article  CAS  PubMed  Google Scholar 

  43. Ozen M, Kitase Y, Vasan V, Burkhardt C, Ramachandra S, Robinson S, et al. Chorioamnionitis precipitates perinatal alterations of heme-oxygenase-1 (HO-1) homeostasis in the developing rat brain. Int J Mol Sci. 2021;22(11):5773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Straughen JK, Misra DP, Divine G, Shah R, Perez G, VanHorn S, et al. The association between placental histopathology and autism spectrum disorder. Placenta. 2017;57:183–8.

    Article  PubMed  Google Scholar 

  45. McCarthy MM. Sex differences in neuroimmunity as an inherent risk factor. Neuropsychopharmacology. 2019;44(1):38–44.

    Article  CAS  PubMed  Google Scholar 

  46. Guma E, Chakravarty MM. Immune Alterations in the Intrauterine Environment Shape Offspring Brain Development in a Sex-Specific Manner. Biol Psychiatry. 2025;97(1):12–27.

    Article  CAS  PubMed  Google Scholar 

  47. Ceasrine AM, Devlin BA, Bolton JL, Green LA, Jo YC, Huynh C, et al. Maternal diet disrupts the placenta-brain axis in a sex-specific manner. Nat Metab. 2022;4(12):1732–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jung E, Romero R, Yeo L, Diaz-Primera R, Marin-Concha J, Para R, et al. The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications. Semin Fetal Neonatal Med. 2020;25(4): 101146.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Mercado L, Rose S, Escalona-Vargas D, Dajani N, Siegel ER, Preissl H, et al. Correlating maternal and cord-blood inflammatory markers and BDNF with human fetal brain activity recorded by magnetoencephalography: an exploratory study. Brain Behav Immun Health. 2024;39: 100804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kaukola T, Kallankari H, Tuimala J, Olsén P, Tammela O, Kingsmore SF, et al. Perinatal immunoproteins predict the risk of cerebral palsy in preterm children. Ann Med. 2013;45(1):57–65.

    Article  CAS  PubMed  Google Scholar 

  51. Lee AC, Cherkerzian S, Tofail F, Folger LV, Ahmed S, Rahman S, et al. Perinatal inflammation, fetal growth restriction, and long-term neurodevelopmental impairment in Bangladesh. Pediatr Res. 2024;96(7):1777–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lawrence AR, Canzi A, Bridlance C, Olivié N, Lansonneur C, Catale C, et al. Microglia maintain structural integrity during fetal brain morphogenesis. Cell. 2024;187(4):962-80.e19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kann O, Almouhanna F, Chausse B. Interferon γ: a master cytokine in microglia-mediated neural network dysfunction and neurodegeneration. Trends Neurosci. 2022;45(12):913–27.

    Article  CAS  PubMed  Google Scholar 

  54. Han VX, Patel S, Jones HF, Nielsen TC, Mohammad SS, Hofer MJ, et al. Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review. Transl Psychiatry. 2021;11(1):71.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Liu NQ, Larner DP, Yao Q, Chun RF, Ouyang Y, Zhou R, et al. Vitamin D-deficiency and sex-specific dysregulation of placental inflammation. J Steroid Biochem Mol Biol. 2018;177:223–30.

    Article  CAS  PubMed  Google Scholar 

  56. Cyprian F, Lefkou E, Varoudi K, Girardi G. Immunomodulatory effects of vitamin D in pregnancy and beyond. Front Immunol. 2019;10: 2739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chen Y, Zhang J, Ge X, Du J, Deb DK, Li YC. Vitamin D receptor inhibits nuclear factor κB activation by interacting with IκB kinase β protein. J Biol Chem. 2013;288(27):19450–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tornatore L, Thotakura AK, Bennett J, Moretti M, Franzoso G. The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation. Trends Cell Biol. 2012;22(11):557–66.

    Article  CAS  PubMed  Google Scholar 

  59. Yamamoto EA, Jørgensen TN. Relationships between vitamin D, gut microbiome, and systemic autoimmunity. Front Immunol. 2019;10:3141.

    Article  CAS  PubMed  Google Scholar 

  60. Aparicio A, Gold DR, Weiss ST, Litonjua AA, Lee-Sarwar K, Liu YY. Association of vitamin D level and maternal gut microbiome during pregnancy: findings from a randomized controlled trial of antenatal vitamin D supplementation. Nutrients. 2023;15(9):2059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sun Z, Lee-Sarwar K, Kelly RS, Lasky-Su JA, Litonjua AA, Weiss ST, et al. Revealing the importance of prenatal gut microbiome in offspring neurodevelopment in humans. EBioMedicine. 2023;90: 104491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vestergaard AL, Andersen MK, Olesen RV, Bor P, Larsen A. High-dose vitamin D supplementation significantly affects the placental transcriptome. Nutrients. 2023;15(24):5032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Eyles D, Burne T, McGrath J. Vitamin D in fetal brain development. Semin Cell Dev Biol. 2011;22(6):629–36.

    Article  CAS  PubMed  Google Scholar 

  64. Saidi L, Hammou H, Sicard F, Landrier JF, Mounien L. Maternal vitamin D deficiency and brain functions: a never-ending story. Food Funct. 2023;14(14):6290–301.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We appreciate the participants in the Ma’anshan Birth Cohort Study. We are grateful to the Scientific Research Center in Preventive Medicine, School of Public Health, Anhui Medical University for the technical support in our experiment.

Funding

This work was supported by the National Natural Science Foundation of China (NSCF-82204053), the University Natural Foundation of Anhui Educational Committee (KJ2021A0222), and the Discipline Construction Project of School of Public Health, Anhui Medical University (0301001872).

Author information

Author notes

  1. Menglong Geng, Zhen Yu and Yafei Wang contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, No. 81 Meishan Road, Hefei, Anhui, 230032, China

    Menglong Geng, Juan Tong, Hui Gao, Peng Ding, Shuangqin Yan, Kun Huang, Xiaoyan Wu & Fangbiao Tao

  2. Anhui Provincial Key Laboratory of Environment and Population Health Across the Life Course, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, China

    Menglong Geng, Juan Tong, Hui Gao, Peng Ding, Kun Huang, Xiaoyan Wu & Fangbiao Tao

  3. School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, China

    Menglong Geng, Juan Tong, Hong Gan, Jixing Zhou, Baolin Wang, Peng Ding, Kun Huang, Xiaoyan Wu & Fangbiao Tao

  4. NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei, Anhui, 230032, China

    Menglong Geng, Juan Tong, Peng Ding, Kun Huang, Xiaoyan Wu & Fangbiao Tao

  5. Scientific Research Center in Preventive Medicine, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui, 230032, China

    Menglong Geng, Juan Tong, Peng Ding & Xiaoyan Wu

  6. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, Anhui, 230022, China

    Zhen Yu

  7. Department of Nursing, Anhui Medical College, Hefei, Anhui, 230601, China

    Yafei Wang

  8. Ma’anshan Maternal and Child Healthcare (MCH) Center, Ma’anshan, 243011, China

    Shuangqin Yan

  9. Department of Maternal, School of Public Health, Anhui Medical University, Child & Adolescent HealthNo. 81 Meishan Road, Hefei, Anhui Province, 230032, China

    Xiaoyan Wu & Fangbiao Tao

Authors
  1. Menglong Geng
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  2. Zhen Yu
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Contributions

FBT, SQY, KH, and XYW were responsible for the concept and design. MLG and FBT were responsible for drafting of the manuscript. MLG, ZY, YFW, and JT were responsible for the acquisition, analysis, or interpretation of data. MLG, JXZ, and HG were responsible for the statistical analysis. MLG and FBT were responsible for the obtained funding. SQY, HG, BLW, and PD were responsible for the administrative, technical, or material support. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiaoyan Wu or Fangbiao Tao.

Ethics declarations

Ethics approval and consent to participate

Approval for the research procedures was obtained from Anhui Medical University’s Ethics and Research Committee (No. 20131195). As children were too young to be able to make decisions, permissions for follow-ups and permissions for use of offspring’s data were provided by women or other family members. Prior to enrollment, written informed consent was obtained from the participants on behalf of their families.

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The authors declare no competing interests.

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Supplementary Information

12916_2025_4096_MOESM1_ESM.doc

Additional file 1. Fig. S1 Flow diagram of study participants. Fig. S2 Directed acyclic graph of the relationship between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment. Fig. S3 Restricted cubic spline for the relationships of placental inflammatory cytokines and children’s domain-specific neurodevelopment. Fig. S4 Restricted cubic spline for the relationships of cord serum inflammatory cytokines and children’s domain-specific neurodevelopment. Table S1 Sequences of the oligonucleotides utilized in RT-qPCR. Table S2 Demographic characteristics between the source population and the study population in Ma’anshan birth cohort [mean ± SD or n (%)]. Table S3 The associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment delay stratified by sex. Table S4 The associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment delay stratified by delivery mode. Table S5 Maternal serum vitamin D levels during the three trimesters [mean ± SD or n (%)]. Table S6 The associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment delay stratified by concentrations of maternal serum vitamin D during the first trimester. Table S7 The associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment delay stratified by concentrations of maternal serum vitamin D during the second trimester. Table S8 The associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment delay stratified by concentrations of maternal serum vitamin D during the third trimester. Table S9 Sensitivity analysis estimating associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment delay, excluded preterm birth children. Table S10 Sensitivity analysis estimating associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment delay, excluded low birth weight children. Table S11 Sensitivity analysis estimating associations between placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment delay, with additional adjusted for maternal folic acid supplementation during pregnancy, children main caregivers, and breastfeeding duration.

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Geng, M., Yu, Z., Wang, Y. et al. Placental and cord serum inflammatory cytokines and children’s domain-specific neurodevelopment at 18 months: effect modification by maternal vitamin D status. BMC Med 23, 252 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12916-025-04096-w

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BMC Medicine

ISSN: 1741-7015

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