Maternal Cytokine Research Articles

Circulating metal concentrations, inflammatory cytokines and gestational weight gain: Shanghai MCPC cohort.

Based on a prospective birth cohort, we aimed to investigate the associations between maternal circulating metals exposure and gestational weight gain (GWG) across pregnancy, and explore whether maternal inflammatory cytokines could contribute to the GWG changes associated with metals exposure. A total of 234 pregnant women from the Shanghai Maternal-Child Pairs cohort were enrolled in this panel study. 547 blood and serum samples were collected from pregnant women during three follow-up visits, and the circulating concentrations of 27 metals were determined by using the ICP-MS method. Five inflammatory cytokines in serum samples were measured through multiplexed immunoassays. The linear mixed models were used to estimate the association between each ln-transformed metal concentration and GWG across pregnancy. Robust generalized linear regression models were used to estimate the associations among circulating metals, GWG, and inflammatory cytokines. The GWG during pregnancy was 13.76±1.40kg. The concentrations Co, Zn, Mo, B, Ag and Te in second or third trimesters were significantly higher than those in early second trimester. The concentration of Mg decreased with the increase of pregnant weeks and no significant statistical differences were found in the concentrations of other metals in different trimesters. Among the detected 26 metals, Li and Sr concentrations were positively associated with GWG in the third trimester. The GWG increased by 0.100kg (95% CI 0.005, 0.195) and 0.120kg (95% CI 0.009, 0.232) with each one ln-concentration increase in circulating Li and Sr concentrations, respectively. Concentrations of Li and Sr in the third trimester were positively associated with tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, but negatively associated with growth differentiation factor-15 (GDF-15) significantly. Besides, IL-6 and GDF-15 levels were associated with the increase or decrease of overall pregnancy GWG, respectively. Results showed that maternal exposure to Li and Sr were associated with increased GWG, in which maternal IL-6 and GDF-15 could contribute to the associations between metal exposures and GWG in pregnant women.

Sex bias in maternal immune activation-induced neurodevelopmental disease begins at the maternal-fetal interface

Abstract Systemic maternal inflammation during pregnancy is increasingly thought to be a risk factor for development of autism spectrum disorder (ASD), which is diagnosed at a rate 4-fold higher in males than in females. Administration of the viral mimic polyI:C to pregnant mice at mid-gestation leads to an ASD-like phenotype in the offspring, consisting of deficits in socialization and communication as well as repetitive behaviors. In this model of maternal immune activation (MIA), elevated production of maternal serum cytokines, specifically IL-6 and IL-17, contributes to alterations in fetal neurodevelopment. Although male and female littermates are exposed to the same maternal inflammation, we show that behavioral deficits manifest only in the male offspring, mirroring the sex bias observed in human ASD. Because the placenta is derived from fetal cells and is the first site of fetal exposure to hematogenous maternal inflammation, we hypothesized that sex-specific reactions to MIA that have deleterious impacts on fetal neurodevelopment originate there. Our preliminary findings show that MIA leads to sexually dimorphic alterations in placental pathology. To further characterize responses to MIA at the maternal-fetal interface over the course of gestation, we conducted bulk RNA-sequencing of the placenta/decidua from polyI:C- and saline-treated embryos at several time points post-injection. Sex of the embryos was determined by PCR genotyping for comparison of male and female placental transcriptomes. We find previously undescribed signatures related to myeloid cells in placentas from MIA males, as well as sex-based differences under homeostasis. This data set will shed light on the immune mechanisms that impact fetal brain health.

In utero exposure to endogenous maternal polyclonal anti-Caspr2 antibody leads to an autism-like phenotype in male mice

Abstract Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with a complex etiology. A strong sex bias has been observed in ASD with boys being four times more likely to be diagnosed than girls. The maternal immune system has been repeatedly implicated in the etiology of ASD. Maternal infection with fever during pregnancy has been linked to ASD. Increased levels of maternal cytokines and chemokines during gestation, including interleukin 6, have been associated with ASD in children with intellectual disabilities. Studies, including our own, have consistently supported the hypothesis that maternal brain-reactive antibodies can predispose to ASD by affecting the developing brain during a critical period. We have previously demonstrated that antibodies targeting the neuronal protein Caspr2 are present at high frequency in mothers with brain-reactive serology and a ASD child. Furthermore, male mice but not female mice exposed in utero to a monoclonal anti-Caspr2 antibody cloned from a mother of a child with ASD, develop an ASD -like phenotype. In the present study we use a new model in which female mice are immunized with the extracellular portion of Caspr2, and therefore harbor anti-Caspr2 antibodies throughout gestation to mimic the human condition. Male mice born to dams harboring polyclonal anti-Caspr2 antibodies exhibit abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as repetitive behaviors and impairments in social interactions as adults. These studies will increase our understanding of the triggers of neurodevelopmental impairment and possibly suggest novel approaches to protecting the fetal brain.

Effects of Progesterone, Dydrogesterone and Estrogen on the Production of Th1/Th2/Th17 Cytokines by Lymphocytes from Women with Recurrent Spontaneous Miscarriage

Anti-inflammatory Th2 cytokines have been shown to be associated with healthy, successful pregnancy while pro-inflammatory Th1 and Th17 cytokines are associated with pregnancy loss due to recurrent spontaneous miscarriage. This nexus between unexplained recurrent spontaneous miscarriage (uRSM) and maternal inflammatory has led to the possibility of using pregnancy-related hormones to modify the maternal cytokine bias in a manner that is conducive to successful pregnancy. We investigated the ability of progesterone, dydrogesterone and estrogen to modulate cytokine production by peripheral blood lymphocytes from women undergoing uRSM. Peripheral blood mononuclear cells (PBMC) from females with uRSM were stimulated in vitro with phytohemagglutinin (PHA) in the presence and absence of progesterone or dydrogesterone or 17β-estradiol. Culture supernatants were assayed for IFN-α, TNF-γ, IL-2, IL-6, IL-10, IL-13, IL-17A, and IL-23 by ELISA. Progesterone and dydrogesterone significantly down-regulated the secretion of the Th1 cytokines IFN-α and TNF-γ, and the Th17 cytokine IL-17A, and IL-23. Additionally, the secretion of the Th2 cytokine IL-6 was up-regulated. Estrogen, on the other hand, decreased the production of IFN-α and IL-2, increased the production of IL-6 but did not affect IL-17A and IL-23 secretion. Progestogens and estrogen can decrease the production of some Th1/Th17 inflammatory cytokines secreted by lymphocytes from uRSM and upregulate the production of anti-inflammatory cytokines. These data support the notion that progestogens can be used for altering maternal cytokine profiles to manage pregnancy complications.

Cytokine profiles in maternal serum are candidates for predicting an optimal timing for the delivery in early-onset fetal growth restriction.

We examined whether maternal serum cytokine profiles of mothers with early-onset fetal growth restriction (FGR) were associated with delivery within 2 weeks after sampling during the third trimester. This exploratory prospective cross-sectional study included a total of 20 singleton fetuses with early-onset FGR and 31 healthy controls. Maternal serum samples during the early third trimester were analyzed for 23 cytokines. Of 20 fetuses with early-onset FGR, 14 had delivery within 2 weeks after sampling. Multivariate analysis revealed that maternal serum concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and soluble CD40 ligand (sCD40L) were independently associated with delivery within 2 weeks in early-onset FGR. Among cases of early-onset FGR, concentrations of almost all maternal serum cytokines were similar. Maternal serum sVEGFR-1 concentrations were high when delivery occurred within 2 weeks. Maternal serum sCD40L concentrations were elicited only in cases in which delivery within 2 weeks occurred due to fetal deterioration. We identified two biomarkers, one specific for FGR and the other dependent on severity, that were significant components of angiogenic activities and inflammation factors. Imbalances in serum protein expression may have a substantial effect on the pathogenesis of FGR.

Inflammatory mechanisms linking maternal and childhood asthma.

Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness, inflammation, and remodeling. Asthma often develops during childhood and causes lifelong decrements in lung function and quality of life. Risk factors for childhood asthma are numerous and include genetic, epigenetic, developmental, and environmental factors. Uncontrolled maternal asthma during pregnancy exposes the developing fetus to inflammatory insults, which further increase the risk of childhood asthma independent of genetic predisposition. This review focuses on the role of maternal asthma in the development of asthma in offspring. We will present maternal asthma as a targetable and modifiable risk factor for childhood asthma and discuss the mechanisms by which maternal inflammation increases childhood asthma risk. Topics include how exposure to maternal asthma in utero shapes structural lung development with a special emphasis on airway nerves, how maternal type-2 cytokines such as IL-5 activate the fetal immune system, and how changes in lung and immune cell development inform responses to aero-allergens later in life. Finally, we highlight emerging evidence that maternal asthma establishes a unique "asthma signature" in the airways of children, leading to novel mechanisms of airway hyperreactivity and inflammatory cell responses.

Cytokine concentrations throughout pregnancy and risk for psychosis in adult offspring: a longitudinal case-control study

Schizophrenia has been associated with pregnancy and birth complications and fetal exposure to inflammation is thought to be a common underlying mechanism. However, whether the risk is specific to particular phases of pregnancy is unclear. The aim of this study was to characterise and compare longitudinal patterns of maternal serum concentrations of cytokines across pregnancy between offspring who were later ascertained to have a psychotic disorder, non-psychotic siblings of these cases, and unrelated, non-psychotic individuals who served as controls. The National Collaborative Perinatal Project was a large-scale prospective longitudinal study that assessed the effects of perinatal factors on infant and child development. At sites across the USA, over 50 000 pregnant women were enrolled during prenatal clinical visits between 1959 and 1965. The present study draws from the Philadelphia cohort, which includes 9236 surviving offspring of 6753 pregnant women. Psychotic disorder diagnoses in adulthood were assessed with review of medical records and were confirmed with a validation study. Concentrations of TNFα, IL-1β, IL-5, IL-6, IL-8, IL-10, and IL-17a were assessed using a multiplex bead assay in archived maternal serum samples collected across prenatal visits and birth. We characterized cytokine patterns with linear mixed models. Our final sample comprised 90 cases, 79 siblings (of 40 cases), and 273 matched controls. Concentrations of proinflammatory cytokines TNFα, IL-1β, and IL-6 were significantly higher in maternal serum of offspring who later developed psychosis compared with maternal serum of matched controls. These differences were greatest in the first half of pregnancy (7-20 weeks), with no difference observed during the second half of pregnancy. Our results suggest that exposure to high maternal proinflammatory cytokine concentrations in early pregnancy might play a part in psychosis. These findings place the timing of risk associated with maternal inflammation much earlier in prenatal development than previously documented in humans and provide insight into a potential developmental pathway to the disorder. National Institute of Mental Health (P50) Silvio O Conte Center at Johns Hopkins, Stanley Foundation, March of Dimes, Yale University, National Science Foundation, and National Institute of Child Health and Human Development/Division of Intramural Population Health Research.

Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure

BackgroundEvidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy—and data from animal models have identified immune disturbances in alcohol-exposed offspring—to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status.MethodsAs part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis.ResultsAnalyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1β, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-β, IL-10, and IL-15 was associated with neurodevelopmental delay.ConclusionsTaken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.

Sex Bias in Maternal Immune Activation-Induced Neurodevelopmental Disorder Begins at the Placenta

Systemic maternal inflammation during pregnancy is increasingly thought to be a risk factor for development of autism spectrum disorder (ASD), which is diagnosed at a rate 4-fold higher in males than in females. Administration of the viral mimic polyI:C to pregnant mice at mid-gestation leads to ASD-related phenotypes in offspring, consisting of deficits in communication and socialization, as well as repetitive behaviors. In this model of maternal immune activation (MIA), elevated production of maternal serum cytokines is known to promote alterations in fetal neurodevelopment. Although male and female littermates are exposed to the same maternal inflammation, we show that behavioral deficits can be elicited preferentially in the male offspring, mirroring the sex bias observed in human ASD. Because the placenta is partially derived from fetal cells and is the first site of fetal exposure to hematogenous maternal inflammation, we hypothesized that sex-specific reactions to MIA may originate at the placenta and that characterization of these sex differences may offer new insights into the orgins of neurodevelopmental disorders. To characterize responses to MIA at the maternal-fetal interface, we conducted bulk RNA sequencing of the placenta from polyI:C- and saline-treated embryos at several time points post-injection. We identified male-biased elevation in the expression of inflammatory signatures involving neutrophils, innate immune signaling, and antigen presentation. Placental transcriptomics analysis also identified male-specific downregulation of cholesterol and fatty acid synthesis as well as a gene signature suggesting failing placental health. Interestingly, we found that MIA induced the differential expression of a large percentage of high-risk autism genes at the placenta. These findings shed new light on how sex and maternal inflammation interface to shape placental responses and may help to reveal new molecular players underpinning sex differences in neurodevelopmental disorders.

Socioeconomic, biological and genetic factors influencing preterm birth

The etiology of preterm birth is mostly underestimated in developing countries. Current presumptions are that both environmental and genetic factors contribute towards its onset and are responsible for the higher frequency of neonatal deaths. Despite there being considerable scientific data on preterm births across the world, the frequency of its occurrence and threat to the survival of neonates are alarming. It is important that variations among populations should be considered as the socioeconomic status, climatic zones and other genetic, as well as epidemiological factors vary, so as to draw definitive conclusions on the pathogenesis of preterm birth. Predictive biomarkers, prevention and optimum treatment strategies are still being discovered, but with well-designed studies and collaborative efforts, maternal and child healthcare can be prioritized. The purpose of this review is to understand the contributing factors of preterm birth as it is a critical issue and needs in-depth understanding with planned scientific studies to decrease the rate of preterm birth and complication related to it. Furthermore, the review enlists various factors linked to preterm birth viz, high maternal age, psychological state, environmental contaminants, infection, cervical length, addiction, cytokine interaction, preeclampsia, genetic composition, ethnicity, oxidative stress and microRNAs. We have summarized the status of preterm birth, its causes, and future line of work required to prevent mortality of mother and neonate that will help us design successful studies which aim to reduce preterm births effectively.

Longitudinal changes in glucose metabolism in women with gestational diabetes, from late pregnancy to the postpartum period.

This study aimed to determine, in women with gestational diabetes (GDM), the changes in insulin sensitivity (Matsuda Insulin Sensitivity Index; ISOGTT), insulin response and disposition index (DI) from late pregnancy (34-37weeks gestation, T1), to early postpartum (1-5days, T2) and late postpartum (6-12weeks, T3). A secondary aim was to correlate the longitudinal changes in maternal lipids, adipokines, cytokines and weight in relation to the changes in ISOGTT, insulin response and DI. ISOGTT, insulin response and DI were calculated at the three time points (T1, T2 and T3) using the results of a 75g OGTT. Adipokines, cytokines and lipids were measured prior to each OGTT. Linear mixed-effects models were used to compare changes across each time point. Changes in ISOGTT, insulin response and DI were correlated with changes in maternal adipokines, cytokines and lipids at each time point. A total of 27 women completed all assessments. Compared with T1, ISOGTT was 11.20 (95% CI 8.09, 14.31) units higher at 1-5days postpartum (p < 0.001) and was 5.49 (95% CI 2.38, 8.60) units higher at 6-12weeks postpartum (p < 0.001). Compared with T1, insulin response values were 699.6 (95% CI 957.5, 441.6) units lower at T2 (p < 0.001) and were 356.3 (95% CI 614.3, 98.3) units lower at T3 (p = 0.004). Compared with T1, the DI was 6434.1 (95% CI 2486.2, 10,381.0) units higher at T2 (p = 0.001) and was 4262.0 (95% CI 314.6, 8209.3) units higher at T3 (p = 0.03). There was a decrease in mean cholesterol, triacylglycerol, LDL-cholesterol and VLDL-cholesterol from T1 to T2 (all p < 0.001), and an increase in mean C-reactive protein, IL-6 and IL-8 from T1 to T2 (all p < 0.001). Mean leptin decreased from T1 to T2 (p = 0.001). There was no significant change in mean adiponectin (p = 0.99) or TNF-α (p = 0.81) from T1 to T2. The mean maternal BMI decreased from T1 to T2 (p = 0.001) and T3 (p < 0.001). There were no significant correlations between any measure of change in ISOGTT, insulin response and DI and change in maternal cytokines, adipokines, lipids or weight from T1 to T2. In women with GDM, delivery was associated with improvement in both insulin sensitivity and insulin production within the first few days. Improvement in insulin production persisted for 6-12weeks, but insulin sensitivity deteriorated slightly. These changes in glucose metabolism were not associated to changes in lipids, leptin, inflammation markers or body weight. ClinicalTrials.gov NCT02082301.

Male fetus susceptibility to maternal inflammation: C-reactive protein and brain development.

Maternal inflammation in early pregnancy has been identified epidemiologically as a prenatal pathogenic factor for the offspring's later mental illness. Early newborn manifestations of the effects of maternal inflammation on human fetal brain development are largely unknown. Maternal infection, depression, obesity, and other factors associated with inflammation were assessed at 16 weeks gestation, along with maternal C-reactive protein (CRP), cytokines, and serum choline. Cerebral inhibition was assessed by inhibitory P50 sensory gating at 1 month of age, and infant behavior was assessed by maternal ratings at 3 months of age. Maternal CRP diminished the development of cerebral inhibition in newborn males but paradoxically increased inhibition in females. Similar sex-dependent effects were seen in mothers' assessment of their infant's self-regulatory behaviors at 3 months of age. Higher maternal choline levels partly mitigated the effect of CRP in male offspring. The male fetal-placental unit appears to be more sensitive to maternal inflammation than females. Effects are particularly marked on cerebral inhibition. Deficits in cerebral inhibition 1 month after birth, similar to those observed in several mental illnesses, including schizophrenia, indicate fetal developmental pathways that may lead to later mental illness. Deficits in early infant behavior follow. Early intervention before birth, including prenatal vitamins, folate, and choline supplements, may help prevent fetal development of pathophysiological deficits that can have life-long consequences for mental health.

Influence of a Concurrent Exercise Training Intervention during Pregnancy on Maternal and Arterial and Venous Cord Serum Cytokines: The GESTAFIT Project.

The aim of the present study was to analyze the influence of a supervised concurrent exercise-training program, from the 17th gestational week until delivery, on cytokines in maternal (at 17th and 35th gestational week, and at delivery) and arterial and venous cord serum. Fifty-eight Caucasian pregnant women (age: 33.5 ± 4.7 years old, body mass index: 23.6 ± 4.1kg/m2) from the GESTAFIT Project (exercise (n = 37) and control (n = 21) groups) participated in this quasi-experimental study (per-protocol basis). The exercise group followed a 60-min 3 days/week concurrent (aerobic-resistance) exercise-training from the 17th gestational week to delivery. Maternal and arterial and venous cord serum cytokines (fractalkine, interleukin (IL)–1β, IL-6, IL-8, IL-10, interferon (IFN)–γ, and tumor necrosis factor (TNF)–α) were assessed using Luminex xMAP technology. In maternal serum (after adjusting for the baseline values of cytokines), the exercise group decreased TNF-α (from baseline to 35th week, p = 0.02), and increased less IL-1β (from baseline to delivery, p = 0.03) concentrations than controls. When adjusting for other potential confounders, these differences became non-significant. In cord blood, the exercise group showed reduced arterial IL-6 and venous TNF-α (p = 0.03 and p = 0.001, respectively) and higher concentrations of arterial IL-1β (p = 0.03) compared to controls. The application of concurrent exercise-training programs could be a strategy to modulate immune responses in pregnant women and their fetuses. However, future research is needed to better understand the origin and clearance of these cytokines, their role in the maternal-placental-fetus crosstalk, and the influence of exercise interventions on them.

Maternal tiredness and cytokine concentrations in mid-pregnancy

ObjectiveSleep disturbances relate to altered levels of inflammatory mediators in general population, but not much is known about the associations between sleep disturbances and inflammatory mediators during pregnancy. The present exploratory study investigated whether insomnia, tiredness, general sleep quality, and insufficient sleep duration during pregnancy relate to the concentrations of maternal peripheral circulating cytokines. As sleep disturbances are frequently observed in mood disorders, the results were controlled for symptoms of depression and anxiety. Methods137 participants were randomly drawn from a representative FinnBrain Birth Cohort. Serum concentrations of selected cytokines were analyzed using Multiplex bead arrays from blood samples drawn at the gestational week 24. The sleep disturbances were evaluated using the Basic Nordic Sleep Questionnaire. Depressive and anxiety symptoms were measured with the Edinburgh Postnatal Depression Scale and the anxiety subscale of the self-rated Symptom Checklist 90, respectively. ResultsEnhanced tiredness was associated with cytokine concentrations of IL-2, IL-10, IL-12, IL-13, and TNF-α. The observed associations resembled a reversed U-shaped curve rather than being linear. Having a good general sleep quality was associated with higher logarithmic cytokine concentrations of IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, and IFN-γ. There was no evidence for associations between insomnia or sleep loss and cytokines. ConclusionsMaternal subjective tiredness and good general sleep quality were associated with altered levels of immunological markers during pregnancy. The association was independent from symptoms of depression and anxiety.

Evaluating mild cachexia syndrome in the HIV-positive pregnant woman

Background Immune activation and inflammation are common symptoms throughout HIV infection and lead to elevated circulating concentrations of cachectic cytokines. Aims To evaluate cachexia-like symptoms among HIV-positive and HIV-negative pregnant women, and investigate whether cachexic mechanisms may contribute to impaired HIV-exposed fetal and infant growth. Methods Pregnant women (n=114; 39% HIV-positive) were prospectively enrolled from an antenatal clinic in semi-rural Tanzania. Maternal cachexia-associated plasma cytokines and hormones, and clinical and anthropometric data were assessed. Cachexia scores were quantified using a novel adaptation of a validated cachexia scoring system. Infant growth anthropometry was measured at birth and after 6 months. Results Maternal cachexia score was inversely associated with infant birth weight, birth length, and weight-for-age z-score at 6 months. Conclusions Symptoms consistent with a mild cachectic state were associated with poorer infant outcomes. This effect was greater for HIV-exposed infants. A better understanding of the maternal cachexia burden and implications for maternal and infant health in HIV, other infections, and inflammatory conditions is needed.

Influences of Maternal Factors Over Offspring Allergies and the Application for Food Allergy.

The prevalence of food allergy has been steadily rising worldwide with the highest incidence noted among younger children, and increasingly recognized as a growing public concern. The first known ingestion of foods often causes allergic reaction, suggesting that sensitization of offspring with food allergens may occur during pregnancy and/or through breastfeeding. This creates a milieu that shapes the neonatal immune responses to these allergens. However, the effects of maternal allergen exposure and maternal sensitization with allergens on development of allergies in offspring remain controversial. This review discusses recent advances from human data in our understanding of how maternal factors, namely, food allergens, allergen-specific immunoglobulins, cytokines, genetics, and environmental factors transferred during pregnancy or breastfeeding influence offspring allergies and how such effects may be applicable to food allergy. Based on information obtained from mouse models of asthma and food allergy, the review also dissects the mechanisms by which maternal factors, including the impact of immune complexes, transforming growth factor-β, vitamin A, and regulatory T-cell responses, contribute to the induction of neonatal tolerance vs. development of allergic responses to maternally transferred allergens.

A rat model of placental inflammation explains the unexplained elevated maternal serum alpha‐fetoprotein associated with adverse pregnancy outcomes

It has been reported in numerous studies that elevated maternal serum alpha-fetoprotein (MS-AFP) is associated with adverse pregnancy outcomes (APO), such as pre-eclampsia, stillbirth, preterm birth and fetal growth restriction. However, the mechanism linking elevated MS-AFP and APO is obscure. In this study, we tried to explore the mechanism by using pregnant rats. Lipopolysaccharide (LPS) was used to induce placental inflammation in pregnant rats. Maternal serum and placental inflammatory cytokines and placental morphology were used to assess the level of placental inflammation. The incidences of APO and the levels of MS-AFP were evaluated. The expressions of alpha-fetoprotein (AFP) in the related organs and fetal serum AFP levels were detected. Compared to saline-treated pregnant rats, LPS led to elevated maternal serum and placental inflammatory cytokines and a higher rate of placental inflammation. Lipopolysaccharide resulted in the features of APO and at the same time elevated MS-AFP. Maternal serum alpha-fetoprotein levels were significantly correlated to the evaluation parameters of APO. Lipopolysaccharide did not increase the expressions of AFP in fetal liver, maternal liver and placenta, but reduced the fetal serum AFP levels. The phenomenon that elevated MS-AFP is associated with APO, which has been reported in human pregnancies, is observed in our rat model. Placental inflammation can be the potential cause linking the two manifestations together. Although the source of elevated MS-AFP is not identified, fetal blood circulation is suspected. Our study may provide an animal model for the future studies on this subject.

Maternal, placental and cord blood cytokines and the risk of adverse birth outcomes among pregnant women infected with Schistosoma japonicum in the Philippines.

BackgroundThe objectives of this study were to 1) evaluate the influence of treatment with praziquantel on the inflammatory milieu in maternal, placental, and cord blood, 2) assess the extent to which proinflammatory signatures in placental and cord blood impacts birth outcomes, and 3) evaluate the impact of other helminths on the inflammatory micro environment.Methods/FindingsThis was a secondary analysis of samples from 369 mother-infant pairs participating in a randomized controlled trial of praziquantel given at 12–16 weeks’ gestation. We performed regression analysis to address our study objectives. In maternal peripheral blood, the concentrations of CXCL8, and TNF receptor I and II decreased from 12 to 32 weeks’ gestation, while IL-13 increased. Praziquantel treatment did not significantly alter the trajectory of the concentration of any of the cytokines examined. Hookworm infection was associated with elevated placental IL-1, CXCL8 and IFN-γ. The risk of small-for-gestational age increased with elevated IL-6, IL-10, and CXCL8 in cord blood. The risk of prematurity was increased when cord blood sTNFRI and placental IL-5 were elevated.ConclusionsOur study suggests that fetal cytokines, which may be related to infectious disease exposures, contribute to poor intrauterine growth. Additionally, hookworm infection influences cytokine concentrations at the maternal-fetal interface.Clinical Trial Registry number and websiteClinicalTrials.gov (NCT00486863).

How are maternal dietary patterns and maternal/fetal cytokines associated with birth weight? A path analysis.

The aim of the study was to investigate how maternal dietary patterns and maternal/fetal cytokines are associated with birth weight and whether cytokines mediate the association. A total of 469 pregnant women and their children were recruited for this prospective study. Dietary patterns in pregnancy were identified using factor analysis of data from three consecutive 24 h dietary recalls. Maternal and umbilical blood serum cytokines (adiponectin (APN), IL-6 and interferon-γ) were measured via ELISA. Path analysis was used to explore the relationships between maternal diet, cytokines and birth weight. Four dietary patterns were identified: a mainly fruit, dairy products and poultry diet (FDP); a mainly vegetables, beans and pork diet (VBP); a mainly fish, shrimp and soup diet (FS) and a mainly tuber and egg diet (TE). Path analysis showed the order of effects of dietary patterns on birth weight was FS&gt;FDP&gt;TE&gt;VBP (β=0·130, 0·109, -0·094 and 0·046, respectively). Only the TE pattern's effect was negative. Maternal and fetal APN were positively associated with birth weight (β=0·045 and 0·226, respectively), and they mediated the association between the TE pattern and birth weight (indirect effect was 5·3 %). Maternal IL-6 was negatively associated with birth weight (β=-0·067) and mediated the association between maternal FDP and VBP patterns and birth weight (indirect effects were 10·1 and 100·0 %, respectively). All variables in the path explained 33·6 % of variation. These results suggested that maternal dietary patterns in pregnancy are associated with birth weight and mediated directly and indirectly through some maternal/fetal serum cytokines.

Reduced Transplacental Transfer of Antimalarial Antibodies in Kenyan HIV-Exposed Uninfected Infants.

BackgroundAltered neonatal immune responses may contribute to the increased morbidity observed in HIV-exposed but uninfected (HEU) infants compared with HIV-unexposed uninfected (HUU) infants. We sought to examine the effects of prenatal HIV and malaria exposure on maternal and neonatal plasma cytokine profiles and transplacental antibody transfer.MethodsForty-nine HIV+ and 50 HIV- women and their HIV-uninfected neonate pairs from Kenya were assessed. All HIV+ mothers received combination antiretroviral therapy. Maternal plasma and cord blood plasma samples at delivery were tested for 12 cytokines, total IgG, and IgG specific to 4 vaccine antigens and 14 Plasmodium falciparum antigens.ResultsHIV+ mothers had lower levels of all 12 plasma cytokines at delivery compared with HIV- mothers, but there were no differences between HEU and HUU neonates. There were no differences in the cord-to-maternal ratios (CMRs) of vaccine-specific IgG between HIV+/HEU and HIV-/HUU maternal–neonate pairs. HIV+/HEU maternal–neonate pairs had significantly lower CMRs for 3 antimalarial IgGs—merozoite surface protein 9, circumsporozoite protein, and erythrocyte binding antigen 181—which remained statistically significant after adjustment for malaria in pregnancy.ConclusionsIn a cohort of optimally treated HIV-infected pregnant women, maternal HIV infection was associated with reduced transplacental transfer of antimalarial antibodies.