Membranous Nephropathy in Pregnancy.

BACKGROUND: Primary membranous nephropathy (pMN) is less common in women of child-bearing age. The kidney risk factors to adverse maternal-fetal outcomes and the effects of pregnancy on pMN process need to be investigated. METHODS: We retrospectively screened all the patients with biopsy-proven pMN from 2008 to 2018. Any cases of pregnancy that occurred at the time of pMN diagnosis or during follow-up were included in the study. Clinical and pathological data were collected from all patients at the time of kidney biopsy and their gestational results were recorded. RESULTS: Of the 27 pregnancies with gestational time of 35.9 ± 4.5 weeks, 10 adverse maternal-fetal events occurred, including fetal loss (11%), preterm delivery (26%), and severe preeclampsia (15%). The kidney parameters were relatively stable with all preserved kidney function. Time-averaged urinary protein (p < 0.001) and serum albumin (p < 0.001), maximum urinary protein (p = 0.001) and minimum serum albumin (p = 0.01) before week 20, anti-phospholipase A2 receptor (PLA2R) positivity (p = 0.03), and no remission during pregnancy (p = 0.004) were risk factors to adverse maternal-fetal outcomes. Time-averaged urinary protein and serum albumin correlated with the birth weight percentile of neonates. CONCLUSIONS: Pregnancy in pMN patients showed risks to adverse maternal-fetal events. Heavy proteinuria, especially before week 20 of gestation, severe hypoalbuminemia, positive anti-PLA2R, and no remission were risk factors to worse outcomes.

Cesarean delivery and the risk of allergic rhinitis in children.

BACKGROUND: Cesarean delivery (C-section) may influence the infant microbiome and affect immune system development and subsequent risk for allergic rhinitis (AR). OBJECTIVE: To investigate the association between C-section and AR at ages 6, 8, and 10 years. METHODS: Data were collected prospectively through Kaiser Permanente Northern Californias (KPNC) integrated healthcare system. Children were eligible if they were born in a KPNC hospital and remained in the KPNC system for minimum 6 years (n = 117,768 age 6; n = 75,115 age 8; n = 40,332 age 10). Risk ratios (RR) for C-section and AR were estimated at each follow-up age and adjusted for important covariates, including intrapartum antibiotics, pre-pregnancy body mass index, maternal allergic morbidities, and breastfeeding. Subanalyses considered information on C-section indication, labor, and membrane rupture. RESULTS: After adjusting for confounders, we did not observe an association between C-section and AR at follow-up ages 6, 8, or 10 years (RR [CI]: 6 years, 0.98 [0.91, 1.04]; 8 years, 1.00 [0.95, 1.07]; 10 years, 1.03 [0.96, 1.10]). In stratified analyses, there was limited evidence that C-section increases the risk of AR in certain subgroups (eg, children of non-atopic mothers, second or higher birth order children), but most estimated risk ratios were consistent with no association. Estimated associations were unaffected by participant attrition, missing data, or intrapartum antibiotics. CONCLUSION: C-section delivery was not associated with AR at follow-up ages of 6, 8, or 10 years in a large contemporary US cohort.

Relationship between birth weight or fetal growth rate and postnatal allergy: A systematic review.

BACKGROUND: Individual susceptibility to allergic diseases is developmentally programmed by early-life exposures. Evidence from preclinical studies suggests that intrauterine growth restriction is protective against later inflammatory responses to allergens. OBJECTIVE: We sought to evaluate whether prenatal growth affects susceptibility to allergy in human subjects. METHODS: We systematically searched for relevant studies in 11 databases, including Web of Science, ProQuest, EMBASE, and PubMed. We included only studies that corrected for gestational age or were restricted to full-term infants to separate effects of fetal growth from those of prematurity. RESULTS: The 42 eligible studies included prospective and retrospective cohort, cross-sectional, and case-control studies. Only 2 studies reported allergic asthma. A birth weight increase of 1 kg was associated with a 44% greater risk of food allergy in children (odds ratio [OR], 1.44; 95% CI, 1.04-1.99; P = .001), a 17% greater risk of ever allergic dermatitis in children (OR, 1.17; 95% CI, 1.04-1.32; P = .008), and a 34% greater risk of ever or current allergic dermatitis in infants up to 2 years of age (OR, 1.34; 95% CI, 1.08-1.68; P = .009). Risks of allergic rhinitis were not associated with birth weight. CONCLUSIONS: The results of these meta-analyses suggest that intrauterine growth restriction protects against allergic diseases in human subjects consistent with preclinical evidence but that effects might differ between allergic diseases. The strongest evidence is available for infancy and early childhood, and additional studies in older children and adults are needed to determine whether the effects of prenatal growth on each allergic disease persist or differ between those with severe and mild phenotypes.

Regulation of inflammation during gestation and birth outcomes: Inflammatory cytokine balance predicts birth weight and length.

OBJECTIVES: The maternal environment during gestation influences offspring health at birth and throughout the life course. Recent research has demonstrated that endogenous immune processes such as dysregulated inflammation adversely impact birth outcomes, increasing the risk for preterm birth and restricted fetal growth. Prior analyses examining this association suggest a relationship between maternal C-reactive protein (CRP), a summary measure of inflammation, and offspring anthropometric outcomes. This study investigates pro- and anti-inflammatory cytokines, and their ratio, to gain deeper insight into the regulation of inflammation during pregnancy. METHODS: IL6, IL10, TNFɑ, and CRP were quantified in dried blood spots collected in the early third trimester (mean = 29.9 weeks) of 407 pregnancies in Metropolitan Cebu, Philippines. Relationships between these immune markers and offspring anthropometrics (birth weight, length, head circumference, and sum of skinfold thicknesses) were evaluated using multivariate regression analyses. Ratios of pro- to anti-inflammatory cytokines were generated. RESULTS: Higher maternal IL6 relative to IL10 was associated with reduced offspring weight and length at birth. Individual cytokines did not predict birth outcomes. CONCLUSIONS: Consistent with the idea that the relative balance of cytokines with pro- and anti-inflammatory effects is a key regulator of inflammation in pregnancy, the IL6:IL10 ratio, but neither cytokine on its own, predicted offspring birth outcomes. Our findings suggest that prior reports of association between CRP and fetal growth may reflect, in part, the balance between pro- and anti-inflammatory cytokines, and that the gestational environment is significantly shaped by cytokine imbalance.

Environmental risk factors for type 1 diabetes.

The incidence of type 1 diabetes has risen considerably in the past 30 years due to changes in the environment that have been only partially identified. In this Series paper, we critically discuss candidate triggers of islet autoimmunity and factors thought to promote progression from autoimmunity to overt type 1 diabetes. We revisit previously proposed hypotheses to explain the growth in the incidence of type 1 diabetes in light of current data. Finally, we suggest a unified model in which immune tolerance to ß cells can be broken by several environmental exposures that induce generation of hybrid peptides acting as neoautoantigens.

Maternal KIR in combination with paternal HLA-C2 regulate human birth weight.

Human birth weight is subject to stabilizing selection; babies born too small or too large are less likely to survive. Particular combinations of maternal/fetal immune system genes are associated with pregnancies where the babies are ≤ 5th birth weight centile, specifically an inhibitory maternal KIR AA genotype with a paternally derived fetal HLA-C2 ligand. We have now analyzed maternal KIR and fetal HLA-C combinations at the opposite end of the birth weight spectrum. Mother/baby pairs (n = 1316) were genotyped for maternal KIR as well as fetal and maternal HLA-C. Presence of a maternal-activating KIR2DS1 gene was associated with increased birth weight in linear or logistic regression analyses of all pregnancies >5th centile (p = 0.005, n = 1316). Effect of KIR2DS1 was most significant in pregnancies where its ligand, HLA-C2, was paternally but not maternally inherited by a fetus (p = 0.005, odds ratio = 2.65). Thus, maternal KIR are more frequently inhibitory with small babies but activating with big babies. At both extremes of birth weight, the KIR associations occur when their HLA-C2 ligand is paternally inherited by a fetus. We conclude that the two polymorphic immune gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birth weight between two extremes with a clear role for paternal HLA.

Placental transfer of IgG antibodies specific to Klebsiella and Pseudomonas LPS and to group B Streptococcus in twin pregnancies.

Group B Streptococcus (GBS), Klebsiella spp. and Pseudomonas spp. are important aetiological agents of neonatal infections in Brazil. There is a lack of data in the literature regarding the specific transport of immunoglobulin G (IgG) against these pathogens in multiple pregnancies. Maternal (n = 55) and umbilical cord (n = 110) blood samples were prospectively collected at birth from 55 twin pregnancies. The factors associated with cord levels and transfer ratios of IgG against GBS, Klebsiella and Pseudomonas were examined. The IgG umbilical cord serum levels specific to GBS, Klebsiella LPS and Pseudomonas LPS were significantly associated with maternal-specific IgG concentrations and the presence of diabetes. The anti-Klebsiella IgG cord serum concentrations were also related to birthweight and the presence of hypertension. The transfer ratios against GBS and Pseudomonas LPS were associated with maternal-specific IgG concentrations. The transfer ratios for GBS and Pseudomonas LPS were associated with gestational age at delivery and the presence of diabetes, respectively. None of the examined parameters were related to Klebsiella LPS transfer ratios. We conclude that in twin pregnancies, specific maternal IgG serum concentrations and diabetes were the parameters associated with umbilical cord serum IgG concentrations reactive with the three pathogens investigated. All the other parameters investigated showed different associations with neonatal-specific IgG levels according to the antigen studied. There was no uniformity of the investigated parameters regarding association with placental IgG transfer ratios against the GBS, Pseudomonas LPS and Klebsiella LPS.

Predictors of interleukin-33 and thymic stromal lymphopoietin levels in cord blood.

BACKGROUND: The fetal immune system is a critical window of development. The epithelial cell-derived cytokines, thymic stromal lymphopoietin (TSLP), and interleukin-33 (IL-33) have received attention for their role in allergic responses but not been studied during this critical window. The objectives were to assess correlations among IL-33, TSLP, and IgE in umbilical cord blood samples and identify prenatal predictors of these biomarkers. METHODS: This study utilized data and banked cord blood collected in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada cohort study of 2001 pregnant women. Our analytic sample comprised the 1254 women with a singleton, term birth with a cord blood sample. Spearman correlation coefficients (SCC) and logistic regression models were used to examine associations between biomarkers and identify potential predictors of elevated biomarker levels. RESULTS: Thymic stromal lymphopoietin and IL-33 were more strongly correlated with each other (SCC = 0.75, p < 0.0001) than with IgE (IL-33 SCC = 0.14, TSLP SCC = 0.21). Maternal allergy, heavy street traffic, and elevated birth weight were significantly associated with jointly elevated TSLP and IL-33 levels, whereas maternal age and female infant sex were inversely associated with elevated IgE. CONCLUSIONS: In this population of Canadian women and infants, TSLP and IL-33 were detectable in cord blood, more strongly correlated with each other than with IgE, and associated with maternal characteristics indicative of inflammatory responses. This study motivates investigation into the value of cord blood IL-33 and TSLP levels as childhood allergy predictors and raises interesting questions regarding in utero coordinated regulation of these cytokines.

Levels of antibodies against tissue transglutaminase during pregnancy are associated with reduced fetal weight and birth weight.

BACKGROUND & AIMS: Celiac disease in pregnant women has been associated with poor growth of the fetus, but little is known about how the level of celiac disease affects fetal growth or birth outcomes. We assessed the associations between levels of antibodies against tissue transglutaminase (anti-tTG, a marker of celiac disease) and fetal growth and birth outcomes for pregnant women. METHODS: We performed a population-based prospective birth cohort study of 7046 pregnant women. Serum samples were collected during the second trimester of pregnancy and analyzed for levels of anti-tTG. Based on these levels, the women were categorized into 3 groups: negative anti-tTG (≤0.79 U/mL; n = 6702), intermediate anti-tTG (0.8 to ≤6 U/mL; n = 308), or positive anti-tTG (>6 U/mL; n = 36). Data on fetal growth and birth outcomes were collected from ultrasound measurements and medical records. RESULTS: Fetuses of women in the positive anti-tTG group weighed 16 g less than those of women in the negative anti-tTG group (95% confidence interval [CI], -32 to -1 g) during the second trimester and weighed 74 g less (95% CI, -140 to -8 g) during the third trimester. Newborns of women in the intermediate and positive anti-tTG groups weighed 53 g (95% CI, -106 to -1 g) and 159 g (95% CI, -316 to -1 g) less at birth, respectively, than those of women in the negative anti-tTG group. The reduction in birth weight in offspring of mothers in the intermediate anti-tTG group was 2-fold greater among mothers who carried HLA-DQ2 or -DQ8 than among those without HLA-DQ2 or -DQ8. CONCLUSIONS: Levels of anti-tTG in pregnant women are inversely associated with fetal growth. Growth was reduced to the greatest extent in fetuses of women with the highest levels of anti-tTG (>6 U/mL). Birth weight was also reduced in women with intermediate levels of anti-tTG (0.8 to ≤6 U/mL) and further reduced in those carrying HLA-DQ2 and -DQ8.

Periodontitis in pregnant baboons: systemic inflammation and adaptive immune responses and pregnancy outcomes in a baboon model.

BACKGROUND/OBJECTIVES: Chronic periodontal infections have been suggested to contribute to the risk of adverse pregnancy outcomes. MATERIAL AND METHODS: This study describes the relationship of patterns of systemic inflammatory mediators and IgG antibody to 20 oral bacteria in pregnant female baboons (Papio anubis) coupled with clinical features of ligature-induced periodontitis, as risk indicators for adverse pregnancy outcomes. Animals showing a preterm delivery and/or low birth weight newborns, as well as those pregnancies resulting in spontaneous abortion, stillbirth, or fetal demise were tabulated as adverse pregnancy outcomes. RESULTS: A significantly greater frequency of the periodontitis group neonates had a low birth weight (18.1%; p = 0.008) and decreased gestational age (9.8%). Spontaneous abortion/stillbirth/fetal demise were increased in the periodontitis (8.7%) versus the control group (3.8%) (p = 0.054). The baseline oral clinical presentation of the experimental animals did not relate to the adverse pregnancy outcomes. Animals with the greatest extent/severity of periodontitis progression during the initial ½ of gestation (ie. to mid-pregnancy) had the greatest risk for adverse pregnancy outcomes. Baseline biological parameters indicating historical responses of the animals to periodontal challenge demonstrated individual variation in selected mediators, some of which became more differential during ligature-induced periodontitis. The relationship of clinical parameters to systemic inflammatory responses was consistent with a temporal contribution to adverse pregnancy outcomes in a subset of the animals. CONCLUSIONS: These results support a link between periodontitis and adverse pregnancy outcomes in the baboons and provide a prospective experimental model for delineating the biologic parameters that contribute to a causal relationship between chronic oral infections and birth events.

A possible second type of maternal-fetal immune interaction involved in both male and female homosexuality.

Recent research has found that the mothers of firstborn homosexual sons produce fewer subsequent offspring than do the mothers of firstborn heterosexual sons. It was hypothesized that a subset of mothers of firstborn homosexuals may be responsible for this finding. If there is a subset of mothers whose immune reactions cause their first male fetus to be homosexual and their subsequent fetuses to die, then their immune reactions should also cause their first male fetus to have a lower birth weight. This leads to the prediction that, within the population of firstborn homosexual men, those with no younger siblings should also tend to have lower birth weights. This prediction was tested using a previously published sample of 1,445 firstborn subjects: 929 heterosexual females, 47 homosexual females, 409 heterosexual males, and 60 homosexual males. The results showed that firstborn homosexuals with no younger siblings (i.e., only children) did have lower birth weights compared with all the other subjects, but the finding applied to firstborn lesbian women as well as firstborn gay men.

Effect of prepartum maternal energy density on the growth performance, immunity, and antioxidation capability of neonatal calves.

This study investigated the effect of prepartum diets differing in energy density on growth performance, immunity, and antioxidation capability of neonatal calves. Thirty Holstein dairy cows were allocated at random into 3 groups: low energy group [L; net energy of lactation (NE(L))=5.25 MJ/kg of dry matter (DM)]; medium energy group (M; NE(L)=5.88 MJ/kg of DM); and high energy group (H; NE(L)=6.48 MJ/kg of DM) at d 21 prepartum. Plasma was sampled for analysis of glucose, total protein, ß-hydroxybutyrate, and nonesterified fatty acids at 21, 14, and 7 d before parturition. After calving, birth weight and measurements of the calves in each group were recorded, and blood samples were collected for analysis of CD4, CD8, CD21, IL-2, IL-4, IL-6, total antioxidant capacity, superoxide dismutase, glutathione peroxidase, and maleic dialdehyde. The results indicated that although maternal weight did not differ among L, M, and H groups at 21, 14, and 7 d before parturition, the concentrations of glucose and ß-hydroxybutyrate at 14 and 7 d in the L group were decreased compared with that in the H group. In addition, nonesterified fatty acids concentrations increased significantly in the L group at 14 and 7 d before parturition compared with that in the M and H groups. Birth weight, body height, body length, abdominal circumference, thoracic girth, umbilical girth, and levels of CD4, CD4:CD8, IL-2, IL-4, total antioxidant capacity, and superoxide dismutase were decreased in calves of the L group compared with those of the H group. For the M group, CD4, CD4:CD8, and superoxide dismutase were decreased; and in the L group glutathione peroxidase and maleic dialdehyde levels were significantly increased compared with those of the H group. Reducing the maternal energy density during the last 21 d before parturition had a negative effect on growth and development, immunity, and antioxidation capability of neonatal calves.

Decreased Monocyte Count Is Associated With Gestational Diabetes Mellitus Development, Macrosomia, and Inflammation.

CONTEXT: The immune system plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). Monocytes, the main innate immune cells, are especially important in the maintenance of a normal pregnancy. OBJECTIVE: Here, we investigated the potential effect of monocytes in GDM. METHODS: Monocyte count was monitored throughout pregnancy in 214 women with GDM and 926 women without in a case-control and cohort study. Circulating levels of inflammatory cytokines, placenta-derived macrophages, and their products were measured. RESULTS: Throughout pregnancy, monocyte count was significantly decreased in women with GDM, and was closely associated with glucose level, insulin resistance, and newborn weight. First-trimester monocyte count outperformed that of the second and third trimester as a risk factor and diagnostic predictor of GDM and macrosomia both in the case-control and cohort study. In addition, our cohort study showed that as first-trimester monocyte count decreased, GDM and macrosomia incidence, glucose level, and newborn weight increased in a stepwise manner. Risk of GDM started to decrease rapidly when first-trimester monocyte count exceeded 0.48 × 109/L. Notably, CD206 and interleukin 10 (IL-10) were significantly lower, whereas CD80, CD86, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) were higher both in GDM placental tissue and peripheral blood. First-trimester monocyte count was positively related to IL-10 and CD206, but negatively related to CD80, CD86, TNF-α, and IL-6. CONCLUSION: Decreased monocyte count throughout pregnancy was closely associated with the development of GDM, macrosomia, and the chronic inflammatory state of GDM. First-trimester monocyte count has great potential as an early diagnostic marker of GDM.

Placental cytokine expression covaries with maternal asthma severity and fetal sex.

In the presence of maternal asthma, we have previously reported reduced placental blood flow, decreased cortisol metabolism, and reductions in fetal growth in response to maternal asthma and asthma exacerbations. We have proposed that these changes in placental function and fetal development may be related to activation of proinflammatory pathways in the placenta in response to maternal asthma. In the present study, we examined the influence of maternal asthma severity, inhaled glucocorticoid treatment, maternal cigarette use, placental macrophage numbers, and fetal sex on placental cytokine mRNA expression from a prospective cohort study of pregnant women with and without asthma. Placental expression of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-5 mRNA were all increased significantly in placentae of female fetuses whose mothers had mild asthma, but no changes were observed in placentae of male fetuses. The proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 were negatively correlated with female cord blood cortisol, but there were no such correlations in placentae from males. Multivariate analysis indicated the strongest predictor of both cytokine mRNA expression in the placenta and birth weight was fetal cortisol but only in females. Placental cytokine mRNA levels were not significantly altered by inhaled glucocorticoid use, placental macrophage numbers, cigarette use, moderate-severe asthma, or male sex. These data suggest that placental basal cytokine mRNA expression is sex specifically regulated in pregnancies complicated by asthma, and interestingly these changes are more prevalent in mild rather than severe asthma.

Primipaternities and human birthweights.

OBJECTIVES: To investigate in singleton multiparous pregnancies the effect of having a new father for an index pregnancy on new-borns' birthweights and intrauterine growth restriction. DESIGN: 20 year-observational cohort study (2001-2020). SETTINGS: Centre Hospitalier Universitaire Hospitalier Sud Reunion's maternity (French overseas department, Indian Ocean). MAIN OUTCOMES AND MEASURES: Comparing the 811 multiparas (cases) who had a new partner with the 49,712 who did not (controls), there were no differences concerning maternal age, education, ovulation induction/IVF, previous miscarriages, exams during pregnancies, pre-pregnancy BMI, gestational diabetes, and chronic hypertension. Cases had more previous pregnancies than controls (gravidity 4.2 vs 2.8, p < 0.001), volunteer abortions (OR1.93, p < 0.001), in vitro fecundations (OR 4.34, p < 0.001), were more likely to be unmarried (OR 2.94, p < 0.001) smoker (OR 2.2, p < 0.0001) and consuming alcohol during pregnancy (OR 2.35, p = 0.001). Cases had a much higher risk of preeclampsia than controls (OR 3.94, p < 0.001), especially early-onset preeclampsia (< 34 weeks) with an OR 4.1 (p < 0.001). Controlling for confounding factors (preeclampsia, smoking, alcohol use, early prematurity < 33 weeks, maternal ethnicity), primipaternity was an independent factor for small for gestational age newborns (OR 1.48, p < 0.001). CONCLUSIONS: It has been known for decades that primiparas have lighter babies than multiparas. Primipaternity represents also a risk for lower birth weights. Human birthweight seems to be linked with a "couple habituation" (to paternal genes) which may be not fully established in the first pregnancy of the couple.

High Antibodies to VAR2CSA in Response to Malaria Infection Are Associated With Improved Birthweight in a Longitudinal Study of Pregnant Women.

Introduction: Pregnant women have an increased risk of P. falciparum infection, which is associated with low birth weight and preterm delivery. VAR2CSA, a variant surface antigen expressed on the parasitized erythrocyte surface, enables sequestration in the placenta. Few studies have prospectively examined relationships between antibody responses during pregnancy and subsequent adverse birth outcomes, and there are limited data outside Africa. Methods: Levels of IgG against VAR2CSA domains (DBL3; DBL5) and a VAR2CSA-expressing placental-binding P. falciparum isolate (PfCS2-IE) were measured in 301 women enrolled at their first visit to antenatal care which occurred mid-pregnancy (median = 26 weeks, lower and upper quartiles = 22, 28). Associations between antibody levels at enrolment and placental infection, birthweight and estimated gestational age at delivery were assessed by linear and logistic regression with adjustment for confounders. For all outcomes, effect modification by gravidity and peripheral blood P. falciparum infection at enrolment was assessed. Results: Among women who had acquired P. falciparum infection at enrolment, those with higher levels of VAR2CSA antibodies (75th percentile) had infants with higher mean birthweight (estimates varied from +35g to +149g depending on antibody response) and reduced adjusted odds of placental infection (aOR estimates varied from 0.17 to 0.80), relative to women with lower levels (25th percentile) of VAR2CSA antibodies. However, among women who had not acquired an infection at enrolment, higher VAR2CSA antibodies were associated with increased odds of placental infection (aOR estimates varied from 1.10 to 2.24). Conclusions: When infected by mid-pregnancy, a better immune response to VAR2CSA-expressing parasites may contribute to protecting against adverse pregnancy outcomes.

Evidence for the involvement of VAR2CSA in pregnancy-associated malaria.

In Plasmodium falciparum-endemic areas, pregnancy-associated malaria (PAM) is an important health problem. The condition is precipitated by accumulation of parasite-infected erythrocytes (IEs) in the placenta, and this process is mediated by parasite-encoded variant surface antigens (VSA) binding to chondroitin sulfate A (CSA). Parasites causing PAM express unique VSA types, VSAPAM, which can be serologically classified as sex specific and parity dependent. It is sex specific because men from malaria-endemic areas do not develop VSAPAM antibodies; it is parity dependent because women acquire anti-VSAPAM immunoglobulin (Ig) G as a function of parity. Previously, it was shown that transcription of var2csa is up-regulated in placental parasites and parasites selected for CSA binding. Here, we show the following: (a) that VAR2CSA is expressed on the surface of CSA-selected IEs; (b) that VAR2CSA is recognized by endemic plasma in a sex-specific and parity-dependent manner; (c) that high anti-VAR2CSA IgG levels can be found in pregnant women from both West and East Africa; and (d) that women with high plasma levels of anti-VAR2CSA IgG give birth to markedly heavier babies and have a much lower risk of delivering low birth weight children than women with low levels.

Parental characteristics, somatic fetal growth, and season of birth influence innate and adaptive cord blood cytokine responses.

BACKGROUND: Immunologic responses at birth likely relate to subsequent risks for allergic diseases and wheezing in infancy; however, the influences of parental characteristics and prenatal factors on neonatal immune responses are incompletely understood. OBJECTIVE: This study investigates potential correlations between urban parental, prenatal, and perinatal factors on innate and adaptive stimuli-induced cytokine responses. METHODS: Five hundred sixty and 49 children of parents with and without allergic disease or asthma, respectively, were enrolled into a prospective birth cohort study (Urban Environment and Childhood Asthma). Cord blood mononuclear cells were incubated with innate and adaptive immune stimuli, and cytokine responses (ELISA) were compared with season of birth, parental characteristics, in utero stressors, and fetal growth. RESULTS: Many cytokine responses varied by season of birth, including 2-fold to 3-fold fluctuations with specific IFN-alpha and IFN-gamma responses. Birth weight was inversely associated with IFN-gamma responses to respiratory syncytial virus (R = -0.16), but positively associated with IL-8 responses to a variety of innate stimuli (R = 0.08-0.12). Respiratory syncytial virus-induced cytokine responses were 21% to 54% lower in children of mothers with asthma. Cytokine responses were generally lower in babies born to parents with allergy/asthma. CONCLUSIONS: Innate cytokine responses are associated with parental allergic or airway disease, somatic fetal growth, ethnicity, and season of birth. Collectively, these findings suggest that urban prenatal exposures and familial factors affect the development of the fetal immune system.

Indicated and non-indicated antibiotic administration during pregnancy and its effect on pregnancy outcomes: Role of inflammation.

The objective of this study was to compare the release of endotoxin and pro-inflammatory cytokines as well as pregnancy outcomes after antibiotic exposure in healthy and bacterial infected pregnant rats. Thirty female Wistar pregnant rats were divided into five groups. Group A considered as control and received intraperitoneal saline 0.9% on 17th day of gestation or DG) and groups B and C treated with 20 mg/kg/day intravenous ceftriaxone and ceftazidime, respectively (DG: 18-20). Groups D and E received intraperitoneal E. coli and LPS on 17th DG respectively. Also, groups F and G received the same treatment as group D but they treated with the exact antibiotics mentioned for groups B and C (same dose and duration). Pregnancy outcomes as well as maternal sera levels of endotoxin, tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6 were assessed using enzyme-linked immunosorbent assay. It was shown that group B had a higher IL-1ß (P = 0.003) and TNF-α (P = 0.003) levels compared to the controls (CTC). Group C expressed a lower gestational duration (P = 0.007) as well as higher IL-6 (P = 0.025) and TNF-α (P < 0.001) levels CTC. Interestingly, both group B (P = 0.021) and C (P < 0.001) had a higher rate of endotoxin release CTC. Moreover, in group C, IL-6 (P < 0.0001 and r = -0.941) had a significant correlation with gestational duration. As the results showed, antibiotic administration in non-indication condition seems to be associated with significantly higher production of endotoxin and inflammatory cytokines which increase the risk of poor pregnancy outcomes.

Associations between maternal inflammation during pregnancy and infant birth outcomes in the Seychelles Child Development Study.

PROBLEM: Markers of maternal inflammation may determine infant birth outcomes. METHOD OF STUDY: Maternal serum samples were collected at 28 weeks gestation (n = 1418) in the Seychelles Child Development Study Nutrition Cohort 2 and analyzed for immune markers by MSD multiplex assay, including cytokines from the Th1 (IFN-γ, IL-1ß, IL-2 and TNF-α) and Th2 (IL-4, IL-5, IL-10) subsets, with IL-6, MCP-1, TARC, sFlt-1 and VEGF-D. Associations of log-transformed immune markers with birthweight, length, head circumference and gestational age were assessed by multiple linear regression models, which were adjusted for maternal age, BMI, parity, child sex, gestational age and socioeconomic status. RESULTS: Neither total Th1, Th2 nor Th1:Th2 were significantly associated with any birth outcome. However, the angiogenesis marker VEGF-D was predictive of a lower birthweight, (ß = -0.058, P = 0.017) and birth length (ß = -0.088, P = 0.001) after adjusting for covariates. Higher concentrations of CRP were predictive of a lower birthweight (ß = -0.057, P = 0.023) and IL-2 (ß = 0.073, P = 0.009) and the chemokine MCP-1 (ß = 0.067, P = 0.016) were predictive of a longer gestational age. CONCLUSIONS: In our cohort of healthy pregnant women, we found no evidence for associations between the Th1 or Th2 inflammatory markers with birth outcomes. However, VEGF-D and CRP appear to predict lower birthweight and IL-2 and MCP-1 a longer gestation. Greater understanding is required of the variation in these immune markers at different gestational stages, as well as the factors which may regulate their balance in healthy pregnancy. n = 233.