Immunogenicity Following Administration of BNT162b2 and Ad26.COV2.S COVID-19 Vaccines in the Pregnant Population during the Third Trimester.

Globally, COVID-19 vaccines are currently being used to prevent transmission and to reduce morbidity and death associated with SARS-CoV-2 infection. Current research reveals that vaccines such as BNT162b2 and Ad26.COV2.S are highly immunogenic and have high short-term effectiveness for most of the known viral variants. Clinical trials showed satisfying results in the general population, but the reluctance in testing and vaccinating pregnant women left this category with little evidence regarding the safety, efficacy, and immunogenicity following COVID-19 vaccination. With the worldwide incidence of COVID-19 remaining high and the possibility of new transmissible SARS-CoV-2 mutations, data on vaccination effectiveness and antibody dynamics in pregnant patients are critical for determining the need for special care or further booster doses. An observational study was developed to evaluate pregnant women receiving the complete COVID-19 vaccination scheme using the BNT162b2 and Ad26.COV2.S, and determine pregnancy-related outcomes in the mothers and their newborns, as well as determining adverse events after vaccination and immunogenicity of vaccines during four months. There were no abnormal findings in pregnancy and newborn characteristics comparing vaccinated versus unvaccinated pregnant women. COVID-19 seropositive pregnant women had significantly higher spike antibody titers than seronegative patients with similar characteristics, although they were more likely to develop fever and lymphadenopathy following vaccination. The same group of pregnant women showed no statistically significant differences in antibody titers during a 4-month period when compared with case-matched non-pregnant women. The BNT162b2 and Ad26.COV2.S vaccines are safe to administer during the third trimester of pregnancy, while their safety, efficacy, and immunogenicity remain similar to those of the general population.

Maternal HPV-antibodies and seroconversion to HPV in children during the first 3 years of life.

To assess the dynamics of human papillomavirus (HPV) serology, we analyzed HPV6-,11-,16-,18-, and 45 antibodies in infants during the first 36 months of their life. Serial serum samples of 276/327 mother-child pairs were collected at baseline (mothers) and at months 1, 2, 6, 12, 24 and 36 (offspring), and tested for HPVL1-antibodies using the GST-L1 assay. Concordance between maternal and infant HPV-antibody levels remained high until month-6 (p < = 0.001), indicating maternal antibody transfer. At 1 month, 40-62% of the infants tested seropositive to any of the 5 HPV-types. Between 1-3 years of age, 53% (58/109) of the children born to HPV-seronegative mothers tested HPV-seropositive. Times to positive seroconversion varied between13.4 and 18.7 months, and times to negative seroconversion (decay) between 8.5 and 9.9 months. Significant independent predictors of infants' seroconversion to LR-HPV were hand warts and mother's history of oral warts and seroconversion to LR-HPV. No predictors of seroconversion to HR-HPV were identified. Maternal HPV-IgG-antibodies are transferred to her offspring and remain detectable for 6 months, corroborating the IgG molecule's half-life. Seroconversion to HPV-genotypes 6, 11, 16 and 18 was confirmed among children born to HPV-seronegative mothers, implicating an immune response to these HPV-genotypes during early infancy.

Cytokine Patterns in Maternal Serum From First Trimester to Term and Beyond.

Pregnancy implies delicate immunological balance between two individuals, with constant changes and adaptions in response to maternal capacity and fetal demands. We performed cytokine profiling of 1149 longitudinal serum samples from 707 pregnant women to map immunological changes from first trimester to term and beyond. The serum levels of 22 cytokines and C-reactive protein (CRP) followed diverse but characteristic trajectories throughout pregnancy, consistent with staged immunological adaptions. Eotaxin showed a particularly robust decrease throughout pregnancy. A strong surge in cytokine levels developed when pregnancies progressed beyond term and the increase was amplified as labor approached. Maternal obesity, smoking and pregnancies with large fetuses showed sustained increase in distinct cytokines throughout pregnancy. Multiparous women had increased cytokine levels in the first trimester compared to nulliparous women with higher cytokine levels in the third trimester. Fetal sex affected first trimester cytokine levels with increased levels in pregnancies with a female fetus. These findings unravel important immunological dynamics of pregnancy, demonstrate how both maternal and fetal factors influence maternal systemic cytokines, and serve as a comprehensive reference for cytokine profiles in normal pregnancies.

White blood cells in pregnancy: reference intervals for before and after delivery.

BACKGROUND: White blood cells (WBC) are commonly measured to investigate suspected infection and inflammation in pregnant women, but the pregnancy-specific reference interval is variably reported, increasing diagnostic uncertainty in this high-risk population. It is essential that clinicians can interpret WBC results in the context of normal pregnant physiology, given the huge global burden of infection on maternal mortality. METHODS: We performed a longitudinal, repeated measures population study of 24,318 pregnant women in Oxford, UK, to map the trajectory of WBC between 8-40 weeks of gestation. We defined 95% reference intervals (RI) for total WBC, neutrophils, lymphocytes, eosinophils, basophils, and monocytes for the antenatal and postnatal periods. FINDINGS: WBC were measured 80,637 times over five years. The upper reference limit for total WBC was elevated by 36% in pregnancy (RI 5.7-15.0×109/L), driven by a 55% increase in neutrophils (3.7-11.6×109/L) and 38% increase in monocytes (0.3-1.1×109/L), which remained stable between 8-40 weeks. Lymphocytes were reduced by 36% (1.0-2.9×109/L), while eosinophils and basophils were unchanged. Total WBC was elevated significantly further from the first day after birth (similar regardless of the mode of delivery), which resolved to pre-delivery levels by an average of seven days, and to pre-pregnancy levels by day 21. INTERPRETATION: There are marked changes in WBC in pregnancy, with substantial differences between cell subtypes. WBC are measured frequently in pregnant women in obstetric and non-obstetric settings, and results should be interpreted using a pregnancy-specific RI until delivery, and between days 7-21 after childbirth. FUNDING: None.

NF-κB regulation in maternal immunity during normal and IUGR pregnancies.

Intrauterine Growth Restriction (IUGR) is a leading cause of perinatal death with no effective cure, affecting 5-10% pregnancies globally. Suppressed pro-inflammatory Th1/Th17 immunity is necessary for pregnancy success. However, in IUGR, the inflammatory response is enhanced and there is a limited understanding of the mechanisms that lead to this abnormality. Regulation of maternal T-cells during pregnancy is driven by Nuclear Factor Kappa B p65 (NF-κB p65), and we have previously shown that p65 degradation in maternal T-cells is induced by Fas activation. Placental exosomes expressing Fas ligand (FasL) have an immunomodulatory function during pregnancy. The aim of this study is to investigate the mechanism and source of NF-κB regulation required for successful pregnancy, and whether this is abrogated in IUGR. Using flow cytometry, we demonstrate that p65+ Th1/Th17 cells are reduced during normal pregnancy, but not during IUGR, and this phenotype is enforced when non-pregnant T-cells are cultured with normal maternal plasma. We also show that isolated exosomes from IUGR plasma have decreased FasL expression and are reduced in number compared to exosomes from normal pregnancies. In this study, we highlight a potential role for FasL+ exosomes to regulate NF-κB p65 in T-cells during pregnancy, and provide the first evidence that decreased exosome production may contribute to the dysregulation of p65 and inflammation underlying IUGR pathogenesis.

Decidual stromal cells support tolerance at the human foetal-maternal interface by inducing regulatory M2 macrophages and regulatory T-cells.

During pregnancy, the semi-allogeneic nature of the foetus requires maternal immune adaption and acquisition of tolerance at the foetal-maternal interface. Macrophages with regulatory properties and regulatory T (Treg) cells are central in promoting foetal tolerance and are enriched in the decidua (the uterine endometrium during pregnancy). Although tissue-resident decidual stromal cells (DSC) have been implicated in regulatory functions, it is not known if they are able to induce the regulatory phenotype of macrophages and T-cells. In this study we report that maternally derived DSC are able to induce homeostatic M2 macrophages and Treg cells. CD14+ monocytes and CD4+ T-cells from healthy non-pregnant women were cultured in the presence or absence of conditioned medium (CM) from DSC isolated from 1st trimester and term placentas. DSC-CM alone was able to promote the survival of macrophages and to induce a regulatory CD14brightCD163+CD209+CD86dim phenotype, typical for decidual macrophages and similar to that induced by M-CSF. Interestingly, DSC-CM was also able to overrule the pro-inflammatory effects of GM-CSF by upregulating CD14, CD163 and CD209. Protein-profiling showed that M-CSF was secreted by DSC, and blocking of M-CSF partially reversed the M2 phenotype and reduced viability. DSC-CM also expanded CD25brightFoxp3+ Treg cells, an expansion that was abolished by a SMAD3-inhibitor, indicating the contribution of TGF-ß signaling. In conclusion, our findings collectively emphasize the role of tissue-resident stromal cells in shaping the tolerogenic environment at the foetal-maternal interface.

Compromised SARS-CoV-2-specific placental antibody transfer.

SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third-trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design.

Placental pathology of the third trimester pregnant women from COVID-19.

AIMS: To explore the clinical characteristics and placental pathological changes of pregnant women with 2019 novel coronavirus (CoV) disease (COVID-19) in the third trimester, and to assess the possibility of vertical transmission. METHODS AND RESULTS: The placenta tissues were evaluated by using immunohistochemistry for inflammatory cells and Hofbauer cells, and using severe acute respiratory syndrome (SARS) CoV-2 RNA Fluorescence In-Situ Hybridization (FISH) and SARS-CoV-2 spike protein immunofluorescence (IF) double staining. All eight placentas from the third trimester pregnancy women were studied. All patients were cured, no clinical or serological evidence pointed to vertical transmission of SARS-CoV-2. Features of maternal vascular malperfusion (MVM) such as increased syncytial knots were present in all 8 cases (8/8), and increased focal perivillous fibrin depositions were presented in 7 cases (7/8). No significate chronic histiocytic intervillositis was noted in the placenta. The number of macrophages and inflammatory cells such as T cells, B cells and plasma cells in the placental villous was not significantly increased in all cases. Moreover, all of eight cases demonstrated negative results by FISH using a SARS-CoV-2 virus RNA probe and by IF using a monoclonal antibody against SARS-CoV-2 spike protein. CONCLUSIONS: We found no evidence of vertical transmission and adverse maternal-fetal outcomes in the placentas of third trimester COVID-19 pregnancy women, which provided further information for the clinical management of those women in the third trimester. However, further studies are still needed for patients with infections in different stage of gestation, especially in first and second trimester.

Decreased circulating levels of plasmacytoid dendritic cells in women with early-onset preeclampsia.

The role of plasmacytoid dendritic cells (pDCs), and myeloid dendritic cells (mDCs) in women with preeclampsia has not been elucidated. We compared the frequency of peripheral pDCs, mDCs, NK cells, and T helper 17 (Th17) cells among non-pregnant/pregnant women, and women with early-/late-onset preeclampsia. We examined pDCs and mDCs using Anti-Human Lineage Cocktail 3 (CD3, CD14, CD19, and CD20), HLA-DR, CD11c, and CD123. We detected NK cells using Lineage cocktail, CD8, CD16, and CD56. We determined Th17 cells using CD3, CD4, CD8, CXCR3, and CCR6. We recruited 13 non-pregnant women, 50 normal pregnant women, 13 women with early-onset preeclampsia (onset at <34 gestational weeks), and 10 women with late-onset preeclampsia. The fraction of pDCs in women with early-onset preeclampsia was significantly lower than in non-pregnant women and normal pregnant women at 19-29 gestational weeks (4.1 % vs. 41.2 % and 19.0 %, respectively [p = 0.0005, and p = 0.025]), however, the fraction of pDCs in late-onset preeclampsia was not significantly different from normal pregnant women at 37 gestational weeks (11.1 % vs. 29.1 %, respectively [p = 0.149]), although it was significantly lower than in non-pregnant women (11.1 % vs. 41.2 %, respectively [p = 0.044]). The fraction of Th17 cells in women with early-onset preeclampsia was significantly higher than in normal pregnant women at 19-29 gestational weeks (p = 0.022). In conclusion, the level of circulating pDCs was lower in early-onset preeclampsia than in non-pregnant and pregnant women, suggesting the role of pDCs in the pathogenesis of early-onset preeclampsia.

Increased placental macrophages and a pro-inflammatory profile in placentas and maternal serum in infants with a decreased growth rate in the third trimester of pregnancy.

PROBLEM: There is growing evidence for the role of placental inflammation in the pathophysiology of pregnancy complications including fetal growth restriction (FGR). This study aimed to characterize the inflammatory profile in the maternal circulation and the placenta of infants who were growth restricted and those that were small for gestational age (SGA). METHOD OF STUDY: Placental villous tissue and maternal serum were obtained from pregnancies where infants were SGA at birth or who had a decreasing growth rate (≥25 centiles) across the third trimester. Immunohistochemical and histological analyses of placental samples were conducted for macrophage number, alongside vascular and cell turnover analysis. Inflammatory profile was analyzed in maternal and placental compartments via ELISAs and multiplex assays. RESULTS: There were significantly more CD163+ macrophages in placentas of infants with a decreased growth rate compared to controls, but not in SGA infants (median 8.6/ nuclei vs 3.8 and 2.9, P = .008 and P = .003, respectively). Uric acid (P = .0007) and IL-8 (P = .0008) were increased in placentas, and S100A8 (P < .0002) was increased in maternal serum of infants with decreased growth rate. No changes in the maternal serum or placental lysates of SGA infants were observed. CONCLUSION: The evidence of an altered inflammatory profile in infants with a decreasing growth rate, but not in those that were born SGA, provides further evidence that inflammation plays a role in true FGR. It remains unclear whether the increased placental macrophages occur as a direct result, or as a consequence of the pro-inflammatory environment observed in fetal growth restriction.

Regulatory B Cells Are Decreased and Impaired in Their Function in Peripheral Maternal Blood in Pre-term Birth.

Preterm birth (PTB) is defined as birth before 37 completed weeks of gestation. The causes of PTB are multiple and complex, the underlying pathophysiology being largely unknown. Interferences in the fine-tuned balance of the maternal immune system have been pointed to as one possible cause of PTB. Regulatory B cells (Breg) are part of the adaptive immune response, and recent data suggest that they may contribute to a healthy pregnancy by their regulatory/suppressive function. We investigated the frequency of Breg cells in peripheral blood of women undergoing PTB and control women immediately before giving birth via cesarean section. We detected an enhanced number of B cells, but a reduced number of Breg cells in women delivering preterm. In addition, the percentage of IL-10-producing B cells was decreased in PTB following stimulation with TLR agonists CpG or LPS, alone or combined with CD40L. This was associated with increased levels of pro-inflammatory cytokines in maternal serum. Moreover, isolated maternal B cells before delivering premature babies secreted higher level of the pro-inflammatory cytokine IL-6. No alterations in the frequency of regulatory T cells were found. Our data indicate that alterations in the number and function of Breg cells in peripheral maternal blood contribute to the immunological changes observed in preterm delivery and suggest these cells as important regulators of maternal immune responses.

Tetanus, diphtheria, and pertussis vaccine (Tdap) in pregnancy and risk of major birth defects in the offspring.

BACKGROUND: The tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine is recommended during pregnancy to protect newborns against pertussis infection in the months prior to their primary pertussis vaccination. Although research on the safety of the vaccine has been reassuring, most previous studies have considered major malformations as a single outcome, and have not examined potential risks for specific malformations. METHODS: Using data from the Slone Epidemiology Center Birth Defects Study collected between 2006 and 2015, we identified exposures to Tdap vaccine in both early and late pregnancy and examined potential risks for specific malformations. We used logistic regression models to calculate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: We identified 2,357 women exposed to Tdap during pregnancy. For first trimester exposures, the risk estimate for malformations overall was 1.0 (0.7, 1.5). We had power to examine nine specific malformations and found adjusted odds ratios ranging from 0.7 to 1.3, none of which had confidence intervals that excluded 1.0. For second or third trimester exposures, we examined 15 malformations with potential late pregnancy etiology, and calculated adjusted risk estimates for nine of these. Risk estimates ranged from 0.5 to 1.9, with no lower confidence bounds that excluded 1.0. CONCLUSIONS: We observed no evidence of appreciable risks for selected specific major malformations associated with Tdap vaccine exposure during early or late pregnancy. As pertussis remains a public health concern and Tdap vaccination levels in pregnancy remain below desired levels, these data provide further reassurance regarding the current recommendations for Tdap vaccination in pregnancy.

Pro-inflammatory immune cell gene expression during the third trimester of pregnancy is associated with shorter gestational length and lower birthweight.

PROBLEM: Altered maternal immune function predicts risk for shorter gestation and low birthweight. Few studies examine associations between prenatal immune cell gene expression and gestational length or birthweight. No studies examine which cell types drive associations. The purpose of this study is to explore associations between peripheral blood immune cell gene expression and gestational length and birthweight, using transcript origin analysis. METHOD OF STUDY: Eighty-nine women were drawn from the Community Child Health Network cohort. Third trimester maternal dried blood spots were used for genome-wide transcriptional (mRNA) profiling. Gestational length and birthweight were obtained from medical charts. Covariates were age, race/ethnicity, pre-pregnancy body mass index, smoking, gestational age at blood sampling, and pregnancy infections. Associations between gene expression profiles and gestational length and birthweight were tested using general linear models. The Transcription Element Listening System (TELiS) bioinformatics analysis quantified upstream transcription factor activity. Transcript origin analysis identified leukocyte subsets mediating observed effects. RESULTS: Shorter gestation was predicted by increased NF-kB (TFBM ratio = -0.582 ± 0.172, P < .001) and monocyte activity (diagnosticity score = 0.172 ± 0.054, P < .001). Longer gestation was associated with increased dendritic cell activity (diagnosticity score = 0.194 ± 0.039, P < .001). Increased AP-1 activity predicted lower birthweight (TFBM ratio = -0.240 ± 0.111, P = .031). Dendritic cells and CD4+ and CD8+ T cells predicted birthweight-related gene expression differences (diagnosticity score P's < 0.021). CONCLUSION: Higher third trimester pro-inflammatory gene expression predicted shorter gestation and lower birthweight. Variations in monocyte and dendritic cell biology contributed to both effects, and T-cell biology contributed to higher birthweight. These analyses clarify the role of myeloid/lymphoid lineage immune regulation in pregnancy outcomes.

Association between the timing of maternal vaccination and newborns' anti-pertussis toxin antibody levels.

BACKGROUND: Pertussis remains an important global public health concern, despite the presence of extensive immunization programs. Incidence and severity of pertussis are typically higher in neonates and young infants. As a strategy to protect these young infants, maternal vaccination with Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) has been recommended in Brazil. The objective of this study was to evaluate the effects of Tdap vaccination during pregnancy on the anti-pertussis toxin (PT) IgG response in mothers and their infants at birth. MATERIAL AND METHODS: Maternal and cord blood samples were collected from vaccinated (n = 243) and unvaccinated (n = 75) pregnant women, at the time of delivery, from July 2015 to August 2016 in São Paulo, Brazil. Anti-PT IgG antibodies were quantified by Enzyme-Linked Immunosorbent Assay (ELISA) and geometric mean concentrations (GMC) were calculated. Relationship between timing of vaccination and antibody concentrations were evaluated. RESULTS: Maternal and cord blood GMCs among the vaccinated group were 5.4 and 5.6 fold higher [66.5 International Units (IU)/mL and 89.8 IU/mL] compared to the unvaccinated group (12.4 IU/mL and 16.1 IU/mL), respectively (p < 0.001). Higher anti-PT IgG GMCs were observed when vaccination occurred ≥60 days before delivery compared to <60 days, suggesting that vaccination early in the third trimester may be more effective than later in pregnancy. CONCLUSION: Tdap maternal vaccination results in significantly higher anti-PT IgG in newborn infants and supports the current recommendation of the Brazilian Immunization Program.

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.

Lymphocytic Choriomeningitis Virus Infection Demonstrates Higher Replicative Capacity and Decreased Antiviral Response in the First-Trimester Placenta.

Lymphocytic choriomeningitis virus (LCMV) is a rodent disease that can be transmitted to humans. A majority of persons infected with LCMV have only minor symptoms; however, it can cross the placental barrier during pregnancy and cause congenital defects in the fetus. Some viral infections early in gestation are hypothesized to lead to worse outcomes compared to those acquired during late gestation; however, LCMV has not been studied in this context. In the present study, differences in immunomodulation between the first- and third-trimester placental explants infected with LCMV were measured. LCMV replication was observed in the first-trimester chorionic villi, but not in term. The term placenta exhibited a robust innate immune response to infection by LCMV, marked by induction of ifn-α, il-6, and tnf-α gene expression which was not seen in the first-trimester explants. Cytokine secretion was also only seen in term explants. The results indicate that the first-trimester and term placentas differ in their permissiveness for LCMV infection, inversely correlating with the innate antiviral responses. This has implications for developing effective mechanisms that protect the fetus from infection based on stage of development.

Changes of γδT cell subtypes during pregnancy and their influences in spontaneous abortion.

A successful pregnancy is a complicated process that involves the precisely timed regulation of endocrine as well as immune system. Despite increasing knowledge about immunology in gestation, the studies of immune cells in endometrium and decidua are still fragmented. Dynamic data is lacking on the transition of pre-pregnancy endometrial lymphocytes to initial pregnancy states as well as to second/third-trimester status. Here, we determined the composition of Gamma delta (γδ) T cells in endometrium and decidua from women with normal pregnancy and unexplained spontaneous abortion. We found that the frequency of γδT cells is fluctuating over the course of pregnancy, and these changes were regulated by progesterone. Different from peripheral blood, Vδ1+ γδT cells accounted for the majority in endometrium and early-pregnancy decidua of healthy women, and endometrial stromal cells (ESCs) may involve in Vδ1/ Vδ2 shift directly. Moreover, an increase in the percentage of γδT cells with Vδ2 subset predominant in early-pregnancy decidua was associated with unexplained spontaneous abortion. Our results unraveled the precise timing of γδT cells occurring during pregnancy and the close relationship among endocrine, immune cells and pregnancy, which can further help understand and solve the problem of infertility and unexplained spontaneous abortion.

Maternal allergen-specific IgG might protect the child against allergic sensitization.

BACKGROUND: Analysis of allergen-specific IgE responses in birth cohorts with microarrayed allergens has provided detailed information regarding the evolution of specific IgE responses in children. High-resolution data regarding early development of allergen-specific IgG are needed. OBJECTIVE: We sought to analyze IgG reactivity to microarrayed allergens in mothers during pregnancy, in cord blood samples, in breast milk, and in infants in the first years of life with the aim to investigate whether maternal allergen-specific IgG can protect against IgE sensitization in the offspring. METHODS: Plasma samples from mothers during the third trimester, cord blood, breast milk collected 2 months after delivery, and plasma samples from children at 6, 12, and 60 months of age were analyzed for IgG reactivity to 164 microarrayed allergens (ImmunoCAP ISAC technology) in 99 families of the Swedish birth cohort Assessment of Lifestyle and Allergic Disease During Infancy (ALADDIN). IgE sensitizations to microarrayed allergens were determined at 5 years of age in the children. RESULTS: Allergen-specific IgG reactivity profiles in mothers, cord blood, and breast milk were highly correlated. Maternal allergen-specific IgG persisted in some children at 6 months. Children's allergen-specific IgG production occurred at 6 months and reflected allergen exposure. Children who were IgE sensitized against an allergen at 5 years of age had significantly higher allergen-specific IgG levels than nonsensitized children. For all 164 tested allergens, children from mothers with increased (>30 ISAC standardized units) specific plasma IgG levels against an allergen had no IgE sensitizations against that allergen at 5 years of age. CONCLUSION: This is the first detailed analysis of the molecular IgG recognition profile in mothers and their children in early life. High allergen-specific IgG reactivity in the mother's plasma and breast milk and in cord blood seemed to protect against allergic sensitization at 5 years of age.

Innate immune activation and depressive and anxious symptoms across the peripartum: An exploratory study.

BACKGROUND: There are complex associations between immune function and mental illness, yet studies in the perinatal period focus primarily on individual inflammatory markers and depressive symptoms only, cross-sectionally. We sought to examine associations between both depressive and anxious symptoms and immune activation longitudinally across the peripartum. METHODS: We measured mood (Beck Depression Inventory, BDI-1 A) and anxiety (State-Trait Anxiety Inventory, STATE) and levels of 23 cytokines at 5 points in pregnancy and postpartum in 51 women. Within subject cytokine trajectories over time by depressive and anxious symptom grouping were assessed using linear mixed effects models with random intercept and slope. We also undertook an exploratory cluster analysis based on third trimester cytokine values. RESULTS: Based on categorical BDI scores, IL-6 (p < 0.001), IL-15 (p = 0.047), GCSF (p = 0.003), and CCL3 (p < .001) were significantly different across time, with IL-6 (p < 0.001), IL-15 (p = 0.003), and CCL3 (p < 0.001) higher at the third trimester visit in more depressed subjects. Based on categorical STATE scores, GM-CSF significantly decreased across pregnancy for the less anxious group (p = 0.016), but not for the more anxious, and CCL3 (p = 0.017), CXCL8 (p = 0.011), and IL-6 (p < 0.001) were higher at the third trimester visit for more anxious subjects. In exploratory cluster analysis based on cytokine level, there were no differences in mood or anxiety scores, but significant differences by race/ethnicity and overweight/obesity status. Women with higher pro-inflammatory cytokine values are more likely to be Hispanics (69.2% vs. 21.4%, p = 0.015), but less likely to be African American (23.1% vs. 60.7%, p = 0.015) or overweight/obese (25% vs. 69.2%, p = 0.016) compared to women with lower pro-inflammatory cytokine values. CONCLUSION: We identified a pro-inflammatory burst at the third trimester, indicative of innate immune activation, in women with higher levels of both depressive and anxious symptoms, as well as differences in pro-inflammatory changes across time. We also found significant differences in cytokine levels by race, ethnicity, and overweight/obesity status. These results point the way toward future longitudinal work that considers race/ethnicity, timing, and weight status, and evaluates perinatal mood and anxiety disorders in the context of changing immune functioning across the peripartum.

The impact of timing of maternal influenza immunization on infant antibody levels at birth.

Pregnant women and infants are at an increased risk of severe disease after influenza infection. Maternal immunization is a potent tool to protect both these at-risk groups. While the primary aim of maternal influenza vaccination is to protect the mother, a secondary benefit is the transfer of protective antibodies to the infant. A recent study using the tetanus, diphtheria and acellular pertussis (Tdap) vaccine indicated that children born to mothers immunized in the second trimester of pregnancy had the highest antibody titres compared to children immunized in the third trimester. The aim of the current study was to investigate how the timing of maternal influenza immunization impacts infant antibody levels at birth. Antibody titres were assessed in maternal and cord blood samples by both immunoglobulin (Ig)G-binding enzyme-linked immunosorbent assay (ELISA) and haemagglutination inhibition assay (HAI). Antibody titres to the H1N1 component were significantly higher in infants born to mothers vaccinated in either the second or third trimesters than infants born to unvaccinated mothers. HAI levels in the infant were significantly lower when maternal immunization was performed less than 4 weeks before birth. These studies confirm that immunization during pregnancy increases the antibody titre in infants. Importantly, antibody levels in cord blood were significantly higher when the mother was vaccinated in either trimesters 2 or 3, although titres were significantly lower if the mother was immunized less than 4 weeks before birth. Based on these data, seasonal influenza vaccination should continue to be given in pregnancy as soon as it becomes available.