Genital Dysbiosis and Different Systemic Immune Responses Based on the Trimester of Pregnancy in SARS-CoV-2 Infection.

Respiratory infections are common in pregnancy with conflicting evidence supporting their association with neonatal congenital anomalies, especially during the first trimester. We profiled cytokine and chemokine systemic responses in 242 pregnant women and their newborns after SARS-CoV-2 infection, acquired in different trimesters. Also, we tested transplacental IgG passage and maternal vaginal-rectal microbiomes. IgG transplacental passage was evident, especially with infection acquired in the first trimester. G-CSF concentration-involved in immune cell recruitment-decreased in infected women compared to uninfected ones: a beneficial event for the reduction of inflammation but detrimental to ability to fight infections at birth. The later the infection was acquired, the higher the systemic concentration of IL-8, IP-10, and MCP-1, associated with COVID-19 disease severity. All infected women showed dysbiosis of vaginal and rectal microbiomes, compared to uninfected ones. Two newborns tested positive for SARS-CoV-2 within the first 48 h of life. Notably, their mothers had acute infection at delivery. Although respiratory infections in pregnancy are reported to affect babies' health, with SARS-CoV-2 acquired early during gestation this risk seems low because of the maternal immune response. The observed vaginal and rectal dysbiosis could be relevant for neonatal microbiome establishment, although in our series immediate neonatal outcomes were reassuring.

Maternal selenium status plays a crucial role on clinical outcomes of pregnant women with COVID-19 infection.

Adequate maternal selenium level is essential for immune response and healthy pregnancy. This study aimed to shed light on the selenium status of pregnant women with COVID-19 and the effects of potential deficiency in serum selenium levels. Totally 141 pregnant women, 71 of them were COVID-19 patients, in different trimesters were included in the study. Maternal serum selenium levels, demographic and clinical parameters were determined. Serum selenium levels of pregnant women in the second (p: .0003) and third (p: .001) trimesters with COVID-19 were significantly lower than in the healthy group. Maternal selenium level was found to be negatively correlated with gestational week (p < .0001, r: -.541), D-dimer (p: .0002, r: -.363) and interleukin-6 (IL-6) level (p: .02, r: -.243). In the second trimester, serum selenium level positively correlated with white blood cell (p: .002, r: .424), neutrophil (p: .006, r: .39), lymphocyte (p: .004, r: .410) count and hemoglobin (p: .02, r: .323), hematocrit (p: .008, r: .38) status. In the third trimester, it was found that maternal selenium level positively correlated with monocyte (p: .04, r: .353) and negatively correlated with C-reactive protein level (p: .03, r: -.384). Serum selenium level was gradually decreased during the pregnancy period, however, this natural decrease was enhanced together with COVID-19 infection. The reason might be increased selenium needs depended on the immune response against infection. The decrease in maternal selenium level was found to be related to IL-6 and D-dimer levels, which indicate selenium's role in disease progression.

Effects of vitamin D supplementation on circulating concentrations of growth factors and immune-mediators in healthy women during pregnancy.

BACKGROUND: For the second aim of the Kellogg Foundation grant, this double-blind RCT investigated the impact of plasma vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) on plasma immune-mediators during pregnancy. We hypothesized that higher 25(OH)D concentrations would associate with reduced pro-inflammatory and increased tolerogenic immune-mediator concentrations. METHODS: Pregnant women enrolled at 10-14 weeks gestation were randomized to 400 or 4400 IU vitamin D3/day. Data on health, safety, circulating 25(OH)D, and 9 immune-mediators were collected at each trimester. Associations between immune-mediators and 25(OH)D at baseline and at second and third trimesters were examined. RESULTS: Baseline TGF-ß and second and third trimesters IFN-γ and IL-2 were associated with baseline 25(OH)D. Baseline immune-mediators were associated with immune-mediators at second and third trimesters for all immune-mediators except IL-5 and IL-10. Race was associated with baseline TGF-ß, VEGF and IL-10 and with IL-10 at second and third trimesters. CONCLUSIONS: Both treatment groups had increased 25(OH)D at second and third trimesters, greatest in the 4400 IU group. Though associations between baseline 25(OH)D and baseline TGF-ß and second and third trimester IFN-γ and IL-2 were noted, vitamin D supplementation throughout pregnancy did not impact immune-mediators at later trimesters. Supplementing with vitamin D before conception conceivably influences immune-mediator responses during pregnancy. IMPACT: In this vitamin D supplementation clinical trial, baseline (first trimester) but not increasing plasma 25(OH)D concentration impacted select plasma immune-mediator profiles in pregnant women. Baseline 25(OH)D was associated with baseline TGF-ß and with IFN-γ and IL-2 at second and third trimesters. Baseline IFN-γ, CRP, TGF-ß, TNF-α, VEGF, IL-2, and IL-4 were associated with concentrations at second and third trimesters for respective immune-mediators; however, 25(OH)D concentration at second and third trimesters were not. Some racial differences existed in immune-mediator concentrations at baseline and at second and third trimesters. This study assesses the impact of vitamin D supplementation on multiple immune-mediators in pregnant women of different racial/ethnic groups using longitudinal data from a relatively large randomized controlled trial. This study found that race was associated with baseline TGF-ß, VEGF, and IL-10 and with IL-10 at second and third trimesters, a novel finding that sheds light where relationships were less well defined. The results of this study suggest that vitamin D supplementation before conception or early in pregnancy, rather than during pregnancy, may be necessary to significantly impact immune-mediator response. This study sets premise for future clinical trials to evaluate the effect of vitamin D supplementation before conception or prior to pregnancy.

Cytokine profiling: variation in immune modulation with preterm birth vs. uncomplicated term birth identifies pivotal signals in pathogenesis of preterm birth.

OBJECTIVES: To assess deviations in longitudinally measured cytokines with preterm birth (PTB). METHODS: Prospective longitudinal study targeting 80 subjects. Phlebotomy specimens for broad panel of cytokine analysis were obtained at three time (T) intervals: first trimester (T1: 8-14 weeks' gestation), second trimester (T2: 18-22 weeks' gestation), and third trimester (T3: 28-32 weeks' gestation). Important demographics and outcomes were tracked. Data were stratified and the target groups were analyzed as follows: "Uncomplicated" (delivered ≥37 weeks) or "Preterm Birth" (<37 weeks). Generalized Linear Modeling determined rate of change T1-T3 by outcome. RESULTS: Complete data replete with phlebotomy at all three visits were obtained on 80 women. Birth outcomes were as follows: 11 Uncomplicated Term Birth (UTB), 28 PTB, 4 low birth weight (LBW), 16 OB complications (OBC), 11 current infections (IFN), and 10 mixed complications (MC=2 or more of the above). 28 PTB were compared to 11 uncomplicated term deliveries. In both groups, T helper type 1 (TH1) cytokine (IL-1ß), pleiotrophic pro-inflammatory cytokine (IL-6), and counter-regulatory cytokine (IL-10) responses decreased over gestation, but rates of change in IL-1ß, IL-6, and IL-10 were significantly different. Stratification of women by smoking status additionally demonstrated significant variance in immune status over the course of pregnancy. CONCLUSIONS: Women delivering PTB demonstrated significant differences in cytokine trajectory over pregnancy; these data further validate key role played by immune regulation in directing pregnancy outcome. Likewise, smoking impacts longitudinal trajectory of cytokines over pregnancy.

Modulation of cytokine patterns and microbiome during pregnancy in IBD.

OBJECTIVE: Pregnancy may affect the disease course of IBD. Both pregnancy and IBD are associated with altered immunology and intestinal microbiology. However, to what extent immunological and microbial profiles are affected by pregnancy in patients with IBD remains unclear. DESIGN: Faecal and serum samples were collected from 46 IBD patients (31 Crohn's disease (CD) and 15 UC) and 179 healthy controls during first, second and third trimester of pregnancy, and prepregnancy and postpartum for patients with IBD. Peripheral blood cytokine profiles were determined by ELISA, and microbiome analysis was performed by sequencing the V4 region of the bacterial 16S rRNA gene. RESULTS: Proinflammatory serum cytokine levels in patients with IBD decrease significantly on conception. Reduced interleukin (IL)-10 and IL-5 levels but increased IL-8 and interferon (IFN)γ levels compared with healthy controls were seen throughout pregnancy, but cytokine patterns remained stable during gestation. Microbial diversity in pregnant patients with IBD was reduced compared with that in healthy women, and significant differences existed between patients with UC and CD in early pregnancy. However, these microbial differences were no longer present during middle and late pregnancy. Dynamic modelling showed considerable interaction between cytokine and microbial composition. CONCLUSION: Serum proinflammatory cytokine levels markedly improve on conception in pregnant patients with IBD, and intestinal microbiome diversity of patients with IBD normalises during middle and late pregnancy. We thus conclude that pregnancy is safe and even potentially beneficial for patients with IBD.

Repeated Measures of Cervicovaginal Cytokines during Healthy Pregnancy: Understanding "Normal" Inflammation to Inform Future Screening.

OBJECTIVE: This study aimed to describe characteristics of cervicovaginal cytokines obtained during pregnancy from women who subsequently delivered at term. STUDY DESIGN: We used repeated measures of 20 cervicovaginal cytokines, collected on average on a monthly basis, from the second to the ninth month of gestation among 181 term pregnancies in the Mexico City Pregnancy Research on Inflammation, Nutrition, & City Environment: Systematic Analyses cohort (2009-2014). Cytokines were quantified using multiplex assay. RESULTS: Cytokine distributions differed more between than within cytokines. Across trimesters, cytokines interleukin (IL)-1Ra, IL-1α, and IL-8 consistently had high concentrations compared with other measured cytokines. Cytokine intraclass correlation coefficients ranged from 0.41 to 0.82. Spearman's correlation coefficients among cytokine pairs varied but correlation directions were stable; 95.3% of the 190 correlation pairs remained either negative or positive across trimesters. Mean longitudinal patterns of log-transformed cytokines from Tobit regression varied across but less within cytokines. CONCLUSION: Although mean concentrations of cervicovaginal cytokines among term pregnancies were high, they were largely stable over time. The high cytokine concentrations corroborate that pregnancy is associated with an active inflammatory state. These characterizations may serve as a baseline for comparison to other obstetric outcomes, which may be helpful in understanding deviations from normal gestational inflammation.

The prevention, screening and treatment of congenital heart block from neonatal lupus: a survey of provider practices.

Objective: To survey an international sample of providers to determine their current practices for the prevention, screening, and treatment of congenital heart block (CHB) due to maternal Ro/SSA antibodies. Methods: A survey was designed by the organizing committee of the 9th International Conference of Reproduction, Pregnancy and Rheumatic Diseases. It was sent to attendants of the conference and authors of recent publications or abstracts at ACR 2012, 2013 or 2014 on rheumatic diseases and pregnancy. Results: In anti-Ro/SSA positive women, 80% of 49 respondents recommended screening by serial fetal echocardiogram (ECHO), with most starting at week 16 (59%) and stopping at week 28 (25%), although the time to stop varied widely. For women without a prior infant with neonatal lupus, respondents recommend every other week (44%) or weekly (28%) fetal ECHOs. For women with a prior infant with neonatal lupus, 80% recommend weekly fetal ECHOs. To prevent CHB, HCQ was recommended by 67% of respondents and most would start pre-pregnancy (62%). Respondents were asked about medications to treat varying degrees of CHB in a 20-week pregnant, anti-Ro and La positive SLE patient. For first degree, respondents recommended starting dexamethasone (53%) or HCQ (43%). For second degree, respondents recommended starting dexamethasone (88%). For third degree, respondents recommended starting dexamethasone (55%) or IVIg (33%), although 27% would not start treatment. Conclusion: Despite the absence of official guidelines, many physicians with a focus on pregnancy and rheumatic disease have developed similar patterns in the screening, prevention and treatment of CHB.

Risk of Preterm or Small-for-Gestational-Age Birth After Influenza Vaccination During Pregnancy: Caveats When Conducting Retrospective Observational Studies.

Vaccines are increasingly targeted toward women of reproductive age, and vaccines to prevent influenza and pertussis are recommended during pregnancy. Prelicensure clinical trials typically have not included pregnant women, and when they are included, trials cannot detect rare events. Thus, postmarketing vaccine safety assessments are necessary. However, analysis of observational data requires detailed assessment of potential biases. Using data from 8 Vaccine Safety Datalink sites in the United States, we analyzed the association of monovalent H1N1 influenza vaccine (MIV) during pregnancy with preterm birth (<37 weeks) and small-for-gestational-age birth (birth weight < 10th percentile). The cohort included 46,549 pregnancies during 2009-2010 (40% of participants received the MIV). We found potential biases in the vaccine-birth outcome association that might occur due to variable access to vaccines, the time-dependent nature of exposure to vaccination within pregnancy (immortal time bias), and confounding from baseline differences between vaccinated and unvaccinated women. We found a strong protective effect of vaccination on preterm birth (relative risk = 0.79, 95% confidence interval: 0.74, 0.85) when we ignored potential biases and no effect when accounted for them (relative risk = 0.91; 95% confidence interval: 0.83, 1.0). In contrast, we found no important biases in the association of MIV with small-for-gestational-age birth. Investigators conducting studies to evaluate birth outcomes after maternal vaccination should use statistical approaches to minimize potential biases.

Characteristics and functions of memory regulatory T cells in normal pregnancy cycle and pregnancy complications.

Regulatory T cells (Tregs) are activated and expanded after exposure to fetal-specific (paternal) antigens. A proportion of Tregs differentiate into memory Tregs (mTregs), exhibiting immune memory function and exerting more potent immunosuppression than naive Tregs (nTregs). However, it is unclear how mTregs are regulated during normal and pathological pregnancies (e.g., gestational diabetes mellitus (GDM) and preeclampsia (PE)). In this study, PD-1, HLA-G, and HLA-DR expressions on memory CD4+ T cells, naive CD4+ T cells, Tregs, mTregs, and nTregs in healthy non-pregnant women (n=20), healthy first (n=20), second (n=20), and third-trimester women (n=20), postpartum women (n=20), GDM (n=20), and PE patients (n=20) were analyzed. The proportion of mTregs out of Tregs was increased (P<0.05) in the first trimester compared with that in non-pregnancy and reduced in the second and third trimesters. The proportions of PD-1+ Tregs and mTregs were significantly increased during the first trimester compared to those of non-pregnancy (P<0.01), reached their maximum in the second trimester. Moreover, the proportions of HLA-G+ memory CD4+ T cells, Tregs, and mTregs were increased in the first and second trimesters (P<0.01), reached their maximum in the third trimester. GDM patients were characterized by significantly lower percentages of PD-1+ and HLA-G+ mTregs (P<0.01), while PE patients were characterized by significantly lower percentages of HLA-G+ mTregs (P<0.01), compared with the healthy third-trimester women. In general, as demonstrated by this study, mTregs increase in number and enhance maternal-fetal immunoregulation during pregnancy, and their dysfunction can result in pregnancy complications such as GMD or PE.

The change of LTB4 and 5-LO during pregnancy.

PURPOSE: The changes of leukotriene B4 (LTB4) in the serum and the 5-lipoxygenase (5-LO) in the decidua in different stages of gestation period were investigated. METHODS: The ELISA double antibody sandwich method was used to detect the concentration of LTB4 in the serum in 21 cases and its levels of the different stages of pregnancy were analyzed. The real-time PCR method was used to detect the mRNA expression level of 5-LO in the decidua tissue of 20 healthy women in early pregnancy and 21 healthy women in third trimester and its levels in the two stages of pregnancy were compared. RESULTS: There were significantly different in the concentration of LTB4 in the serum during the four stages of healthy pregnancy. There were also markedly differences in the mRNA expression of 5-LO in the decidua during the two stages of healthy pregnancy. After pregnancy, the concentration of LTB4 in the serum of the subjects in early pregnancy and second trimester decreased, while in third trimester, its level increased. And after pregnancy, its level decreased. The 5-LO mRNA expression in the decidua in third trimester was obviously higher than the early pregnancy group. CONCLUSIONS: The changes of LTB4 concentration in serum and the mRNA expression level of 5-LO in decidua may play an important role in the success and maintenance of a healthy pregnancy.

Longitudinal modulation of immune system cytokine profile during pregnancy.

OBJECTIVE: To characterize immune modulation as expressed by cytokine assays at three time-points in human pregnancy. STUDY DESIGN: This is a prospective, longitudinal study of a broad panel of cytokine expression during singleton pregnancies resulting in an uncomplicated, full-term, live births. Peripheral blood was obtained at 8-14, 18-22, and 28-32 weeks gestation. Six cytokines - IFN-γ, IL-4, TNF-α, IL-1ß, IL-6, and IL-10 - were measured in supernatants obtained from whole blood stimulations with PHA or LPS and were compared to unstimulated controls. Samples were processed by Luminex-100 MAP®. We used Generalized Linear Models (GLM) to evaluate cytokine trajectories. RESULTS: Complete data were obtained for 45 uncomplicated pregnancies. Overall, peripheral blood WBC's demonstrated dampened cytokine responses. However, over the course of pregnancy, we found enhanced counter-regulatory cytokine expression (e.g., shown by increased IL-10). CONCLUSION: The overall decrease in pro-inflammatory cytokines and increase in counter-regulatory cytokines as uncomplicated pregnancy progresses supports the evolving concepts of immunoregulation for the maintenance of a viable pregnancy.

Exploring the Immunopathogenesis of Pregnancy With COVID-19 at the Vaccination Era.

Since December 2019, Wuhan, China, has experienced an outbreak of coronavirus disease (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pregnant women are deductively considered to be in immunosuppressive condition for the safety of semi-allograft fetuses, which increases the risk of being infected by the virus. In this review, we analyzed the unique immunological characteristics of pregnant women and reviewed their known outcomes at different trimesters from the perspective of underlying mechanisms that have been studied and speculated so far.

The expression patterns of immune response genes in the Peripheral Blood Mononuclear cells of pregnant women presenting with subclinical or clinical HEV infection are different and trimester-dependent: A whole transcriptome analysis.

Hepatitis E is an enteric disease highly prevalent in the developing countries. The basis for high mortality among pregnant hepatitis E patients remains unclear. Importantly, a large proportion of infected pregnant women present with subclinical infection as well. In order to understand the possible mechanisms influencing clinical presentation of hepatitis E in pregnant women, we explored a system biology approach. For this, PBMCs from various categories were subjected to RNAseq analysis. These included non-pregnant (NPR, acute and convalescent phases) and pregnant (PR, 2nd and 3rd trimesters, acute phase and subclinical HEV infections) patients and corresponding healthy controls. The current study deals with immune response genes. In contrast to exclusive up-regulation of nonspecific, early immune response transcripts in the NPR patients, the PR patients exhibited broader and heightened expression of genes associated with innate as well as adaptive T and B cell responses. The study identified for the first time (1) inverse relationship of immunoglobulin (Ig) genes overexpression and (2) association of differential expression of S100 series genes with disease presentation. The data suggests possible involvement of TLR4 and NOD1 in pregnant patients and alpha defensins in all patient categories suggesting a role in protection. Induction of IFNγ gene was not detected during the acute phase irrespective of pregnancy. Association of response to vitamin D, transcripts related to NK/NKT and regulatory T cells during subclinical infection are noteworthy. The data obtained here could be correlated with several studies reported earlier in hepatitis E patients suggesting utility of PBMCs as an alternate specimen. The extensive, informative data provided here for the first time should form basis for future studies that will help in understanding pathogenesis of fulminant hepatitis E.

In-depth characterization of monocyte subsets during the course of healthy pregnancy.

Pregnancy represents an immunological challenge for the maternal immune system. Pregnancy augments innate immune responses, and particularly monocytes contribute to maintaining the balance between pro- and anti-inflammatory immune responses required for the successful sequence of distinct immunological phases throughout pregnancy. Nonetheless, studies that focus on the heterogeneity of monocytes and analyze the alteration of monocyte subsets in a longitudinal approach throughout healthy pregnancies have remained scarce. In this study, we characterized the gradual phenotypic changes of monocyte subsets and the secretory potential of bulk monocytes in peripheral blood mononuclear cells of healthy pregnant women from a population-based prospective birth cohort study. Blood samples at predefined time points were analyzed using flow cytometry for in-depth characterization of monocyte subsets, which confirmed a shift from classical towards intermediate monocytes throughout pregnancy. Principal component analysis revealed characteristic phenotypic changes on monocyte subsets, especially on the intermediate monocyte subset, throughout pregnancy. Pregnancy-related hormones were measured in serum and ß-human chorionic gonadotropin levels were significantly associated with expression of CD11b, CD116 and CCR2 on monocyte subsets. TLR4 and TLR7/8 stimulation of monocytes furthermore showed reduced polycytokine production towards the end of pregnancy. These data provide a comprehensive overview of phenotypic changes and secretory potential of monocytes in healthy pregnant women and establish a selective contribution of different monocyte subsets to healthy pregnancy. The results from this study therefore build a basis for future comparisons and evaluation of women with adverse pregnancy outcomes.

Maternal antigen presenting cells are a source of plasmatic HLA-G during pregnancy: longitudinal study during pregnancy.

The aim of this work was to investigate the longitudinal evolution of plasmatic soluble HLA-G (sHLA-G: shed HLA-G1 plus HLA-G5) during pregnancy, and if peripheral maternal antigen presenting cells (APC) can be a source of sHLA-G. Blood samples were obtained from 45 volunteers during normal pregnancy, 8 of them monthly; from 8 pregnant volunteers in the first weeks of pregnancy who had later a miscarriage, and from 14 healthy nonpregnant control women. Monocytes obtained during pregnancy showed a moderately HLA-G cell surface expression and stimulation with interferon (IFN)-gamma increased this expression. Monocytes-derived dendritic cells obtained from pregnant women during the first and third trimester of pregnancy secreted more sHLA-G than those obtained from nonpregnant women. Plasmatic sHLA-G concentration in pregnant women was significatively higher than in nonpregnant women, with a peak in the third month. We can conclude that maternal APC are a source of sHLA-G. Women who experienced miscarriage had previously very low or undetectable plasmatic sHLA-G levels in the second month of pregnancy. Data suggest that undetectable sHLA-G could be a risk of complications.

Sleep disruption during pregnancy: how does it influence serum cytokines?

Women report their sleep to be disrupted during pregnancy. Sleep deprivation has been linked to elevations in pro-inflammatory cytokine levels. No information currently addresses the sleep-immune relationship during pregnancy. This study explores the relationship between subjectively reported sleep variables and circulating serum cytokine levels. Pregnant women (n=35; mean age=31.0+/-3.7 years) seen once a trimester completed sleep questionnaires, gave blood and recorded their sleep on a sleep diary at home for 2 weeks. Nonpregnant women (n=43; mean age=28.2+/-5.2 years) underwent the same protocol once. Subjective sleep variables were compared to serum cytokine levels for IL-4, -6, -10 and TNF-alpha as well as C-reactive protein (CRP) determined by ELISA. Nonparametric analyses and linear regression were performed to explore relationships between the sleep and immune variables. Pregnant women subjectively reported their sleep to be worse than in the nonpregnant group. Serum cytokine levels differed between the two groups and varied by trimester. As anticipated, IL-10 was significantly higher in all trimesters; however CRP, an indicator of systemic inflammation, was higher in all trimesters compared to the nonpregnant sample. Subjectively reported sleep disruption was associated with increases in TNF-alpha in the pregnant sample and CRP in the nonpregnant sample. These data confirm that disrupted sleep experienced during pregnancy, as well as during the nonpregnant state, is related to increases in inflammatory markers. Future exploration of these relationships should include functional assessments of immunity as well as polysomnographically recorded sleep.

Elevated serum levels of interleukin-15 and interleukin-16 in preeclampsia.

A generalized inflammatory response has been considered to be the main pathology and has an important role in the pathogenesis of preeclampsia. The immune aberrations per se and immunomodulatory milieu present in serum need to be elucidated. The purpose of the current investigation was to characterize changes in serum levels of interleukin (IL)-15 and IL-16 in preeclampsia. Thirty-seven women with preeclampsia were recruited and 36 age- and gestational age-matched women with normal pregnancy served as control. Levels of IL-15 and IL-16 were detected with immune assays in all serum samples. We found that serum levels of IL-15 and IL-16 were significantly higher in preeclampsia than in normal pregnancy (p<0.001 for both). There were significant differences in serum IL-15 and IL-16 between mild and severe preeclampsia (p<0.01 for both). Our data corroborate the hypothesis of an increased inflammatory response in preeclampsia, as illustrated by the elevated serum levels of IL-15 and IL-16, suggesting their possible role in the pathogenesis of preeclampsia. These associations may offer insight into the pathophysiology of preeclampsia.

Physiology of alpha-fetoprotein as a biomarker for perinatal distress: relevance to adverse pregnancy outcome.

The many physiologic roles of human alpha-fetoprotein (HAFP) and its correlation with perinatal distress/pregnancy outcome are rarely addressed together in the biomedical literature, even though HAFP has long been used as a biomarker for fetal birth defects. Although the well being of the fetus can be monitored by the measurement of gestational age-dependent HAFP in biologic fluid levels (serum, amniotic fluid, urine, and vaginal fluids) throughout pregnancy, the majority of clinical reports reflect largely second trimester and (less likely) first trimester testing due to regulatory clinical restrictions. However, reports of third-trimester and pregnancy term measurement of HAFP levels performed in clinical research and/or investigational settings have gradually increased over the years and have expanded our base knowledge of AFP-associated pregnancy disorders during these stages. The different structural forms of HAFP (isoforms, epitopes, molecular variants, etc.) detected in the various biologic fluid compartments have been limited by antibody recognition of specific epitopic sites developed by the kit manufacturers based on antibody specificity, sensitivity, and precision. Concomitantly, the advances in elucidating the various biologic actions of AFP are opening new vistas toward understanding the physiologic roles of AFP during pregnancy. The present review surveys HAFP as a biomarker for fetal distress during the perinatal period in view of its structural and functional properties. An attempt is then made to relate the AFP fluid levels to adverse pregnancy complications and outcomes. Hence, the present review was divided into two major sections: (I) AFP structure and function considerations and (II) the relationship of AFP levels to the distressed fetus during the third trimester and at term.

Pregnancy-induced expansion of regulatory T-lymphocytes may mediate protection to multiple sclerosis activity.

Pregnancy represents a physiological transitory state of immune tolerance to avoid the rejection of the foetus, and concomitantly of stabilisation of many autoimmune diseases, such as multiple sclerosis (MS). Alterations in regulatory T-lymphocytes (T(Reg)) are known to be involved in organ-specific autoimmune disease pathophysiology. Our goal was to quantify CD4+ CD25+ and CD4+ CD25hi+ T(Reg) and activated (CD4+ HLA-DR+ CD38+) T-lymphocytes during pregnancy and puerperium in 13 MS patients in comparison with healthy pregnant and non-pregnant women. During pregnancy, a progressive parallel increase in CD4+ CD25+ T-lymphocytes in healthy pregnants as well as MS pregnant patients was observed. The proportion of T(Reg) was significantly higher in all pregnants than in non-pregnant women (p=0.01), whereas no differences were observed neither in the percentages of total nor activated CD4+ T-lymphocytes. In MS patients, CD4+ CD25+ T-lymphocytes significantly decreased when comparing the third trimester with the puerperal period proportions (p = 0.01), whereas CD4+ CD25hi+ T-lymphocytes significantly increased (p = 0.002). Our findings are consistent with the expansion of circulating regulatory CD4+ CD25+ T-lymphocytes pool with suppressive activity during normal pregnancy and in MS. A different pattern of CD+ CD25hi+ T-lymphocytes between healthy pregnants and MS women, which may represent relevant factors in the activity course of MS.

The Maternal Cytokine and Chemokine Profile of Naturally Conceived Gestations Is Mainly Preserved during In Vitro Fertilization and Egg Donation Pregnancies.

This prospective longitudinal study aimed at comparing maternal immune response among naturally conceived (NC; n = 25), in vitro fertilization (IVF; n = 25), and egg donation (ED; n = 25) pregnancies. The main outcome measures were, firstly, to follow up plasma levels of interleukin (IL) 1 beta, IL2, IL4, IL5, IL6, IL8, IL10, IL17, interferon gamma, tumor necrosis factor-alpha (TNFα), transforming growth factor-beta (TGFß), regulated upon activation normal T-cell expressed and secreted (RANTES), stromal cell-derived factor 1 alpha (SDF1α), and decidual granulocyte-macrophage colony-stimulating factor (GM-CSF) during the three trimesters of pregnancy during the three trimesters of pregnancy; secondly, to evaluate if the cytokine and chemokine pattern of ED pregnant women differs from that of those with autologous oocytes and, thirdly, to assess if women with preeclampsia show different cytokine and chemokine profile throughout pregnancy versus women with uneventful pregnancies. Pregnant women in the three study groups displayed similar cytokine and chemokine pattern throughout pregnancy. The levels of all quantified cytokines and chemokines, except RANTES, TNFα, IL8, TGFß, and SDF1α, rose in the second trimester compared with the first, and these higher values remained in the third trimester. ED pregnancies showed lower SDF1α levels in the third trimester compared with NC and IVF pregnancies. Patients who developed preeclampsia displayed higher SDF1α plasma levels in the third trimester.