Immune-checkpoint proteins, cytokines, and microbiome impact on patients with cervical insufficiency and preterm birth.

Background: Microenvironmental factors, including microbe-induced inflammation and immune-checkpoint proteins that modulate immune cells have been associated with both cervical insufficiency and preterm delivery. These factors are incompletely understood. This study aimed to explore and compare interactions among microbiome and inflammatory factors, such as cytokines and immune-checkpoint proteins, in patients with cervical insufficiency and preterm birth. In particular, factors related to predicting preterm birth were identified and the performance of the combination of these factors was evaluated. Methods: A total of 220 swab samples from 110 pregnant women, prospectively recruited at the High-Risk Maternal Neonatal Intensive Care Center, were collected between February 2020 and March 2021. This study included 63 patients with cervical insufficiency receiving cerclage and 47 control participants. Endo- and exocervical swabs and fluids were collected simultaneously. Shotgun metagenomic sequencing for the microbiome and the measurement of 34 immune-checkpoint proteins and inflammatory cytokines were performed. Results: First, we demonstrated that immune-checkpoint proteins, the key immune-regulatory molecules, could be measured in endocervical and exocervical samples. Secondly, we identified significantly different microenvironments in cervical insufficiency and preterm birth, with precise cervical locations, to provide information about practically useful cervical locations in clinical settings. Finally, the presence of Moraxella osloensis (odds ratio = 14.785; P = 0.037) and chemokine CC motif ligand 2 levels higher than 73 pg/mL (odds ratio = 40.049; P = 0.005) in endocervical samples were associated with preterm birth. Combining M. osloensis and chemokine CC motif ligand 2 yielded excellent performance for predicting preterm birth (area under the receiver operating characteristic curve = 0.846, 95% confidence interval = 0.733-0.925). Conclusion: Multiple relationships between microbiomes, immune-checkpoint proteins, and inflammatory cytokines in the cervical microenvironment were identified. We focus on these factors to aid in the comprehensive understanding and therapeutic modulation of local microbial and immunologic compositions for the management of cervical insufficiency and preterm birth.

Afterbirth oral fluid secretory leukocyte protease inhibitor decreased in acute histologic chorioamnionitis in preterm birth.

BACKGROUND: Secretory leukocyte protease inhibitor (SLPI) is an innate anti-inflammatory and anti-microbial peptide and produced in amnion of fetal membranes during pregnancy. However, studies on the association between SLPI levels in amniotic fluid and acute chorioamnionitis are limited. Afterbirth oral fluid (AOF) of the baby could be useful for representing the intra-amniotic environment precisely just before delivery. This study aimed to determine the relationship between SLPI levels in AOF and acute histologic chorioamnionitis (HC). METHODS: AOF of the baby was obtained during delivery from 24(0/7) to 36(6/7) weeks of gestational age (preterm group, n = 94) and from 37(0/7) to 41(6/7) weeks of gestational age (term group, n = 27) just after birth. SLPI expression levels among five classifications were compared to the intensity of acute HC as follows: no inflammation, acute subchorionitis, acute chorionitis, acute chorioamnionitis, and funisits. The SLPI and matrix metalloproteinase-8 (MMP-8) concentrations of AOF were determined using Enzyme Linked Immunosorbent Assay. Histologic examination of the placenta and membranes was performed after delivery. RESULTS: SLPI concentrations in AOF inversely decreased according to the intensity of acute HC (161.62 ng/mL in funisitis, 134.83 ng/mL in acute chorioamnionitis, 749.35 ng/mL in acute chorionitis, 953.05 ng/mL in acute subchorionitis, and 1126.77 ng/mL in no inflammation [p = .021]). The MMP-8 concentrations in AOF and maternal serum C-reactive protein were the highest in funisitis. The SLPI/ MMP-8 ratio was low in subgroup with acute chorioamnionitis and funisitis. CONCLUSION: Along with increased MMP-8 levels, decreased SLPI levels in AOF of the baby could be an additional factor in predicting acute HC immediately after birth.

Altered Influenza Vaccination Coverage and Related Factors in Pregnant Women in Korea from 2007 to 2019.

BACKGROUND: Pregnant women are at a high-risk of influenza infection. We have previously reported a low influenza vaccination coverage rate (4.0%) in Korea during the 2006-2007 influenza season. We conducted follow-up studies in 2011-2012 and 2018-2019 to observe changes in influenza vaccination coverage. METHODS: Women who delivered at Inha University Hospital (Incheon, Korea) in 2011-2012 and 2018-2019 were enrolled in the study. We surveyed the rate of influenza vaccination, perception scores, and related factors through telephonic interviews and compared the results from 2011-2012 and 2018-2019 with those from 2006-2007. RESULTS: The number of survey respondents was 227 in 2006-2007, 152 in 2011-2012, and 171 in 2018-2019. The rate of vaccination coverage increased from 4.0% in 2006-2007 to 42.0% in 2011-2012 and 59.3% in 2018-2019. Perception scores also increased progressively from 3.8 in 2006-2007 to 4.2 in 2011-2012 and 5.1 in 2018-2019. Physician recommendations for influenza vaccination also increased from 4.8% in 2006-2007 to 36.8% in 2011-2012 and 49.7% in 2018-2019. The most common reason for not getting vaccinated was the lack of awareness of influenza vaccination during pregnancy (36.9%). The perception scores and physician recommendation rates were significantly lower for unvaccinated women (3.87 and 8.4%, respectively) than for vaccinated women (5.14 and 69.1%, respectively). CONCLUSION: The influenza vaccination coverage rate in pregnant women has increased significantly since our study in 2006-2007. However, further improvement in the coverage rate is needed. There is a need for active and comprehensive publicity and education regarding this issue among physicians and pregnant women.

The Relationship Between Matrix Metalloproteinase-8 in After Birth Oral Fluid and Acute Histologic Chorioamnionitis in Preterm Delivery.

Elevated concentration of matrix metalloproteinase-8 (MMP-8) in amniotic fluid is a known predictor of intra-amniotic inflammation and infection. The aim of this study was to determine the nature of the association between MMP-8 levels in oral fluid obtained immediately after birth and acute histologic chorioamnionitis (HCA) in preterm delivery. Oral fluid was collected from 93 consecutive preterm birth newborns between gestational weeks of 24 + 0 and 36 + 6. Concentrations of MMP-8 and interleukin-8 (IL-8) in after birth oral fluid were measured by ELISA. Acute HCA was defined as the presence of neutrophils infiltration into chorioamnionic membranes. Logistic regression analysis was used for the statistical analysis. MMP-8 concentrations in after birth oral fluid were significantly higher for women with acute HCA than for those without (median [range]; 68.3 ng/mL [0.06-12,479.6] vs. 10.2 ng/mL [0.06-1808.2], p = 0.002). A strong association was observed between MMP-8 and IL-8 levels (γ2 = 0.87, p < 0.01). The cutoff level of MMP-8 in after birth oral fluid for acute HCA was 39.7 ng/mL (sensitivity of 63.2%, specificity of 81.1%). Multivariable logistic regression analysis showed MMP-8 in after birth oral fluid had an odds ratio of 4.17 for acute HCA (95% confidence interval [CI] = 1.08-16.17, p = 0.03). An elevated MMP-8 level in after birth oral fluid is associated with acute HCA in preterm birth. Newborn oral fluid immediately after birth might provide another source for information of intra-amniotic condition just before birth.

Associations of exposure to phthalates and environmental phenols with gynecological disorders.

Phthalates and environmental phenols might be associated with some benign diseases that have been found to be hormone-sensitive. Current knowledge on adverse effects of these chemicals among reproductive women is limited and often controversial. Therefore, the purpose of this study was to investigate the association between the urinary concentration of phthalates and environmental phenols and gynecological disorders from 512 women of reproductive age. The association between chemical concentration and disease in the control and case groups was statistically determined with the questionnaire survey data and measurements using the LC-MS/MS. The results have shown that DEHP metabolites, ethyl paraben and 3,4-DHB showed significant direct associations with leiomyoma and benign ovarian tumors (p < 0.05). We found statistically significant positive relationships between exposure to chemicals (some DEHP metabolites, DHB) and prevalence of gynecologic disorders (p < 0.05). Furthermore, the ORs for leiomyoma associated with these compounds in always user for personal care products (PCPs) was higher than those of sometimes user. High levels of urinary concentrations of these compounds such as DEHP metabolites and parabens and their metabolites showed significant associations with leiomyoma and benign ovarian tumors.

Decreased expression of progesterone receptor membrane component 1 in fetal membranes with chorioamnionitis among women with preterm birth.

PURPOSE: Progesterone receptor membrane component 1 (PGRMC1) have anti-inflammatory and anti-apoptotic properties. This study aimed to determine the expression of PGRMC1 in fetal membranes among women with preterm labor (PTL), preterm premature rupture of membranes (PPROM), and acute histologic chorioamnionitis (HCA) during preterm birth. METHODS: Full thickness fetal membranes were obtained from women with gestational age-matched (32-34 weeks of gestational age), and categorized as PTL without HCA (PTL, n = 10), PPROM without HCA (PPROM, n = 10), PPROM with HCA (HCA, n = 10), and term without labor and HCA (term birth (TB), n = 9). The expression of PGRMC1 was assessed using western blot and Immunohistochemistry (IHC). As CD14 is a component of the innate immune system during inflammation, CD14 was used as inflammatory indicator. Nonparametric statistics were used for analysis. RESULTS: PGRMC1 expression for all of preterm birth was lower than in TB (P = 0.01). In HCA, PGRMC1 expression was significantly decreased compared to that in PTL and PPROM (P = 0.006. P = 0.001, respectively). PGRMC1 expression in PPROM was higher than that in PTL (P = 0.002). There was a negative correlation between PGRMC1 and CD 14/ß-actin ratio (r = - 0.518; P = 0.002). IHC showed that PGRMC1 was predominant in the cytoplasm of cells, these results were consistent with those of the western blot analysis. CONCLUSION: Preterm birth with PTL, PPROM, and especially HCA is associated with a decreased PGRMC1 in fetal membranes and inversely associated with increased CD 14.

Neutrophil elastase in cervical fluid in women with short cervical length.

OBJECTIVE: The aim of the study was to determine the relationships between short cervical length (CL) and levels of cervical fluid neutrophil elastase (NE), secretory leukocyte protease inhibitor (SLPI), and interleukin 8 (IL-8) in the second trimester of pregnancy of women who underwent ultrasound-indicated cervical cerclage. MATERIALS AND METHODS: CL of <25 mm or cervical funneling were included in the short CL group (n = 26) and the normal CL group (n = 22) included women who had CL of ≥25 mm and had no cervical funneling in women between 17 + 0 and 24 + 6 weeks of gestation. Levels of NE, SLPI, and IL-8 were measured by using enzyme-linked immunosorbent assay kits. Mann-Whitney U tests and Spearman's correlation analysis were used for statistical analyses. RESULTS: Compared with the normal CL group, the short CL group had significantly higher median NE levels (P < 0.001) and higher, though not significant, median IL-8 levels by approximately three times (2107.0 vs. 798.3 pg/mL, P = 0.132). The median SLPI levels in cervical fluid was similar between the two groups (107.6 vs. 103.2 ng/mL, P = 0.499). Short CL had a significant correlations with cervical fluid NE levels (r = -0.475, P = 0.001). CONCLUSION: Increased cervical fluid NE associated with cervical shortening in second trimester of pregnancy, whereas cervical fluid SLPI had constant levels.

Tuberculous peritonitis in the first trimester of pregnancy.

Tuberculous peritonitis in pregnancy is a rare form of extrapulmonary tuberculosis that is not easily diagnosed. The clinical presentations of tuberculous peritonitis are usually non-specific and mimic those of other diseases, such as ovarian malignancy or chronic liver disease, and this non-specificity can cause diagnostic delays and complications. The authors report the case of a 31-year-old primigravida woman who presented with uncontrolled fever, dyspnea, elevated liver enzymes, and mild abdominal distension at 13+2 weeks of gestation. At 14+2 weeks, a therapeutic abortion was conducted and tuberculous peritonitis was confirmed by laparoscopic excisional biopsy of peritoneal nodules and histopathologic examination. The patient recovered on antituberculosis therapy and abdomen and chest follow up radiographic findings have confirmed improvement.

Is a cause of postpartum hemorrhage of using of tocolytic agents in preterm delivery?

OBJECTIVE: Tocolytic agents are used to inhibit uterine contraction in preterm. The authors undertook this study to determine whether using of tocolytic agents before delivery is associated with increase postpartum hemorrhage in preterm delivered women. METHOD: 296 singleton pregnancies delivered preterm from 24 + 1 to 37 + 0 weeks gestation were retrospectively reviewed. Hemoglobin (HB) and hematocrit (HCT) levels were checked before and after delivery to access postpartum blood loss. Multivariate logistic regression analysis was performed to determine whether delivery within the half-lives of tocolytic agents was associated with decreased HB and HCT levels. RESULTS: After adjusting for maternal age, parity, gestational age at delivery, birth weight, delivery method, and induction of labor, postpartum HB and HCT levels of those delivered within half-lives of tocolytic agents were found to be significantly diminished (HB: OR 3.306, 1.308-8.356 95% CI, p = 0.011; HCT: OR 2.692, 1.077-6.726 95% CI, p = 0.034). In addition, blood transfusion rates were elevated for deliveries made within the half-lives of tocolytic agents, (p = 0.006). CONCLUSIONS: Delivery within half-lives of tocolytic agents was found to be associated with low HB and HCT levels after delivery and higher blood transfusion rates in preterm delivered women.

Association of food consumption during pregnancy with mercury and lead levels in cord blood.

In utero exposure to mercury and lead has been linked to various adverse health effects related to growth and development. However, there was no evidence on the relationship between food consumption during pregnancy and mercury or lead level in cord blood. Therefore we measured mercury and lead levels in bloods, urines, and cord bloods obtained from 302 pregnant women and estimated relationships between food consumption during pregnancy and mercury or lead level in cord blood to identify perinatal mercury and lead exposures originated from foods during pregnancy. Relationship between food consumption and mercury or lead level was estimated using a generalized linear model after adjustment for body mass index (BMI), delivery experience, income, recruitment year, and other dietary factors for mercury and age, BMI, cesarean section, delivery experience, recruitment year, and other dietary factors for lead. Fish consumption was positively associated with mercury level in cord blood (p=0.0135), while cereal and vegetable consumptions were positively associated with lead level in cord blood (p=0.0517 for cereal and p=0.0504 for vegetable). Furthermore, tea consumption restrained increase of lead level in cord blood (p=0.0014). Our findings support that mercury or lead exposure in Korean pregnant women may come from frequent fish and cereal or vegetable consumption while tea consumption may decrease lead exposure in pregnant women. Therefore, careful intervention through food consumption should be considered.

Borderline amniotic fluid index and perinatal outcomes in the uncomplicated term pregnancy.

OBJECTIVE: To determine perinatal outcomes in uncomplicated term pregnancies with a borderline amniotic fluid index (AFI). METHODS: A retrospective review was conducted of uncomplicated singleton pregnancies at term (>37 weeks). Borderline and normal AFI were defined as 5.1 ≤ AFI ≤ 8.0 cm and 8.1 ≤ AFI ≤ 24 cm, respectively. Adverse perinatal outcomes, cesarean delivery for non-reassuring fetal heart rate testing, meconium-stained amniotic fluid, a 5-min Apgar score of <7, admission to the neonatal intensive care unit (NICU), and whether the neonate was small for gestational age were compared between the borderline and normal AFI groups. RESULTS: Borderline AFI was not significantly associated with cesarean delivery for non-reassuring fetal heart rate testing (p = 0.513), meconium-stained amniotic fluid (p = 0.641), admission to the NICU (p = 0.368), or a 5-min Apgar score of <7 (p = 1.00). However, the number of neonates who were small for gestational age (p = 0.021) and rates of induction of labor (p < 0.001) were significantly higher in the borderline group. Multiple logistic regression analysis showed that borderline AFI was not associated with cesarean delivery for non-reassuring fetal heart rate testing (odds ratio [OR] = 0.72, 95% confidence interval [CI] 0.27-1.91, p = 0.52). CONCLUSION: In uncomplicated term pregnancies, a borderline AFI does not increase the risk of adverse perinatal outcomes.