Absolute counts of leukocyte subsets in peripheral blood in pregnancies complicated by preterm prelabour rupture of membranes.

BACKGROUND: This study aimed to assess variations in the absolute counts of various leukocyte subsets in the peripheral blood of women with pregnancies affected by preterm prelabour rupture of membranes (PPROM), in relation to the presence of intra-amniotic inflammation (IAI). METHODS: The study included fifty-two women with singleton pregnancies experiencing PPROM. Absolute counts of different leukocyte subpopulations, such as granulocytes, monocytes, lymphocytes, T cells and their subsets, B cells and their subsets, and NK cells and their subsets, were measured in maternal peripheral blood samples using multicolour flow cytometry. IAI was identified by elevated concentrations of interleukin 6 (IL-6) in the amniotic fluid, which was collected through transabdominal amniocentesis. RESULTS: Women with IAI exhibited higher absolute counts of leukocytes (p = 0.003), granulocytes (p = 0.008), and monocytes (p = 0.009). However, the presence of IAI did not significantly affect the absolute counts of lymphocytes or their subpopulations. CONCLUSIONS: The study found that IAI is associated with changes in the absolute counts of leukocytes from the innate immunity compartment in the peripheral blood of women with pregnancies complicated by PPROM. Conversely, it does not significantly alter the counts of cells from the adaptive immune system. The changes observed may reflect the natural, temporal, and localised characteristics of IAI.

Preterm birth is the most serious complication in contemporary perinatal medicine. Preterm birth, which is defined as a labour before the completion of 37 weeks of pregnancy, is often accompanied by premature rupture of the amniotic membranes and drainage of amniotic fluid. Such a situation is often complicated by inflammation, which adversely affects the health of the foetus. A number of procedures and markers have been developed for the diagnosis of inflammation, but they are determined from hard-to-reach amniotic fluid. It is therefore appropriate to try to find reliable markers of inflammation in the much more accessible maternal peripheral blood. Such a marker can be increased numbers of leukocytes, which have been repeatedly investigated in this context. However, little attention is directed to other leukocyte populations and especially to various lymphocyte subpopulations. This study aimed to test changes in absolute counts of different types of leukocytes and lymphocyte subpopulations in women with premature rupture of membranes with respect to ongoing inflammation. The results of the study showed that inflammation is accompanied by increased numbers of leukocytes, granulocytes and monocytes, however, the results did not show significant changes in the number of lymphocytes and their subpopulations.

Plasma Kallistatin and Progranulin as Predictive Biomarkers of Intraamniotic Inflammation, Microbial Invasion of the Amniotic Cavity, and Composite Neonatal Morbidity/Mortality in Women With Preterm Premature Rupture of Membranes.

PROBLEM: To explore the clinical utility of nine inflammatory immune-, adhesion-, and extracellular matrix-related mediators in the plasma for predicting intraamniotic inflammation and/or microbial invasion of the amniotic cavity (IAI/MIAC) and composite neonatal morbidity and/or mortality (CNMM) in women with preterm premature rupture of membranes (PPROM) when used alone or in combination with conventional blood-, ultrasound-, and clinical-based factors. METHODS OF STUDY: This retrospective cohort comprised 173 singleton pregnant women with PPROM (24 + 0 - 33 + 6 weeks), who underwent amniocentesis. Amniotic fluid was cultured for microorganisms and assayed for IL-6 levels. Plasma levels of AFP, CXCL14, E-selectin, Gal-3BP, kallistatin, progranulin, P-selectin, TGFBI, and VDBP were determined by ELISA. Ultrasonographic cervical length (CL) and neutrophil-to-lymphocyte ratio (NLR) were measured. RESULTS: Multivariate logistic regression analyses revealed significant associations between (i) decreased plasma kallistatin levels and IAI/MIAC and (ii) decreased plasma progranulin levels and increased CNMM risk after adjusting for baseline variables (e.g., gestational age at sampling [or delivery] and parity). Using stepwise regression analysis, noninvasive prediction models for IAI/MIAC and CNMM risks were developed, which included plasma progranulin levels, NLR, CL, and gestational age at sampling, and provided a good prediction of the corresponding endpoints (area under the curve: 0.79 and 0.87, respectively). CONCLUSIONS: Kallistatin and progranulin are potentially valuable plasma biomarkers for predicting IAI/MIAC and CNMM in women with PPROM. Particularly, the combination of these plasma biomarkers with conventional blood-, ultrasound-, and clinical-based factors can significantly support the diagnosis of IAI/MIAC and CNMM.

Evaluating the predictive efficacy of first trimester biochemical markers (PAPP-A, fß-hCG) in forecasting preterm delivery incidences.

In this investigation, we explored the correlation between first-trimester biochemical markers and the incidence of preterm birth (PTB), irrespective of the cause, spontaneous preterm birth (sPTB), and preterm premature rupture of membranes (pPROM) within a cohort comprising 1164 patients. It was discovered that diminished levels of Pregnancy-Associated Plasma Protein-A (PAPP-A) between 11 and 13 + 6 weeks of gestation significantly contributed to the risk of preterm deliveries both before 35 and 37 weeks, as well as to pPROM instances. Furthermore, women experiencing sPTB before the 37th week of gestation also exhibited lower concentrations of PAPP-A. Moreover, reduced first-trimester concentrations of free beta-human chorionic gonadotropin (fb-HCG) were identified as a risk factor for deliveries preceding 37 weeks, pPROM, and sPTB before 35 weeks of gestation. Despite these correlations, the area under the curve for these biochemical markers did not surpass 0.7, indicating their limited diagnostic potential. The most significant discriminatory capability was noted for PAPP-A levels, with a threshold of < 0.71 multiples of the median (MoM) predicting PTB before 37 weeks, yielding an odds ratio of 3.11 (95% Confidence Interval [CI] 1.97-4.92). For sPTB, the greatest discriminatory potential was observed for PAPP-A < 0.688, providing an OR of 2.66 (95% CI 1.51-4.66). The cut-off points corresponded to accuracies of 76.05% and 79.1%, respectively. In regression analyses, the combined predictive models exhibited low explanatory power with R2 values of 9.2% for PTB and 7.7% for sPTB below 35 weeks of gestation. In conclusion, while certain biochemical markers demonstrated associations with outcomes of preterm birth, their individual and collective predictive efficacies for foreseeing such events were found to be suboptimal.

The relationships of inflammatory blood markers with maternal periodontal and dental states and their effects on preterm membrane rupture development.

BACKGROUND: The influence of maternal oral and dental health on the occurrence of Preterm Premature Rupture of Membranes (P-PROM) and its underlying mechanisms remain uncertain. This research seeks to investigate the impact of maternal oral and dental health on the incidence of P-PROM and its association with inflammatory markers in the blood. METHODS: This study adopts a prospective case-control design methodology. The study involved 70 women diagnosed with P-PROM and delivered by an obstetrician and 79 women who had healthy deliveries with no prenatal complications. The values for DMFT (Number of decayed, missing and filled teeth) index, Gingival Index (GI), Plaque index (PI), Pocket depth (PD), Clinical attachment loss (CAL) and medical history were recorded. Mann-Whitney U test and hierarchical binomial logistic regression analysis were applied. It was considered statistically significant at p < 0.05. RESULTS: The case group's DMFT, PI, GI, PD values were statistically significantly higher than the control group (p < 0.001). There was no relationship between DMFT, GI, PD, CAL and inflammatory blood markers (p > 0.05). In the regression analysis for possible risk factors that may be effective in P-PROM, oral and dental health parameters were the most effective. CONCLUSIONS: Oral and dental health of women with P-PROM was found to be worse than that of the control group. Oral and dental health may be a potential risk factor that may contribute to adverse pregnancy outcomes associated with P-PROM.

Chemokine and cytokine profiles in preterm and term labor, in preterm prelabor rupture of the membranes, and in normal pregnancy.

The objective of this study was to investigate the immune mechanisms involved in preterm labor (PTL), preterm prelabor rupture of the membranes (PPROM), and normal pregnancies. The second objective was to explore immune profiles in PTL for association with early ( < 34 gestational weeks (gw)) or instant ( < 48 h) delivery. This prospective observational multi-center study included women with singleton pregnancies with PTL (n = 80) or PPROM (n = 40) before 34 gw, women with normal pregnancies scheduled for antenatal visits (n = 44), and women with normal pregnancies in active labor at term (n = 40). Plasma samples obtained at admission were analyzed for cytokine and chemokine quantification using a multiplex bead assay in order to compare the immune profiles between PTL, PPROM, and normal pregnancies. In PTL, CXCL1 and CCL17 were significantly higher compared to gestational age-matched women at antenatal visits, whereas for PPROM, CXCL1 and IL-6 were increased. Women in term labor had a more pronounced inflammatory pattern with higher levels of CXCL1, CXCL8, and IL-6 compared with PTL (p = 0.007, 0.003, and 0.013, respectively), as well as higher levels of CCL17, CXCL1 and IL-6 (all p < 0.001) compared with the women at antenatal visits. In PTL, CXCL8 was higher in women with delivery before 34 gw, whereas CXCL8, GM-CSF, and IL-6 were significantly higher in women with delivery within 48 h. To conclude, PTL and PPROM were associated with a complex pattern of inflammation, both involving Th17 (CXCL1) responses. Although further studies are needed, CXCL8, GM-CSF, and IL-6 may be potential candidates for predicting preterm birth in PTL.

Changes in serum inflammatory factors in group B streptococcal infection and their predictive value for premature rupture of membranes complicated by chorioamnionitis.

Objective: The aim of this study as to unveil changes in serum inflammatory factors in pregnant women with genital tract group B Streptococcus (GBS) infection and their predictive value for premature rupture of membranes (PROM) complicated by chorioamnionitis (CS) and adverse pregnancy outcomes. Methods: The value of serum inflammatory factor levels in predicting PROM complicating CS and adverse pregnancy outcomes in GBS-infected pregnant women was evaluated by ELISA. Results: Serum IL-6, TNF-α, PCT and hs-CRP levels were higher in pregnant women with GBS infection. The combined diagnosis of these factors had excellent diagnostic value in PROM complicating CS and adverse pregnancy outcomes. Conclusion: Joint prediction of IL-6, TNF-α, PCT and hs-CRP has the best predictive value for PROM complicating CS and adverse pregnancy outcomes.

[Box: see text].

Angiogenic imbalance in pregnancies with preterm prelabor rupture of membranes between 34 and 37 weeks of gestation.

INTRODUCTION: This study aimed to identify whether microbial invasion of the amniotic cavity and/or intra-amniotic inflammation in women with late preterm prelabor rupture of membranes (PPROM) was associated with changes in concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and its ratio in maternal serum, and whether placental features consistent with maternal vascular malperfusion further affect their concentrations. MATERIAL AND METHODS: This historical study included 154 women with singleton pregnancies complicated by PPROM between gestational ages 34+0 and 36+6 weeks. Transabdominal amniocentesis was performed as part of standard clinical management to evaluate the intra-amniotic environment. Women were categorized into two subgroups based on the presence of microorganisms and/or their nucleic acids in amniotic fluid (determined by culturing and molecular biology method) and intra-amniotic inflammation (by amniotic fluid interleukin-6 concentration evaluation): (1) those with the presence of microorganisms and/or inflammation (at least one present) and (2) those with negative amniotic fluid for infection/inflammation (absence of both). Concentrations of sFlt-1 and PlGF were assessed using the Elecsys® sFlt-1 and Elecsys® PlGF immunoassays and converted into multiples of medians. RESULTS: Women with the presence of microorganisms and/or inflammation in amniotic fluid had lower serum concentrations of sFlt-1 and sFlt-1/PlGF ratios and higher concentrations of PlGF compared with those with negative amniotic fluid. (sFlt-1: presence: median 1.0 multiples of the median (MoM), vs negative: median: 1.5 MoM, P = 0.003; PlGF: presence: median 0.7 MoM, vs negative: median 0.4 MoM, P = 0.02; sFlt-1/PlGF: presence: median 8.9 vs negative 25.0, P = 0.001). Higher serum concentrations of sFlt-1 and sFlt-1/PlGF ratios as well as lower concentrations of PlGF were found in the subsets of women with maternal vascular malperfusion than in those without maternal vascular malperfusion. CONCLUSIONS: Among women experiencing late PPROM, angiogenic imbalance in maternal serum is primarily observed in those without both microbial invasion of the amniotic cavity and intra-amniotic inflammation. Additionally, there is an association between angiogenic imbalance and the presence of maternal vascular malperfusion.

CX3CL1/Fractalkine as a biomarker for early pregnancy prediction of preterm premature rupture of membranes.

OBJECTIVES: The objective of our study was to evaluate serum CX3CL1/Fractalkine, a monocyte/macrophage chemoattractant expressed in cytotrophoblasts and decidual cells, as a predictive biomarker for the occurrence of preterm premature rupture of membranes (PPROM). METHODS: A case-control study of 438 pregnancies including 82 PPROM cases and 64 preterm labor with intact membranes cases with blood samples collected at first trimester, second trimester and delivery was conducted. The predictive ability of CX3CL1 and maternal risk factors for the occurrence of PPROM was assessed by receiver operating characteristic curve analysis. A second, independent cohort was prospectively constituted to confirm the case-control study results. RESULTS: First trimester CX3CL1 was significantly increased in PPROM cases when compared to matched controls. Multivariate regression analysis highlighted a significant difference for CX3CL1 measured during the first trimester (p<0.001). Alone, CX3CL1 predicts PPROM with a 90 % sensitivity and a specificity around 40 %. The area under the receiver operating characteristic curve for PPROM prediction were 0.64 (95% confidence interval: 0.57-0.71) for first trimester CX3CL1, and 0.61 (95% confidence interval: 0.54-0.68) for maternal risk factors (body mass index<18.5 kg/m2, nulliparity, tobacco use and the absence of high school diploma). The combination of CX3CL1 and maternal risk factors significantly improved the area under the curve: 0.72 (95% confidence interval: 0.66-0.79) (p<0.001). The results were confirmed on a second independent cohort. CONCLUSIONS: CX3CL1 is a promising blood biomarker in the early (first trimester) prediction of PPROM.

Pneumoprotein CC16 in the Umbilical Cord Blood of Preterm Neonates.

OBJECTIVE: We examined the impact of perinatal factors on cord serum club cell protein (CC16) and the association of CC16 with mechanical ventilation and bronchopulmonary dysplasia (BPD) in preterm neonates. STUDY DESIGN: A retrospective cohort study including 60 neonates born with gestational age (GA) < 34 weeks. The impact of categorical perinatal factors on cord blood levels of CC16 was examined with univariate and multivariate regression analyses. RESULTS: In neonates with GA < 32 weeks, cord blood CC16 concentrations were significantly lower compared to neonates with GA between 320/7 and 336/7 weeks (5.4 ± 2.5 compared to 7.6 ± 2.9 ng/mL, p = 0.039). Neonates with prolonged rupture of membranes had significantly lower CC16 compared to those without prolonged rupture of membranes (4.0 ± 1.9 compared to 7.2 ± 2.2, p < 0.001). Finally, neonates with BPD had significantly lower CC16, compared to neonates without BPD (4.2 ± 2.1 compared to 7.0 ± 2.2 ng/mL, p = 0.004).Prolonged rupture of membranes was significantly negatively associated with CC16 (b = -2.67, 95% confidence interval [CI] -0.49 to -4.85, p = 0.017), after adjusting for GA (b = 0.23, 95% CI 0.03-0.42, p = 0.022), mode of conception, and mode of delivery. Finally, higher CC16 levels were significantly inversely associated with BPD (odds ratio = 0.33, 95% CI 0.12-0.88, p = 0.028), after adjusting for GA (b = 0.27, 95% CI 0.09-0.78, p = 0.015), and birth weight. CONCLUSION: Prolonged rupture of membranes was significantly negatively associated with cord serum CC16, after adjusting for GA, conception, and delivery mode, and CC16 was significantly inversely associated with BPD, after adjusting for GA and birth weight. KEY POINTS: · Neonates with prolonged rupture of membranes had lower CC16 levels.. · CC16 was significantly negatively associated with BPD.. · CC16 could be a biomarker of lung injury and BPD..

Genome and transcriptome profiling of spontaneous preterm birth phenotypes.

Preterm birth (PTB) occurs before 37 weeks of gestation. Risk factors include genetics and infection/inflammation. Different mechanisms have been reported for spontaneous preterm birth (SPTB) and preterm birth following preterm premature rupture of membranes (PPROM). This study aimed to identify early pregnancy biomarkers of SPTB and PPROM from the maternal genome and transcriptome. Pregnant women were recruited at the Liverpool Women's Hospital. Pregnancy outcomes were categorised as SPTB, PPROM (≤ 34 weeks gestation, n = 53), high-risk term (HTERM, ≥ 37 weeks, n = 126) or low-risk (no history of SPTB/PPROM) term (LTERM, ≥ 39 weeks, n = 188). Blood samples were collected at 16 and 20 weeks gestation from which, genome (UK Biobank Axiom array) and transcriptome (Clariom D Human assay) data were acquired. PLINK and R were used to perform genetic association and differential expression analyses and expression quantitative trait loci (eQTL) mapping. Several significant molecular signatures were identified across the analyses in preterm cases. Genome-wide significant SNP rs14675645 (ASTN1) was associated with SPTB whereas microRNA-142 transcript and PPARG1-FOXP3 gene set were associated with PPROM at week 20 of gestation and is related to inflammation and immune response. This study has determined genomic and transcriptomic candidate biomarkers of SPTB and PPROM that require validation in diverse populations.

Transcriptome changes in maternal peripheral blood during term parturition mimic perturbations preceding spontaneous preterm birth†.

The complex physiologic process of parturition includes the onset of labor, which requires the orchestrated stimulation of a common pathway involving uterine contractility, cervical ripening, and chorioamniotic membrane activation. However, the labor-specific processes taking place in these tissues have limited use as predictive biomarkers unless they can be probed in non-invasive samples, such as the peripheral blood. Herein, we utilized a transcriptomic dataset to assess labor-specific changes in the peripheral blood of women who delivered at term. We identified a set of genes that were differentially expressed with labor and enriched for immunological processes, and these gene expression changes were strongly correlated with results from prior studies, providing in silico validation of our findings. We then identified significant correlations between labor-specific transcriptomic changes in the maternal circulation and those detected in the chorioamniotic membranes, myometrium, and cervix of women at term, demonstrating that tissue-specific labor signatures are partly mirrored in the peripheral blood. Finally, we demonstrated a significant overlap between the peripheral blood transcriptomic changes in term parturition and those observed in asymptomatic women, prior to the diagnosis of preterm prelabor rupture of the membranes, who ultimately delivered preterm. Collectively, we provide evidence that the normal process of labor at term is characterized by a unique immunological expression signature, which may serve as a useful tool for assessing labor status and for potentially identifying women at risk for preterm birth.

Plasma fibulin-1 levels during pregnancy and delivery: a longitudinal observational study.

BACKGROUND: Fibulin-1 is an extracellular matrix protein expressed at high levels in the placenta. Elevated circulating fibulin-1 have been observed in women with severe pre-eclampsia, whereas low levels have been found in the fetal membranes, prior to membrane rupture. The aim of the study was primarily to evaluate plasma fibulin-1 during expected normal pregnancy and delivery, and secondarily to explore fibulin-1 levels in women developing pre-eclampsia or preterm premature rupture of fetal membranes (PPROM). METHODS: From the historical longitudinal cohort originally consisting of 801 healthy Danish women with a singleton pregnancy, 128 women (632 samples) were selected. Of these, 107 women had normal pregnancies, nine experienced PPROM, and 12 pre-eclampsia. All samples were analyzed for fibulin-1, and levels were compared with blood donors. Differences in mean fibulin-1 between groups were estimated using a linear mixed model. RESULTS: The mean concentration of fibulin-1 in 120 blood donors was 15.7 µg/mL, (25th-75th-percentiles, 12.3-18.2), with no significant difference in groups stratified by gender or age. Compared to baseline levels in week 12-20, fibulin-1 levels increased significantly from week 29-34 (estimated difference, 5.6 µg/mL; standard error, 1.7; p < 0.001) and 35-42 (12.5 µg/mL; 1.6; p < 0.001) and normalized after birth. The decrease at delivery tended to be more pronounced after elective (-7.0 µg/mL; 2.3; p = 0.002) and emergency (-5.6 µg/mL; 2.9; p = 0.05) cesarean section than after vaginal delivery (reference group). Women who developed PPROM had lower fibulin-1 levels throughout their pregnancies (-11.6 µg/mL; 4.2; p = 0.006). We did not observe a correlate between late pre-eclampsia and fibulin-1 (-0.2 µg/mL; 3.0; p = 0.9). CONCLUSIONS: Fibulin-1 was above non-pregnant levels at week 12 and increased significantly throughout pregnancy. We observed an association between low levels of fibulin-1 and PPROM. Further studies are needed to examine if fibulin-1 could serve as biomarker for the risk of PPROM. However, its role in late preeclampsia is doubtful. TRIAL REGISTRATION: The study was conducted in accordance with the Declaration of Helsinki. The participants provided written informed consent, including storage for future use. The study was approved on July 18, 2005 by The Danish National Committee on Bioethics (No. KA 05065 and S-20,090,061) and the Danish Data Protection Agency.

The protective role of serum uric acid against premature membrane rupture in gestational diabetes: a cross-sectional study.

BACKGROUND: Uric acid has strong antioxidant activity, whereas its oxidative damage is closely related to many diseases. We assessed the association between serum uric acid (SUA) levels and premature rupture of membranes (PROM) in pregnant women with gestational diabetes (GDM) in China. METHODS: In this cross-sectional study, a total of 456 pregnant women were enrolled. Anthropometric parameters for pregnant women were collected within 12 weeks of gestation. Weight gain during pregnancy was obtained from the patients' records. GDM was diagnosed according to 75-g oral glucose tolerance tests at the 24-28th week of gestation, and SUA was determined simultaneously. PROM was identified as the natural rupture of foetal membranes before the first stage of labour. Logistic models were fitted to identify the presence of PROM using clinical characteristics with (Model 2) or without serum uric acid (Model 1). RESULTS: There were differences in BMI, haemoglobin A1c, fasting blood glucose, 1-h postprandial glucose (PG), 2-h PG, insulin levels, triglycerides,weight gain during pregnancy, the rate of macrosomia, fetus birth weight and PROM between women with and without GDM (all P < 0.05). Furthermore, GDM women with PROM had lower levels of SUA compared to those without PROM (P = 0.030). The odds ratio of PROM decreased with increasing SUA levels. The area under the receiver operating characteristic curves for PROM based on Model 2 was larger than that in Model 1 (0.86 versus 0.71, P < 0.05). CONCLUSION: Relatively elevated SUA levels at the 24-28th weeks of gestation were associated with a lower risk of PROM in women with GDM. Therefore, SUA may be a protective factor for PROM in GDM patients. The optimal concentration of uric acid in different diseases and different populations needs to be further studied.

Maternal serum IL-22 concentrations are significantly upregulated in patients with preterm premature rupture of membranes.

OBJECTIVES: This study aimed to compare the serum IL-22 levels between preterm premature rupture of membranes (PPROM) patients and the control group with intact membranes. We also hypothesized whether serum IL-22 upregulation might contribute to defense against inflammatory responses and improve the pregnancy outcomes. MATERIAL AND METHODS: We performed this prospective case-control study between 24-34 weeks of pregnancy. We enrolled 40 singleton pregnant patients with PPROM and 40 healthy gestational age- and gravidity-matched patients without PPROM. The degree of association between variables and IL-22 were calculated by Spearman correlation coefficients where appropriate. Scatter plots were given for statistically significant correlations. ROC curve was constructed to illustrate the sensitivity and specificity performance characteristics of IL-22, and a cutoff value was estimated by using the index of Youden. RESULTS: Maternal serum IL-22 levels were significantly higher in PPROM patients (60.34 ± 139.81 pg/mL) compared to the participants in the control group (20.71 ± 4.36 pg/mL, p < 0.001). When we analyze the area under the ROC curve (AUC), the IL-22 value can be considered a statistically significant parameter for diagnosing PPROM. According to the Youden index, a 23.86 pg/mL cut-off value of IL-22 can be used to diagnosing PPROM with 72% sensitivity and 61.5% specificity. There was no positive correlation between serum IL-22 levels and maternal C-reactive protein (CRP) value, procalcitonin value, latency period, birth week, birth weight, and umbilical cord blood pH value. CONCLUSIONS: Maternal serum IL-22 levels were significantly higher in PPROM patients than healthy pregnant women with an intact membrane. We suggest that IL-22 might be a crucial biomarker of the inflammatory process in PPROM.

Unfolding the pathophysiology of congenital thrombotic thrombocytopenic purpura in pregnancy: lessons from a cluster of familial cases.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP), a rare, potentially life-threatening thrombotic microangiopathy, manifests either as congenital TTP or acquired forms. It is caused by the absence or severe depletion of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) protease, leading to the accumulation of ultra large von Willebrand factor multimers as well as extensive platelet adhesion and clumping, which can ultimately cause severe secondary end-organ damage. Pregnancy can provoke or exacerbate TTP, leading to maternal and fetal complications. OBJECTIVE: In this report, we focused on pregnancy outcomes in a recently recognized cohort of congenital TTP patients of Bedouin Arab descent in southern Israel who were all homozygous for a novel c.3772delA variant of the ADAMTS13 gene, leading to the clinical manifestations of TTP largely during pregnancy. STUDY DESIGN: All patients presented in this study belong to 2 closely related families of Arab Bedouin descent and were found to be homozygous for a novel ADAMTS13-c.3772delA variant. The cohort consisted of 19 females; 16 of them had congenital TTP and had been pregnant and were thus included. Patient data were collected from electronic medical records. RESULTS: Of note, 13 women from our cohort, who delivered 14 fetuses (owing to 1 twin pregnancy), were diagnosed with congenital TTP following complicated pregnancies, which included recurrent pregnancy loss, stillbirth, early onset preeclampsia (both mild and severe), hemolysis, elevated liver enzymes and low platelet count syndrome, intrauterine growth restriction with abnormal Doppler flow, preterm premature rupture of membranes, and a total perinatal mortality rate of 30.7% (4/13). An additional 3 women, who were diagnosed owing to complications outside of pregnancy and at older ages, experienced TTP during their pregnancies, which occurred before diagnosis. Subsequent pregnancies were treated with fresh frozen plasma leading to a 100% fetal survival rate in the pregnancies that reached fetal viability. All placentas had lesions consistent with maternal vascular underperfusion. However, the severity and frequency of these lesions were lower in the 8 placentas from pregnancies treated with fresh frozen plasma. CONCLUSION: This case series details a distinctive cohort of congenital TTP patients, all homozygous for the same, novel ADAMTS13 variant, who presented with clinical complications during pregnancy and maternal vascular lesions of underperfusion in the placenta. Our findings imply that the variant identified in the ADAMTS13 gene in our cohort may have a specific functional impact on the placenta, and that treatment with fresh frozen plasma during pregnancy ameliorates the course of the disease, leading to a milder phenotype or a normal pregnancy in the majority of cases.

Serum Decorin, Biglycan, and Extracellular Matrix Component Expression in Preterm Birth.

Preterm birth is a leading cause of infant morbidity and mortality. Decorin and biglycan are proteoglycans that play key roles in maintaining the connective tissue matrix and tensile strength of human fetal membranes and have been previously linked to PPROM. Extracellular matrix proteins, such as matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), TIMP metallopeptidase inhibitor 1 (TIMP-1), TIMP metallopeptidase inhibitor 2 (TIMP-2), and collagen VI (COL-6), have also been linked to PPROM and may have utility in a serum-based screening model for this condition. To define the natural course of serum decorin and biglycan expression throughout the duration of healthy pregnancy, to explore patterns of serum decorin and biglycan expression in serum of asymptomatic women who go on to develop spontaneous preterm labor, and to investigate the potential role for matrix metalloproteinases, their inhibitors, and collagen VI in a serum-based screening model to predict PPROM. Serum decorin level decreases less than 1% per week, and serum biglycan decreases by 2.9% per week over the duration of healthy pregnancy. Serum decorin and biglycan concentrations do not differ in spontaneous preterm labor cases compared with those in controls. Mean concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, and COL-6 do not differ in PPROM cases compared with those in controls. We have demonstrated that serum decorin and biglycan concentrations remain stable throughout the duration of normal pregnancy and are not early indicators of preterm labor, while common MMPs, TIMPs, and collagen VI are not early indicators of PPROM.

Maternal Serum Haptoglobin Levels as a Marker of Preterm Premature Rupture of Membranes.

OBJECTIVE: We aimed to investigate the prognostic value of maternal serum haptoglobin levels in patients presenting with preterm premature rupture of fetal membranes (PPROM) during the second and the third trimesters of pregnancy. METHODS: In this case control study, 60 patients were recruited (30 pregnant women with PPROM between 26-34 weeks of gestation and 30 healthy, gestational-age-matched pregnant women without PPROM). White blood cell count (WBC), interleukin 6 (IL-6), C-reactive protein (CRP), sedimentation rate, and haptoglobin levels were measured. RESULTS: The mean age, gestational week, gravida, and parity of the 2 groups were statistically comparable (P>0.001). There was a statistically significant difference between the 2 groups in terms of haptoglobin values (p<0.001). The mean haptoglobin level was 115.5+33.1(mg/dl) in the PPROM group and 66.5+42.6 (mg/dl) in the control group. ROC curve analysis was performed to determine whether the level of haptoglobin alone could diagnose PPROM as an independent marker. It was shown that the level of 94.5 mg/dL for haptoglobin could indicate the diagnosis of PPROM with 80% sensitivity and specificity CONCLUSION: Maternal serum haptoglobin levels may be a diagnostic marker for suspected PPROM cases when membrane rupture diagnosis is not accurate based on physical examination and other diagnostic tests.

Alpha-2-macroglobulin from circulating exosome-like vesicles is increased in women with preterm pregnancies.

Preterm labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) impose substantial morbimortality on mothers and newborns. Exosomes act in intercellular communication carrying molecules involved in physiopathological processes. Little is known about exosomal proteins in prematurity. Our aim was to evaluate the protein expression of hemopexin, C1 inhibitor (C1INH) and alpha-2-macroglobulin (A2M) from circulating exosomes of women with PTL and PPROM. Plasma was obtained from PTL, PPROM, Term in labor and Term out of labor (T) patients, exosomes were isolated by ultracentrifugation, then lysed and the proteins quantified. Western Blot (WB) and Nanoparticle Tracking Analysis (NTA) were performed. Data were compared by Kruskal-Wallis, unpaired T-test and one-way ANOVA. WB and NTA confirmed exosome isolation (concentration: 4.3 × 1010 particles/ml ± 1.9 × 1010). There was no difference regarding hemopexin or C1INH expression between the groups. For A2M, the fold change was significantly higher on preterm groups when compared to term groups (1.07 ± 0.30 vs. 0.42 ± 0.17, p < 0.0001). Higher levels of A2M in circulating exosomes are linked to preterm pregnancies. sEV are strong candidates to intermediate maternal-fetal communication, carrying preterm labor-related immunomodulatory proteins.

Application of a Prediction Model Based on the Laboratory Index Score in Prelabor Rupture of Membranes with Histologic Chorioamnionitis During Late Pregnancy.

BACKGROUND This study aimed to establish a prediction model based on the maternal laboratory index score (Lab-score) for histologic chorioamnionitis (HCA) in patients with prelabor rupture of membranes (PROM) during late pregnancy. MATERIAL AND METHODS Sixty-nine cases of pregnant women with PROM were retrospectively analyzed. The general information and laboratory indicators were compared between the HCA (n=22) and non-HCA (n=47) groups. A multivariate logistic regression method was used to establish the prediction model. We plotted the receiver operating characteristic curve and calculated the area under the curve (AUC). The clinical effectiveness of each model was compared by decision curve analysis. RESULTS Only C-reactive protein (CRP) in the laboratory index predicted HCA, but its diagnostic efficacy was not ideal (AUC=0.651). Then, we added CRP to the platelet/white blood cell count ratio and triglyceride level to construct the Lab-score. Based on the Lab-score, important clinical parameters, including body mass index, diastolic blood pressure, and preterm birth, were introduced to construct a complex joint prediction model. The AUC of this model was significantly larger than that of CRP (0.828 vs. 0.651, P=0.035), but not significantly different from that of Lab-score (0.828 vs. 0.724, P=0.120). Considering the purpose of HCA screening, the net benefit of the complex model was better than that of Lab-score and CRP. CONCLUSIONS The complex model based on Lab-score is useful in the clinical screening of high-risk populations with PROM and HCA during late pregnancy.

Congenital dysfibrinogenaemia presented with preterm premature rupture of the membranes and vaginal bleeding.

A 26-year-old woman was found to have congenital dysfibrinogenaemia after presenting to our hospital with premature rupture of the membranes and vaginal bleeding. Given the absence of clear guidelines for the management of pregnancy complicated by dysfibrinogenaemia, we followed expert consensus that exists among published works, with some modifications. This case was managed by a multidisciplinary team of obstetrics-gynaecology, haematology and paediatric haematology. Here we review how the patient presented, the investigations that led to the diagnosis and the treatment options.