The vaginal immunoproteome for the prediction of spontaneous preterm birth: A retrospective longitudinal study.

Background: Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB. Methods: Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations. Results: Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (<34 weeks) sPTB. Conclusions: The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes. Funding: This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.

Human pregnancies last 40 weeks on average. Preterm births, defined as live births before 37 weeks, occur in about one in ten pregnancies. Being born too early is the main cause of a number of diseases and death in newborn babies. Preterm births are further divided into those that happen early ­ before 34 weeks ­ and those that happen late ­ between 34 and 37 weeks. There are also differences between preterm births in which the amniotic sac ruptures before or after the start of labor. Although several factors can lead to spontaneous preterm birth, bacteria getting into the amniotic fluid around the fetus are a well-known trigger. These bacteria usually come from the vagina. In the past, researchers have studied the number and types of bacteria in the vagina of people who had a normal pregnancy and those that had a preterm birth to predict who is more at risk of preterm birth. However, predictions based only on data about bacteria have been less useful so far. Instead, it might be better to investigate a person's immune response during pregnancy. Shaffer et al. addressed this gap by asking whether measuring the levels of proteins involved in the immune response could help predict preterm births. Shaffer et al. collected vaginal fluids from 739 individuals of predominately African American ethnicity with an average BMI of 28.7 ­ representing a population at high risk for spontaneous preterm birth. The swabs were taken at multiple points during their pregnancy, and 31 different immune-related proteins in those fluids were measured. The researchers further noted whether these individuals had a normal or a preterm birth. The data showed that, compared to normal births, preterm births are associated with higher levels of proteins that attract white blood cells and promote inflammation, such as IL-6 and IL-1ß. Vaginal fluids from individuals who went on to have an early preterm birth where the amniotic sac ruptured before labor, contained lower levels of proteins known as defensins, which defend the body from bacteria. With these new data from vaginal swabs, Shaffer et al. could make better predictions about the likelihood of preterm birth in general and early preterm birth with the amniotic sac ruptured before labor. For the latter scenario, the predictions were not improved when combining immune protein data with other characteristics of the pregnant person, such as age. These findings suggest that clinicians may be able to use measurements of immune-related proteins to help predict preterm births, so that pregnant individuals at high risk can receive extra care. Further research will have to validate the data and determine whether the findings apply more widely.

The adenosine deaminase family acting on RNA 1 can be a useful diagnostic biomarker in chorioamnionitis.

INTRODUCTION: Chorioamnionitis (CAM) involves infection and inflammation of the chorion and amniotic membrane, but there are still no effective diagnostic biomarkers for CAM. METHODS: We investigated the correlation between RNA editing enzyme Adenosine deaminase family acting on RNA 1 (ADAR1) and CAM in chorion and amniotic membrane specimens derived from premature rupture of the membrane (PROM), CAM (pathologically diagnosed), and clinical CAM (clinically diagnosed) patients using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: ADAR1 was upregulated in the chorion and amniotic membrane specimens of CAM and clinical CAM patients (p < 0.001 and p = 0.005). ADAR1 had a significantly higher area under the curve (AUC) (0.735 and 0.828) than markers of inflammation characteristics in diagnosing CAM and clinical CAM patients. ADAR1 also had significantly higher AUC (0.701 and 0.837) than clinical characteristics for CAM and clinical CAM patients. DISCUSSION: ADAR1 can be a useful diagnostic biomarker in CAM patients.

Short-term variation of the fetal heart rate as a marker of intraamniotic infection in pregnancies with preterm prelabor rupture of membranes: a historical cohort study.

INTRODUCTION: Intraamniotic infection (IAI) and subsequent early-onset neonatal sepsis (EONS) are among the main complications associated with preterm prelabor rupture of membranes (PPROM). Currently used diagnostic tools have been shown to have poor diagnostic performance for IAI. This study aimed to investigate whether the exposure to IAI before delivery is associated with short-term variation of the fetal heart rate in pregnancies with PPROM. METHODS: Observational cohort study of 678 pregnancies with PPROM, delivering between 24 + 0 and 33 + 6 gestational weeks from 2012 to 2019 in five labor units in Stockholm County, Sweden. Electronic medical records were examined to obtain background and exposure data. For the exposure IAI, we used the later diagnosis of EONS in the offspring as a proxy. EONS is strongly associated to IAI and was considered a better proxy for IAI than the histological diagnosis of acute chorioamnionitis, since acute chorioamnionitis can be observed in the absence of both positive microbiology and biochemical markers for inflammation. Cardiotocography traces were analyzed by a computerized algorithm for short-term variation of the fetal heart rate, which was the main outcome measure. RESULTS: Twenty-seven pregnancies were categorized as having an IAI, based on the proxy diagnosis of EONS after birth. Fetuses exposed to IAI had significantly lower short-term variation values in the last cardiotocography trace before birth than fetuses who were not exposed (5.25 vs 6.62 ms; unadjusted difference: -1.37, p = 0.009). After adjustment for smoking and diabetes, this difference remained significant. IAI with a later positive blood culture in the neonate (n = 12) showed an even larger absolute difference in STV (-1.65; p = 0.034), with a relative decrease of 23.5%. CONCLUSION: In pregnancies with PPROM, fetuses exposed to IAI with EONS as a proxy have lower short-term variation of the fetal heart rate than fetuses who are not exposed. Short-term variation might be useful as adjunct surveillance in pregnancies with PPROM.

Semi-quantitative metalloproteinase-8 rapid test for the prediction of adverse pregnancy outcomes in patients with preterm premature rupture of membranes.

OBJECTIVE: We aimed to determine whether the semi-quantitative metalloproteinase-8 (MMP-8) bedside test is a worthwhile indicator in reflecting the severity of of intra-amniotic inflammation (IAI) and in predicting adverse pregnancy outcomes. STUDY DESIGN: This retrospective cohort study comprised 76 singleton-pregnant women admitted to the Seoul National University Bundang Hospital with a diagnosis of preterm premature rupture of membranes (preterm PROM) between 20 weeks 0 days and 33 weeks 6 days of gestation who underwent trans-abdominal amniocentesis to confirm intra-amniotic infection by positive results for aerobic/anaerobic bacteria, fungi, and genital mycoplasma and evaluate lung maturity. The semi-quantitative MMP-8 rapid test kit employs a colourimetric assay to quantify MMP-8 levels in amniotic fluid (AF), expressing results from 0 to 100 percent. Participants were divided into three groups: group 1, including negative MMP-8 test with colour scale of 0 % (negative, n = 17); group 2, including positive MMP-8 test with colour scale < 51 % (weak positive, n = 21); and group 3, including positive MMP-8 test with colour scale of 51 %-100 % (strong positive, n = 38). RESULTS: Approximately 78 % (59/76) of the participants showed a positive MMP-8 test result; all culture-proven AF samples (33.3 % [25/75]) yielded positive MMP-8 test, categorizing these patients into either group 2 or group 3. A significant trend was observed where the rate of positive culture-proven samples increased with the progression from group 1 (negative) to group 3 (strong positive). Both white blood cell counts in AF and maternal serum C-reactive protein levels were found to escalate with the progression of test results from negative to strong positive. This progression was associated with an increased risk of spontaneous preterm birth within 48 h, 7 days, and 14 days from amniocentesis and within 34 weeks of gestation. CONCLUSION: The more the test results progress from negative to strong positive, the shorter the interval from amniocentesis to delivery becomes, and the higher the risk of intra-amniotic infection, spontaneous preterm delivery, and other perinatal complications. This relationship highlights the critical value of the semi-quantitative MMP-8 rapid test in predicting adverse pregnancy outcomes in patients with preterm PROM.

Value of fetal echocardiographic examination in pregnancies complicated by preterm premature rupture of membranes.

OBJECTIVES: Cardiopulmonary and infectious complications are more common in preterm newborns after preterm premature rupture of membranes (pPROM). Fetal echocardiography may be helpful in predicting neonatal condition. Our aim was to assess the cardiovascular changes in fetuses from pregnancies complicated by pPROM and possible utility in predicting the intrauterine or neonatal infection, and neonatal heart failure (HF). METHODS: It was a prospective study enrolling 46 women with singleton pregnancies complicated by pPROM between 18+0 and 33+6 weeks of gestation and followed until delivery. 46 women with uncomplicated pregnancies served as a control group. Fetal echocardiographic examinations with the assessment of cardiac structure and function (including pulmonary circulation) were performed in all patients. RESULTS: Mean gestational age of pPROM patients was 26 weeks. Parameters suggesting impaired cardiac function in fetuses from pPROM were: higher right ventricle Tei index (0.48 vs. 0.42 p<0.001), lower blood flow velocity in Ao z-score (0.14 vs. 0.84 p=0.005), lower cardiovascular profile score (CVPS), higher rate of tricuspid regurgitation (18.2 % vs. 4.4 % p=0.04) and pericardial effusion (32.6 vs. 0 %). Intrauterine infection was diagnosed in 18 patients (39 %). 4 (8.7 %) newborns met the criteria of early onset sepsis (EOS). HF was diagnosed in 9 newborns. In fetal echocardiographic examination HF group had shorter mitral valve inflow time and higher left ventricle Tei index (0.58 vs. 0.49 p=0.007). CONCLUSIONS: Worse cardiac function was observed in fetuses from pPROM compared to fetuses from uncomplicated pregnancies.

Characterizing of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta marked by elevated amniotic fluid interferon gamma-induced protein 10 (IP-10) in pregnancies complicated by preterm prelabor rupture of membranes.

OBJECTIVES: This study aimed to determine the occurrence of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta, marked by elevated levels of interferon gamma-induced protein 10 (IP-10) (≥2200 pg/mL) in the amniotic fluid of women with preterm prelabor rupture of membranes (PPROM). Specifically, the study investigated whether these intra-amniotic inflammatory changes were more common in women with microbial invasion of amniotic cavity (MIAC) and intra-amniotic inflammation (IAI), as indicated by increased amniotic fluid interleukin (IL)-6 concentration (≥3000 pg/mL). STUDY DESIGN: A cohort of 114 women with singleton pregnancies complicated by PPROM between 24+0 and 36+6 weeks of gestation were included. Amniotic fluid samples were obtained via amniocentesis upon admission. MIAC diagnosis involved aerobic and anaerobic cultures, as well as polymerase chain reaction (PCR) analysis of the amniotic fluid. Immunoassay tests and enzyme-linked immunosorbent assay (ELISA) were used to determine IL-6 and IP-10 concentrations, respectively. RESULTS: Among the participants, 19.3 % and 15.8 % had MIAC and IAI, respectively. The occurrence of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta was similar between women with and without MIAC (25 % vs. 40.9 %, p = 0.136, adjusted p = 0.213). The rate of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta was significantly higher in women with IAI compared to those without, after adjusting for gestational age at sampling (55.6 % vs. 22.9 %, p = 0.005, adjusted p = 0.011). CONCLUSION: This study revealed comparable rates of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta in women with and without MIAC, but a higher prevalence of intra-amniotic inflammatory changes associated with chronic inflammation in the placenta in women with IAI. These findings suggest involvement of chronic inflammation even in women with PPROM with acute intra-amniotic inflammation.

Non-invasive prediction model of histologic chorioamnionitis with preterm prelabour rupture of membranes.

BACKGROUND: The aim of this study is to identify risk factors associated with histological chorioamnionitis (HCA) and develop a predictive model for antepartum assessment of the risk of PPROM with HCA. METHODS: This study retrospectively analyzed pregnant women who experienced PPROM between 25 + 0 and 35 + 0 weeks of gestational age. The women were divided into two groups based on the presence or absence of HCA. Univariate and multivariate logistic regression analyses were conducted to identify maternal risk factors and develop a clinical prediction model for HCA. The model's discrimination and consistency were evaluated using receiver operating characteristic (ROC) and calibration curves. RESULTS: Seventeen thousand one hundred forty-six (17,146) pregnant women were screened, and 726 (4.23 %) had PPROM. Out of the 286 subjects with PPROM, 160 developed HCA. The maternal age of these subjects ranged from 18 to 43 years (30.0 ± 5.4), while their gestational age (GA) ranged from 25 + 0 to 35 + 0 weeks (31.6 ± 2.0). The average GA at delivery was 32.2 ± 2.0 (weeks).Compared with the non-HCA group, the expectant time > 48 h, GA at delivery > 32 weeks, twin pregnancy, HGB (<110 g/Lg/L), degree of LGB (IIb-III), and WBC (>9.5 × 109 /L) were significantly more than in the PPROM with HCA group. The results show that the best model was obtained by leave-one-out logistic regression (AUC = 0.785, CA = 0.741, F1 = 0.739, Precision = 0.740, Recall = 0.741). In the validation set, logistic regression also achieved good results (AUC = 0.710, CA = 0.671, F1 = 0.654, Precision = 0.683, Recall = 0.671). Combining the previous analysis, we found that the prognostic model constructed using the core six features had the best predictive effect. CONCLUSIONS: Six features were associated with the occurrence of chorioamnionitis. These features were used to construct a diagnostic model that can accurately predict the probability of chorioamnionitis occurrence and provide a beneficial tool for the prevention and management of PPROM with HCA.

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.

Ambulation for latency during expectant management of preterm prelabor rupture of membranes: a randomized controlled trial (AMBLE).

BACKGROUND: Individuals hospitalized with preterm prelabor rupture of membranes are often advised to limit their activity or adhere to bed rest. Some evidence suggests that greater activity is associated with longer latency and improved outcomes, but no high-quality evidence from a randomized controlled trial exists. OBJECTIVE: This study aimed to evaluate whether encouragement to ambulate at least 2000 steps daily affects latency among individuals with preterm prelabor rupture of membranes compared with usual care. STUDY DESIGN: This was a multisite unblinded, 2-arm randomized trial of individuals at 23 0/7 to 35 0/7 weeks of gestation undergoing inpatient expectant management of preterm prelabor rupture of membranes with planned delivery at least 7 days away. Each participant wore a Fitbit Inspire that tracked steps. The intervention arm was encouraged (verbal and Fitbit-based reminders) to reach a goal of 2000 steps per day. The usual-care arm was allowed ad libitum activity with no step goal or reminders. The primary outcome was latency (days) from randomization to delivery. Secondary analyses included composite neonatal and maternal clinical outcomes and maternal mental health survey results. Statistical analyses were conducted with an intent-to-treat approach under a Bayesian framework using neutral priors (a priori assumed 50:50 likelihood of longer latency in either arm). A total of 100 participants were required to have 80% power to demonstrate a 4-day difference in latency with 75% certainty (Bayesian probability). RESULTS: Among 163 eligible individuals, 100 (61%) were randomized, and after loss to follow-up, 95 were analyzed. Gestational age at randomization was 29 3/7 weeks (interquartile range, 26 2/7 to 31 5/7) in the intervention arm and 27 4/7 weeks (interquartile range, 25 4/7 to 29 6/7) in the usual-care arm. Median step counts were 1690 per day in the intervention arm (interquartile range, 1031-2641) and 1338 per day in the usual-care arm (interquartile range, 784-1913). Median days of latency were 9 days in the intervention arm (interquartile range, 4-17) and 6 days in the usual-care arm (interquartile range, 2-14). The primary analysis indicated a 65% posterior probability that the intervention increased latency relative to usual care (posterior relative risk, 1.09; 95% credible interval, 0.70-1.71). The relative risk was 0.55 (95% credible interval, 0.32-0.82) for the composite neonatal adverse outcome, with 99% posterior probability of intervention benefit, and was 0.94 (95% credible interval, 0.72-1.20) for the composite maternal adverse outcome, with 70% posterior probability of intervention benefit. There was a 94% posterior probability of the intervention arm having a greater decrease in maternal stress score from baseline to before delivery compared with the usual-care arm (mean arm difference, 3.24 points [95% credible interval, -7.23 to 0.79]). Adjustment for gestational age at randomization had minimal impact on secondary outcome results. CONCLUSION: Individuals with preterm prelabor rupture of membranes randomized to encouragement to ambulate had a longer latency to delivery and improved neonatal and mental health outcomes, with similar maternal clinical outcomes compared with usual care.

Frontiers in the Etiology and Treatment of Preterm Premature Rupture of Membrane: From Molecular Mechanisms to Innovative Therapeutic Strategies.

Preterm premature rupture of membranes (pPROM) poses a significant threat to fetal viability and increases the risk for newborn morbidities. The perinatal period of preterm infants affected by pPROM is often characterized by higher rates of mortality and morbidity, with associated risks of cerebral palsy, developmental delays, compromised immune function, respiratory diseases, and sensory impairments. pPROM is believed to result from a variety of causes, including but not limited to microbially induced infections, stretching of fetal membranes, oxidative stress, inflammatory responses, and age-related changes in the fetal-placental interface. Maternal stress, nutritional deficiencies, and medically induced procedures such as fetoscopy are also considered potential contributing factors to pPROM. This comprehensive review explores the potential etiologies leading to pPROM, delves into the intricate molecular mechanisms through which these etiologies cause membrane ruptures, and provides a concise overview of diagnostic and treatment approaches for pPROM. Based on available therapeutic options, this review proposes and explores the possibilities of utilizing a novel composite hydrogel composed of amniotic membrane particles for repairing ruptured fetal membranes, thereby holding promise for its clinical application.

FIGO good practice recommendations for preterm labor and preterm prelabor rupture of membranes: Prep-for-Labor triage to minimize risks and maximize favorable outcomes.

Preterm labor occurs in around 10% of pregnancies worldwide. Once diagnosed, significant efforts must be made to reduce the likelihood of morbidity and mortality associated with preterm birth. In high-resource settings, access to hospitals with a neonatal intensive care unit (NICU) is readily available, whereas access to NICU care is limited in low- and middle-income countries (LMICs) and many rural settings. Use of FIGO's Prep-for-Labor triage method rapidly identifies low- and high-risk patients with preterm labor to enable clinicians to decide whether the patient can be managed on site or if transfer to a level II-IV facility is needed. The management steps described in this paper aim to minimize the morbidity and mortality associated with preterm labor and in the setting of preterm labor with preterm premature rupture of membranes (PPROM). The methods for accurate diagnosis of PPROM and chorioamnionitis are described. When the risk of preterm birth is high, antenatal corticosteroids should be administered for lung maturation combined with limited tocolysis for 48 hours to permit the corticosteroid course to be completed. Magnesium sulfate is also administered for fetal neuroprotection. Implementation of FIGO's Prep-for-Labor triage method in an LMIC setting will help improve maternal and neonatal outcomes.

Active versus expectant management for premature rupture of membranes at term: A randomized, controlled study.

OBJECTIVE: To compare the effects on feto-maternal outcomes of expectant versus active management for premature rupture of membranes (PROM) at term. METHODS: This was a prospective randomized (1:1) controlled study involving 86 pregnant-women who received either expectant management (n = 43) or active management with misoprostol (n = 43) for PROM at term. Primary outcome was route of delivery. Secondary outcomes were: PROM to presentation interval; latency period; PROM to delivery interval; recruitment to delivery interval; labour and delivery complications. RESULTS: Baseline-characteristics were similar between groups. There was no significant difference between active and expectant groups in mean PROM to presentation/admission, or PROM to delivery. However, mean latency period (11.1 ± 7.3 hours vs 8.8 ± 5.5 hours) and mean recruitment to delivery intervals after PROM (14.7 ± 5.2 hours vs 11.8 ± 5.0 hours) were significantly shorter for the active group compared with the expectant group. Although the rate of caesarean section was less in expectant management group (21%) compared with the active management group (30%), the difference was not statistically significant. There were no significant differences between groups in delivery or perinatal complications. CONCLUSION: Active and expectant management for PROM at term gave comparable outcomes in terms of methods of delivery and complications. However, active management significantly shortened the latency period and induction to delivery intervals compared with expectant management.Trial-Registration: Pan-African-trial-registry-(PACTR)-approval-number PACTR202206797734088.

Validation of parental recall questionnaire to classify preterm delivery subtypes: Spontaneous preterm labour, preterm premature rupture of membranes and clinician-initiated preterm delivery.

BACKGROUND: Preterm delivery (PTD) includes three main presenting subtypes: spontaneous preterm labour (sPTL), preterm premature rupture of membranes (pPROM) and clinician-initiated preterm delivery (ciPTD). PTD subtype data are rarely available from birth registries and are onerous to derive from medical records. OBJECTIVES: To develop and test the validity of a questionnaire to classify PTD subtype based on birthing parent recall of labour and delivery events. METHODS: The questionnaire was sent in 2022 to 581 patients with PTD history documented in the LIFECODES study, a hospital-based birth cohort in Boston, Massachusetts. Eighty-two respondents reported 94 PTDs that could be linked to medical records. Data on PTD subtype were extracted from medical records as the reference standard. RESULTS: Medical records indicated 47 spontaneous (24 sPTL, 23 pPROM) and 47 ciPTD deliveries occurring a median eight years earlier. The sensitivity and specificity of the recall questionnaire were 88% (95% confidence interval: 68, 97%) and 89% (79, 95%) for sPTL; 96% (78, 100%) and 94% (86, 98%) for pPROM; and 83% (69, 92%) and 100% (92, 100%) for ciPTD, respectively. Greater time since pregnancy did not degrade the sensitivity or specificity of the parental recall questionnaire. CONCLUSIONS: Although derived from a modest sample, the moderate-to-high sensitivity and specificity of the parental recall questionnaire to classify sPTL, pPROM and ciPTD demonstrates its potential for large studies of PTD and for correction of misclassification bias. Future studies are required to test the questionnaire in a variety of populations.

Residual amniotic fluid volume predicts the sealing of preterm prelabor rupture of fetal membranes in the pre- and periviable period.

OBJECTIVE: Preterm prelabor rupture of fetal membranes (pPROM) is a leading cause of preterm birth. When pPROM occurs around the pre- and periviable period, the perinatal outcome is unfavorable. However, there have been a few cases in which the leakage of amniotic fluid ceases and the ruptured fetal membranes are spontaneously sealed. MATERIALS AND METHODS: The prognosis of 38 cases of pPROM at less than 27 weeks of gestation in Kyoto University Hospital were studied. The clinical factors related to the sealing of fetal membranes were investigated. RESULTS: Spontaneous sealing was confirmed in five patients (13%), and sealing occurred within 14 days of pPROM. Women in the no sealing group delivered at 26.3 ± 0.5 weeks of gestation, whereas women in the sealing group delivered at term at 38.8 ± 0.4 weeks (p < 0.0001). The maximum vertical pocket (MVP) of amniotic fluid at the time of pPROM diagnosis was 2.2 ± 0.3 cm in the no sealing group and 3.8 ± 0.5 cm in the sealing group (p = 0.043). All cases of sealing occurred when the MVP at diagnosis was more than 2 cm, and there were no cases of sealing if the MVP at diagnosis was less than 2 cm. In addition, the value of C-reactive protein at ROM was less than 0.4 mg/dL in all cases in the sealing group. CONCLUSION: The residual volume of sterile amniotic fluid at the onset of pPROM may predict the possibility of fetal membrane sealing.

Biomarkers for Pregnancy Latency Prediction after Preterm Premature Rupture of Membranes-A Systematic Review.

Preterm premature rupture of membranes, leading to preterm birth, is associated with neonatal and maternal morbidity and mortality. The study aimed to review the existing data on the best predictive value of pregnancy latency for known biomarkers in pregnancies after preterm premature rupture of membranes. The following databases were screened for the purposes of this systematic review: Pubmed/MEDLINE, Web of Science, EMBASE, Scopus, and the Cochrane Library. The study was conducted according to the PRISMA guidelines for systematic reviews. Only a few studies assessed biomarkers predicting pregnancy duration after PPROM. IL-6, IL-8, CRP, IL1RA, s-endoglin, ßhCG, AFP, PCT, urea, creatinine, oxygen radical absorbance capacity, MDA, lipocalin-2, endotoxin activity, MMP-8, MMP-9 and S100 A8/A9 were found to have a positive predictive value for delivery timing prediction. Proinflammatory biomarkers, such as IL-6 or CRP, proved to be best correlated with delivery timing, independent of the occurrence of intrauterine infection.

Predicting chorioamnionitis in patients with preterm premature rupture of membranes using inflammatory indexes: a retrospective study.

OBJECTIVE: The prognosis of preterm premature rupture of membranes (PPROM) combined with chorioamnionitis is often unsatisfactory for both mother and newborn. Although tragic outcomes can be avoided if treated early, no effective prediction method for decision-making is available currently. This study aimed to establish an effective method with maternal inflammation indexes to predict preterm premature rupture of membranes with concomitant chorioamnionitis. MATERIALS AND METHODS: This retrospective study examined the data of 206 singleton PPROM cases and 60 normal full-term cases. The PPROM cases included 93 cases of PPROM with chorioamnionitis and 113 cases of PPROM without chorioamnionitis based on clinical manifestations, laboratory examinations, and histopathological diagnosis. Normal full-term cases were included as the control group. Peripheral blood levels of selected inflammatory indicators were observed 12 h after fetal membrane rupture. Associations between selected inflammatory indicators and chorioamnionitis diagnosis were analyzed. RESULTS: Selected factors except for procalcitonin predicted chorioamnionitis in PPROM patients. Combined results of C-reactive protein and white blood cell (WBC) count showed best predictive ability with area under curve, sensitivity, and specificity of 0.702, 60.22%, and 76.11%, respectively. Furthermore including Interleukine-6 and neutrophil count provided similar predictive results. CONCLUSIONS: The best predictive factor combinations for PPROM-CAM were C-reactive protein and white blood cell count. Results of this study provide a useful clinical reference for PPROM-CAM and may improve maternal and infant prognostic outcomes.

Vaginal fluid urea and creatinine, an untapped diagnostic tool for premature rupture of membranes.

PURPOSE: The diagnosis of premature rupture of membranes (PROM) can be difficult in equivocal cases. This study was designed to test the validity of vaginal fluid urea and creatinine in the diagnosis of PROM against the gold standard, the Amnisure ROM test™ METHODS: The study was a prospective observational study. All consenting eligible pregnant women between gestational ages of 28 weeks to 41 weeks + 6 days were recruited from the obstetrics emergency and antenatal clinic of the Federal medical centre, Keffi. Patients with history of drainage of liquor were recruited as the case group, and controls who match for age, parity and gestational age were recruited from the antenatal clinic to constitute the control group. Vaginal fluid aspirated was assessed in the laboratory for urea and creatinine levels and an Amnisure ROM test™ done. The sensitivity, specificity, negative and positive predictive values of vaginal fluid urea and creatinine were assessed in the diagnosis of PROM. RESULTS: Vaginal fluid urea and creatinine had sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), respectively, of 94%, 82%, 93.18% and 83.93%, and 98%, 90%, 97.82% and 90.74%. The cutoff values for vaginal fluid urea and creatinine were 1.25 mg/dl and 0.23 mg/dl, respectively. CONCLUSIONS: This study has found that vaginal fluid urea and creatinine are very effective tests in diagnosis of PROM. It is a cheaper and more readily available alternative to the Amnisure test. It is especially useful in our environment, especially in cases of equivocal PROM, as a cost-effective means to confirm the diagnosis. TRIAL REGISTRATION NUMBER (NIGERIA CLINICAL TRIAL REGISTRY): 72961653, retrospectively registered on the 2020-07-09.

The significance of TNF-α and MMP-8 concentrations in non-invasively obtained amniotic fluid predicting fetal inflammatory response syndrome.

OBJECTIVE: To determine the significance of tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-8 (MMP-8) in vaginally obtained amniotic fluid predicting fetal inflammatory response syndrome (FIRS) after preterm premature rupture of membranes (PPROM). METHODS: In this prospective case-control study, TNF-α and MMP-8 concentrations were evaluated in vaginally obtained amniotic fluid from women with PPROM at 22-34 weeks of pregnancy. Biomarkers' concentrations were determined using an enzyme-linked immunosorbent assay. Patients were divided into two groups: the FIRS group (cord blood interleukin-6 > 11 pg/ml or histological funisitis) and the non-FIRS group (without these findings). The data were analyzed using R package (R-4.0.5). RESULTS: The median TNF-α and MMP-8 concentrations in amniotic fluid from the 145 women included in the study were higher in the FIRS group than in the non-FIRS group. The area under the curve of TNF-α and MMP-8 was 0.77 and 0.75, respectively. The TNF-α concentration cut-off predicting FIRS was 89.20 pg/ml and was 170.76 pg/ml for MMP-8. In regression analysis, MMP-8 concentration was an independent predictor for FIRS. An MMP-8 concentration greater than 170 ng/ml and a TNF-α concentration greater than 89 pg/ml increased the odds of FIRS 7.62 and 14.92 times, respectively. CONCLUSIONS: MMP-8 and TNF-α concentrations in vaginally obtained amniotic fluid may be good predictors for FIRS after PPROM before 34 weeks of pregnancy. The non-invasive amniotic fluid analysis could be an alternative method to invasive amniocentesis.