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Background: Previous study has indicated a potential link between gut microbiota and maternal pregnancy outcomes. However, the causal relationship between gut microbiota and premature rupture of membranes (PROM) remains a topic of ongoing debate. Methods: A two-sample Mendelian Randomization (MR) study was used to investigate the relationship between gut microbiota and PROM. Genetic data on gut microbiota was obtained from the MiBioGen consortium's largest genome-wide association study (GWAS) (n=14,306). Genetic data on PROM (3011 cases and 104247 controls) were sourced from publicly available GWAS data from the Finnish National Biobank FinnGen consortium. Various methods including Inverse variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode were utilized to assess the causal relationship by calculating the odd ratio (OR) value and confidence interval (CI). Sensitivity analyses for quality control were performed using MR-Egger intercept tests, Cochran's Q tests, and leave-one-out analyses. Results: The IVW method revealed that class Mollicutes (IVW, OR=0.773, 95%CI: 0.61-0.981, pval = 0.034), genus Marvinbryantia (IVW, OR=00.736, 95%CI: 0.555-0.977, pval = 0.034), genus Ruminooccaceae UCG003 (IVW, OR=0.734, 95%CI: 0.568-0.947, pval = 0.017) and phylum Tenericutes (IVW, OR=0.773, 95%CI: 0.566-1.067, pval = 0.034) were associated with a reduced risk of PROM, while genus Collinsella (IVW, OR=1.444, 95%CI: 1.028-2.026, pval = 0.034), genus Intestinibacter (IVW, OR=1.304, 95%CI: 1.047-1.623, pval = 0.018) and genus Turicibacter (IVW, OR=1.282, 95%CI: 1.02-1.611, pval = 0.033) increased the risk of PROM. Based on the other four supplementary methods, six gut microbiota may have a potential effect on PROM. Due to the presence of pleiotropy (pval=0.045), genus Lachnoclostridium should be ruled out. No evidence of horizontal pleiotropy or heterogeneity was found in other microbiota (pval >0.05). Conclusions: In this study, we have discovered a causal relationship between the presence of specific probiotics and pathogens in the host and the risk of PROM. The identification of specific gut microbiota associated with PROM through MR studies offers a novel approach to diagnosing and treating this condition, thereby providing a new strategy for clinically preventing PROM.

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Fetal inflammatory response syndrome or infection after preterm premature rupture of membranes (PPROM) increases neonatal morbidity in preterm deliveries. Biochemical markers from the amniotic fluid (AF) have been used to evaluate possible intra-amniotic infection during the asymptomatic phase after PPROM. This study aimed to describe whether soluble urokinase-type plasminogen activator receptor (suPAR) or procalcitonin (PCT) from AF or maternal sera could reveal fetal inflammatory response or infection after PPROM. AF and maternal serum samples were collected weekly after PPROM (23+ 0 - 34+ 6 gestational weeks) until delivery from twenty women and two women with possible chorioamnionitis with intact membranes. Levels of suPAR, PCT, interleukin-6 (IL-6), glucose, lactate dehydrogenase (LDH), and bacterial PCR were determined from AF and suPAR and PCT and IL-6 from maternal sera. Fetal infection or inflammation response were determined by the histology of the placenta after delivery. AF glucose was significantly lower and AF LDH higher in the fetal site histologic chorioamnionitis (HCA) group, while AF suPAR concentrations tended to be higher in this group. AF suPAR correlated significantly with AF glucose and LDH. Based on receiver operating characteristic (ROC) analysis, AF glucose had the best predictability for fetal site histological chorioamnionitis. The findings of AF PCT were insignificant considering HCA. AF glucose had the highest accuracy in predicting fetal site histologic chorioamnionitis. AF suPAR may be a promising marker; however, our findings were limited by a small study population.

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OBJECTIVE: To determine the value of the Aggregate index of systemic inflammation (AISI) in predicting admission to neonatal intensive care unit (NICU) and chorioamnionitis. METHODS: The present retrospective cohort study with pregnant women who were diagnosed with preterm premature rupture of membranes (PPROM) in the Department of Perinatology, Ministry of Health Ankara City Hospital between January 1, 2021, and June 1, 2023 (n = 357). The patients were categorized into subgroups: (1) cases with (n = 27) or without (n = 330) chorioamnionitis, (2) admission (n = 182) or no admission (n = 175) to NICU; (3) gestational age at birth <28 weeks or 28 weeks or longer; and (4) gestational age at birth <34 weeks or 34 weeks or longer. AISI values were compared between the subgroups, and cut-off values for AISI were determined to predict adverse outcomes. RESULTS: AISI values were significantly higher in the admission to NICU group compared with the no admission to NICU group (707.0 vs 551.2) (P < 0.05). AISI values were also significantly higher in the chorioamnionitis group compared with those without chorioamnionitis (850.3 vs 609.4) (P < 0.05). AISI levels were significantly higher in cases delivered before 28 weeks of gestation compared with the cases delivered at 28 weeks of gestation or later (945.6 vs 604.9) (P < 0.05), and were also significantly higher in cases delivered before 34 weeks of gestation compared with the cases delivered at 34 weeks of gestation or later (715.5 vs 550.1) (P < 0.05). Optimal cut-off values of AISI were found to be 626.19 (74.1% sensitivity, 52.8% specificity), 506.09 (68.9% sensitivity and, 47.7% specificity), and 555.1 (69.8% sensitivity, 48.1% specificity) in predicting NICU admission, chorioamnionitis, and delivery before 28 weeks, respectively. CONCLUSION: The novel inflammatory marker AISI may be used in the prediction of chorioamnionitis and NICU admission in PPROM cases. SYNOPSIS: Aggregate index of systemic inflammation may be used as a novel marker in predicting high-risk for chorioamnionitis and neonatal intensive care unit admission in women with preterm premature rupture of membranes.

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Background: Preterm premature rupture of membranes (PPROM) contributes to over one-third of preterm births, and PPROM infants are more susceptible to infections. However, the risk factors remain poorly understood. We here aim to investigate the association of duration of premature rupture of membranes (PROM) and environmental microbiota with the gut microbiota and infection in PPROM infants. Methods: Forty-six premature infants were recruited from two hospitals, and infant fecal and environmental samples were collected. 16 s rRNA sequencing was performed to analyze the fecal and environmental microbiome. Human inflammatory cytokines in cord vein plasma were measured. Results: The gut microbiota composition of PPROM infants was different from that of non-PPROM infants, and the microbiome phenotypes were predicted to be associated with a higher risk of infection, further evidenced by the significantly increased levels of IL-6 and IL-8 in cord vein plasma of PPROM infants. The diversity of the gut microbiota in PPROM infants increased significantly as the duration of PROM excessed 12 h, and Pseudomonas contributed significantly to the dynamic changes. The Pseudomonas species in the gut of PPROM infants were highly homologous to those detected in the ward environment, suggesting that prolonged PROM is associated with horizontal transmission of environmental pathogens, leading to a higher risk of infection. Conclusions: This study highlights that the duration of PROM is associated with the accumulation of environmental pathogens in the gut of PPROM infants, which is a risk factor for nosocomial infections. Improving environmental hygiene could be effective in optimizing the clinical care of PPROM infants.

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PROBLEM: To determine whether altered concentrations of various inflammation/immune-, acute phase-, extracellular matrix-, adhesion-, and serine protease-related proteins in the amniotic fluid (AF) are independently associated with microbial invasion of the amniotic cavity and/or intra-amniotic inflammation (MIAC/IAI), imminent spontaneous preterm delivery (SPTD; ≤7 days), and major neonatal morbidity/mortality (NMM) in women with early preterm prelabor rupture of membranes (PPROM). METHOD OF STUDY: This was a retrospective cohort study involving 111 singleton pregnant women with PPROM (24-31 weeks) undergoing amniocentesis to diagnose MIAC/IAI. The following proteins were measured in stored AF samples by enzyme-linked immunosorbent assay (ELISA): APRIL, DKK-3, Gal-3BP, IGFBP-2, IL-8, VDBP, lumican, MMP-2, MMP-8, SPARC, TGFBI, TGF-ß1, E-selectin, ICAM-5, P-selectin, haptoglobin, hepcidin, SAA1, kallistatin, and uPA. RESULTS: Multivariate logistic regression analyses revealed that (i) elevated APRIL, IL-8, MMP-8, and TGFBI levels in the AF, reduced lumican and SPARC levels in the AF, and high percentages of samples above the lower limit of quantification for AF TGF-ß1 and uPA were significantly associated with MIAC/IAI; (ii) elevated AF levels of IL-8 and MMP-8 were significantly associated with SPTD within 7 days; and (iii) elevated AF IL-6 levels were significantly associated with increased risk for major NMM, when adjusted for baseline covariates. CONCLUSION: ECM (lumican, SPRAC, TGFBI, and TGF-ß1)- and serine protease (uPA)-associated proteins in the AF are involved in the regulation of the host response to infection/inflammation in the amniotic cavity, whereas AF inflammation (IL-8, MMP-8, and IL-6)-associated mediators are implicated in the development of preterm parturition and major NMM in early PPROM.

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OBJECTIVE: This study aimed to assess whether a partial term prelabor rupture of membranes (partial TPROM) had an impact on the spontaneous onset of labor compared to complete TPROM. METHODS: We performed a retrospective study in a French level III maternity hospital. We included all singleton cephalic pregnancies presenting with prelabor rupture of membranes ≥37 weeks gestational age. Patients with a partial TPROM (P group) were compared to patients with a complete TPROM (C group). Induction of labor was performed following expectative management of 24-48 h, and antibiotic prophylaxis was started 12 h after rupture. Our main outcome measure was the rate of patients who had spontaneous labor 24 h following prelabor rupture. RESULTS: Overall, 389 women were included in the study, 148 in the P group, 241 in the C group. The proportion of women who went into spontaneous labor in the 24 h following TPROM was significantly lower in the P group (45% vs 64%, P < 0.001). A partial TPROM was a predictive factor for absence of labor at 24 h following rupture (adjusted odds ratio: 0.44 [0.29-0.68]). There were more cases of induction of labor (50% vs 20%, P < 0.001) and antibiotic prophylaxis (91% vs 73%, P < 0.001) in the P group. However, obstetrical and neonatal outcomes were comparable between the two groups. CONCLUSION: Compared to complete TPROM, partial TPROM is associated with a lower probability of spontaneous labor in the 24 h following rupture. The persistence of a residual membrane has been identified as a risk factor for delaying labor beyond 24 h.

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BACKGROUND: Most guidelines propose inducing labor within 24 h following term (37 or more weeks of gestation) prelabor rupture of membranes (PROM). However, the exact timing for initiating induction within the 24 h period remains unknown. This study aims to comparatively assess the efficacy and safety of the use of vaginal dinoprostone within 6 h versus within 6-24 h for singleton pregnancies with PROM and an unfavorable cervix (Bishop score < 6). METHODS: This was a retrospective cohort study including singleton pregnancies with PROM and an unfavorable cervix (Bishop score < 6) in which labor was induced using vaginal dinoprostone. Women were divided into two groups according to the timing of the use of induction (within 6 h versus within 6-24 h after PROM). Baseline maternal data, maternal and neonatal outcomes were recorded for statistical analysis. RESULTS: 450 women were included, 146 (32.4%) of whom were induced within 6 h of PROM and 304 (67.6%) were induced within 6-24 h. Cesarean delivery rate (15.8% versus 29.3%, p = 0.002) and nonreassuring fetal heart rate tracing (4.8% versus 10.5%, p = 0.043) in group with vaginal dinoprostone within 6 h were significantly lower than those in group with vaginal dinoprostone within 6-24 h. There was no significant differences in terms of duration from IOL to vaginal delivery. CONCLUSION: Induction of labor within 6 h with vaginal dinoprostone after PROM for singleton pregnancies with an unfavorable cervix (Bishop score < 6) significantly associated with less cesarean section, less nonreassuring fetal heart rate tracing, compared to induction of labor within 6-24 h after PROM.

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BACKGROUND: Our study aimed to investigate the value of inflammatory indices in predicting the latency period until birth in patients with preterm premature rupture of membranes (PPROM). METHODS: This retrospective study was conducted on PPROM cases between 24 and 34 weeks of gestation at Ankara Etlik City Hospital Perinatology Department from October 2023 to April 2024. A total of 146 participants were divided into two groups: Group 1 included 73 patients who gave birth within 72 hours (h) of PPROM diagnosis, and Group 2 included 73 patients who gave birth after 72 h. RESULTS: This study evaluated the prognostic significance of various inflammatory markers neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), systemic immune inflammation index (SII), systemic inflammatory response index (SIRI), pan-immune inflammation value (PIV), immature granulocytes (IG), multi-inflammatory index (MII)-1, MII-2, and MII-3 in predicting the latency period in patients with PPROM. Only MII-1, MII-2, and MII-3 reliably predicted labor within 72 h. The cut-off value for MII-1 was > 48.3, with a sensitivity of 57.7% and specificity of 57.3% (AUC: 0.598, 95% CI: 0.503-0.692, p = 0.042). For MII-2, the cut-off was > 1037.6, with a sensitivity of 57.7% and specificity of 57.3% (AUC: 0.611, 95% CI: 0.516-0.705, p = 0.021). MII-3 had a cut-off of > 10919.9, with a sensitivity of 53.5% and specificity of 52% (AUC: 0.595, 95% CI: 0.501-0.690, p = 0.046). CONCLUSION: Our findings show that, among NLR, PLR, MLR, SII, SIRI, PIV, IG, MII-1, MII-2, and MII-3, only MII-1, MII-2, and MII-3 levels are statistically significant in predicting birth timing.

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(1) Background: Preterm premature rupture of membranes (PPROM) has been associated with increased perinatal morbidity, but the effect of PPROM on respiratory disease has not been previously quantified. We hypothesised that PPROM would be associated with a higher incidence of invasive ventilation. (2) Methods: A retrospective cohort study at the Neonatal Unit at King's College Hospital NHS Foundation Trust, London, UK, was conducted on infants born before 37 weeks of gestation. PPROM was defined as the rupture of membranes for >48 h. (3) Results: We reviewed 1901 infants (434 with PPROM) with a median (IQR) gestational age of 32.4 (28.7-35.0) weeks. The median (IQR) duration of rupture of membranes in the infants with PPROM was 129 (78-293) h. The incidence of invasive ventilation was 56% in the infants with PPROM and 46% in the infants without PPROM (p < 0.001). Following regression analysis, PPROM was significantly related to a higher incidence of invasive ventilation (odds ratio: 1.48; 95% CI: 1.13-1.92, adjusted p = 0.004) after adjusting for birth weight [odds ratio = 0.34; 95% CI: 0.33-0.43, adjusted p < 0.001], Apgar score at 10 min [odds ratio =0.61; 95% CI: 0.56-0.66, adjusted p < 0.001] and antenatal corticosteroid use (adjusted p = 0.939). (4) Conclusions: PPROM was associated with a 1.48-fold higher risk of needing invasive ventilation.

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INTRODUCTION: Treatment of oligohydramnios in the mid-trimester is challenging, because of the high incidence of adverse perinatal outcomes mainly due to bronchopulmonary dysplasia. Antenatal amnioinfusion has been proposed as a possible treatment for oligohydramnios with intact amnions, but there are few relevant studies. This study aimed to evaluate the effectiveness of transabdominal amnioinfusion in the management of oligohydramnios without fetal lethal malformations in the second and early third trimesters. MATERIAL AND METHODS: It is a historical cohort study. A total of 79 patients diagnosed with oligohydramnios at 18-32 weeks gestation were enrolled. In the amnioinfusion group (n = 39), patients received transabdominal amnioinfusion with the assistance of real-time ultrasound guidance. In the expectant group (n = 41), patients were treated with 3000 mL of intravenous isotonic fluids daily. The perioperative complications and perinatal outcomes were analyzed. RESULTS: Compared with the expectant group, the delivery latency was significantly prolonged, and the rate of cesarean delivery was significantly reduced in the amnioinfusion group (p < 0.05). Although the rate of intrauterine fetal death was significantly reduced, the incidence of spontaneous miscarriage, premature rupture of membranes (PROMs), and threatened preterm labor were significantly higher in the amnioinfusion group than in the expectant group (p < 0.05). There was no significant difference in terms of perinatal mortality (28.9% vs. 41.4%, p > 0.05). Multivariate logistic regression revealed that amnioinfusion (odds ratio [OR] 0.162, 95% confidence interval [CI] 0.04-0.61, p = 0.008) and gestational age at diagnosis (OR 0.185, 95% CI 0.04-0.73, p = 0.016) were independently associated with neonatal adverse outcomes. Further subgrouping showed that amnioinfusion significantly reduced the frequency of bronchopulmonary hypoplasia for patients ≤26 weeks (26.7% vs. 75.0%, p = 0.021). The rates of other neonatal complications were similar in both groups. CONCLUSIONS: Amnioinfusion has no significant effect on improving the perinatal mortality of oligohydramnios in the second and early third trimesters. It may lead to a relatively high rate of PROM and spontaneous abortion. However, amnioinfusion may significantly improve the latency period, the rate of cesarean delivery, and neonatal outcomes of oligohydramnios, especially for women ≤26 weeks with high risk of neonatal bronchopulmonary hypoplasia.

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BACKGROUND: Seven days of antibiotics are recommended in the setting of preterm premature rupture of membranes to promote latency. Azithromycin has generally replaced a 7-day course of erythromycin in current clinical practice. Azithromycin clears from plasma quickly and concentrates in local tissue, which is why daily dosing is not always needed, and local tissue, rather than plasma, concentrations are used to determine dosing. On the basis of limited pharmacokinetic studies in pregnancy, a 1-time dose of 1 g azithromycin may not maintain local (amniotic fluid) drug concentrations above minimum inhibitory concentrations for common genitourinary pathogens (50-500 ng/mL). OBJECTIVE: We aimed to compare the pharmacokinetics of 1-time vs daily dosing of azithromycin in the setting of preterm prelabor rupture of membranes. STUDY DESIGN: This is a randomized clinical trial of singletons with preterm prelabor rupture of membranes randomized to 1 g oral azithromycin once or 500 mg oral azithromycin daily for 7 days. The primary outcome was amniotic fluid azithromycin concentrations over 8 days. Secondary outcomes included plasma azithromycin trough concentrations. Plasma was collected at 1-4 hours and 12-24 hours after the first dose and then every 24 hours through 8 days. Amniotic fluid was collected opportunistically throughout the day noninvasively with Always Flex foam pads. We aimed to enroll 20 participants to achieve n=5 still pregnant through 8 days in each group. Continuous variables were compared using the Mann-Whitney U test, and the relationship between azithromycin concentration and time was assessed using linear regression. RESULTS: The study was halted after 6 enrolled because of lagging enrollment, with 3 in each group. The mean gestational age of enrollment was 27.1±1.7 weeks in the 1 g group and 31.0±1.4 weeks in the 500 mg daily group. One participant in each group had latency to delivery >7 days. Regarding amniotic fluid azithromycin concentration, there was a difference in change in amniotic fluid azithromycin concentration over time between groups (P<.001). The amniotic fluid concentration of azithromycin was relatively stable in the 1 g once group (B,-0.07; 95% confidence interval, -0.44 to 0.31; P=.71), whereas amniotic fluid concentration (ng/mL) increased over time (hours) in the 500 mg daily group (B, 1.3; 95% confidence interval, 0.7-1.9; P<.001). By ≥96 hours, median amniotic fluid levels of azithromycin were lower in the 1 g once group (median, 11; interquartile, 7-56) compared with 500 mg daily (median, 46; interquartile, 23-196), with a median difference of -27 (interquartile,-154 to -1; P=.03). In plasma, there was higher azithromycin concentration during the first 24 hours with 1 g once vs 500 mg daily (median difference, 637 ng/mL; 101-1547; P=.01); however, by ≥96 hours plasma azithromycin declined and was virtually undetectable in the 1 g once group, whereas trough plasma levels in the 500 mg remained elevated (median difference -207 ng/mL; interquartile, -271 to -155; P=.03). CONCLUSION: Approximately 500 mg daily dosing of azithromycin maintains higher amniotic fluid concentrations and more consistently greater than common minimum inhibitory concentrations over 8 days compared with 1 g once in the setting of PPROM. El resumen está disponible en Español al final del artículo.

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Previable and periviable preterm prelabor rupture of membranes are challenging obstetrical complications to manage given the substantial risk of maternal morbidity and mortality, with no guarantee of fetal benefit. The following are the Society for Maternal-Fetal Medicine recommendations for the management of previable and periviable preterm prelabor rupture of membranes before the period when a trial of neonatal resuscitation and intensive care would be considered appropriate by the healthcare team and desired by the patient: (1) we recommend that pregnant patients with previable and periviable preterm prelabor rupture of membranes receive individualized counseling about the maternal and fetal risks and benefits of both abortion care and expectant management to guide an informed decision; all patients with previable and periviable preterm prelabor rupture of membranes should be offered abortion care, and expectant management can also be offered in the absence of contraindications (GRADE 1C); (2) we recommend antibiotics for pregnant individuals who choose expectant management after preterm prelabor rupture of membranes at ≥24 0/7 weeks of gestation (GRADE 1B); (3) antibiotics can be considered after preterm prelabor rupture of membranes at 20 0/7 to 23 6/7 weeks of gestation (GRADE 2C); (4) administration of antenatal corticosteroids and magnesium sulfate is not recommended until the time when a trial of neonatal resuscitation and intensive care would be considered appropriate by the healthcare team and desired by the patient (GRADE 1B); (5) serial amnioinfusions and amniopatch are considered investigational and should be used only in a clinical trial setting; they are not recommended for routine care of previable and periviable preterm prelabor rupture of membranes (GRADE 1B); (6) cerclage management after previable or periviable preterm prelabor rupture of membranes is similar to cerclage management after preterm prelabor rupture of membranes at later gestational ages; it is reasonable to either remove the cerclage or leave it in situ after discussing the risks and benefits and incorporating shared decision-making (GRADE 2C); and (7) in subsequent pregnancies after a history of previable or periviable preterm prelabor rupture of membranes, we recommend following guidelines for management of pregnant persons with a previous spontaneous preterm birth (GRADE 1C).

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INTRODUCTION: To compare neonatal, obstetrical, and maternal outcomes associated with outpatient versus inpatient management of pregnancies with preterm prelabor rupture of membranes (PPROM). MATERIAL AND METHODS: A search of MEDLINE, EMBASE, the Cochrane Database and Central Register from January 1, 1990 to July 31, 2023 identified randomized controlled trials (RCTs) and cohort studies comparing outpatient with inpatient management for pregnant persons diagnosed with PPROM before 37 weeks' gestation. No language restriction was applied. We applied a random effects model for meta-analysis. Trustworthiness was assessed using recently published guidance and Risk of bias using the RoB 2.0 tool for RCTs and ROBINS-I tool for cohort studies. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was used to assess the certainty of evidence (COE). Outcomes of interest included perinatal mortality, neonatal morbidities, latency and gestational age at delivery, and maternal morbidities. RCTs and cohort studies were analyzed separately. This study was registered in the International Prospective Register of Systematic Reviewsr: CRD42022295275. RESULTS: From 2825 records, two RCTs and 10 cohort studies involving 1876 patients were included in the review and meta-analysis. Outpatient management protocols varied but generally included brief initial hospitalization, strict eligibility criteria, and surveillance with laboratory and ultrasound investigations. Outpatient management showed lower rates of neonatal respiratory distress syndrome (cohort: RR 0.63 [0.52-0.77, very low COE]), longer latency to delivery (RCT: MD 7.43 days [1.14-13.72 days, moderate COE], cohort: MD 8.78 days [2.29-15.26 days, low COE]), higher gestational age at birth (cohort: MD 7.70 days [2.02-13.38 days, low COE]), lower rates of Apgar scores <7 at 5 min of life (cohort: RR 0.66 [0.50-0.89, very low COE]), and lower rates of histological chorioamnionitis (cohort: RR 0.74 [0.62-0.89, low COE]) without increased risks of adverse neonatal, obstetrical, or maternal outcomes. CONCLUSIONS: Meta-analysis of data from RCTs and cohort studies with very low-to-moderate certainty of evidence indicates that further high-quality research is needed to evaluate the safety and potential benefits of outpatient management for selected PPROM cases, given the moderate-to-high risk of bias in the included studies.

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Vitamin C is a micronutrient assumed to have effects on the occurrence of "preterm premature rupture of membranes" (PPROM) and "premature rupture of membranes" (PROM). The objective of this review was to find the pooled incidence of PROM and/or PPROM between subgroups in relation to dose, mode of therapy (monotherapy vs. combination therapy) and history of PROM/PPROM in previous pregnancies. A search was conducted in the electronic databases (PubMed, Google Scholar, Scopus) from inception to November 2022, using the search terms "Vitamin C", "Ascorbic acid", "preterm premature rupture of membrane" and "premature rupture of membrane". The lists of references of all the selected eligible articles were also searched to find studies of interest. A total of nine randomized controlled trials (published in English) with 16,076 participants involving the supplementation of vitamin C during pregnancy were picked up for analysis. Data management was done using the Review Manager (RevMan 5.3). A statistical test for publication bias was done in jamovi, version 2.3.18. In comparison to placebo, vitamin C supplementation was not found to be significantly effective in preventing the occurrence of PPROM/PROM. However, a low dose of vitamin C and the monotherapy mode of administration significantly decreased the occurrence of PPROM/PROM. Vitamin C has significant beneficial effects in women with a history of PROM in a previous pregnancy. Hence, we conclude that vitamin C administered as monotherapy in low doses (preferably 100 mg/day) has definite benefits in preventing the occurrence of PROM/PPROM with greater advantages seen in those with a history of similar complications in a previous pregnancy.

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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.

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BACKGROUND: Intrapartum fever (>38°C) is associated with adverse maternal and neonatal outcomes. However, the correlation between low-grade fever (37.5°C-37.9°C) and adverse perinatal outcomes remains controversial. OBJECTIVE: This study aimed to compare maternal and neonatal outcomes of women with prolonged rupture of membranes (≥12 hours) at term between those with low-grade fever and those with normal body temperature. STUDY DESIGN: This retrospective study included women hospitalized in a tertiary university-affiliated hospital between July 2021 and May 2023 with singleton term and rupture of membranes ≥12 hours. Women were classified as having intrapartum low-grade fever (37.5°C-37.9°C) or normal body temperature (<37.5°C). The co-primary outcomes, postpartum endometritis and neonatal intensive care unit admission rates, were compared between these groups. The secondary maternal outcomes were intrapartum leukocytosis (>15,000/mm2), cesarean delivery rate, postpartum hemorrhage, postpartum fever, surgical site infection, and postpartum length of stay. The secondary neonatal outcomes were early-onset sepsis, 5-minute Apgar score of <7, umbilical artery cord pH<7.2 and pH<7.05, neonatal intensive care unit admission length of stay, and respiratory distress. The data were analyzed according to rupture of membranes 12 to 18 hours and rupture of membranes ≥18 hours. In women with rupture of membranes ≥18 hours, intrapartum ampicillin was administered, and chorioamniotic membrane swabs were obtained. The likelihood ratios and 95% confidence intervals were calculated for the co-primary outcomes. A multivariate logistic regression model was used to predict puerperal endometritis controlled for rupture of membranes duration, low-grade fever (compared with normal body temperature), positive group B streptococcus status, mechanical cervical ripening, cervical ripening by prostaglandins, artificial rupture of membranes, meconium staining, epidural analgesia, and cesarean delivery. A multivariate logistic regression model was used to predict neonatal intensive care unit admission controlled for rupture of membranes duration, low-grade fever, positive group B streptococcus status, mechanical cervical ripening, artificial rupture of membranes, meconium staining, cesarean delivery, and neonatal weight of <2500 g. RESULTS: This study included 687 women with rupture of membranes 12 to 18 hours and 1109 with rupture of membranes ≥18 hours. In both latency groups, the rates were higher for cesarean delivery, endometritis, surgical site infections, umbilical cord pH<7.2, neonatal intensive care unit admission, and sepsis workup among those with low-grade fever than among those with normal body temperature. Among women with low-grade fever, the positive likelihood ratios were 12.7 (95% confidence interval, 9.6-16.8) for puerperal endometritis and 3.2 (95% confidence interval, 2.0-5.3) for neonatal intensive care unit admission. Among women with rupture of membranes ≥18 hours, the rates were higher of Enterobacteriaceae isolates in chorioamniotic membrane cultures for those with low-grade fever than for those with normal intrapartum temperature (22.0% vs 11.0%, respectively; P=.006). Low-grade fever (odds ratio, 9.0; 95% confidence interval, 3.7-21.9; P<.001), artificial rupture of membranes (odds ratio, 4.2; 95% confidence interval, 1.5-11.7; P=.007), and cesarean delivery (odds ratio, 5.4; 95% confidence interval, 2.2-13.4; P<.001) were independently associated with puerperal endometritis. Low-grade fever (odds ratio, 3.2; 95% confidence interval, 1.7-6.0; P<.001) and cesarean delivery (odds ratio, 1.9; 95% confidence interval, 1.1-13.1; P=.023) were independently associated with neonatal intensive care unit admission. CONCLUSION: In women with rupture of membranes ≥12 hours at term, higher maternal and neonatal morbidities were reported among those with low-grade fever than among those with normal body temperature. Low-grade fever was associated with a higher risk of Enterobacteriaceae isolates in chorioamniotic membrane cultures. Moreover, low-grade fever may be the initial presentation of peripartum infection.

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OBJECTIVES: To systematically review randomized controlled trials (RCTs) and perform a meta-analysis comparing early amniotomy with delayed amniotomy in individuals undergoing pre-induction cervical ripening by Foley balloon. The primary outcome was the rate of cesarean delivery. Understanding the impact of the timing of amniotomy on the rate of cesarean delivery is crucial for obstetricians and healthcare providers when making decisions about the management of labor induction. DATA SOURCES: Data were sourced from electronic databases, including PubMed, OVID, Cochrane Library, Web of Science, and ClinicalTrials.gov through February 2024. The review adhered to Preferred Reporting Item for Systematic Reviews guidelines and registered with PROSPERO (ID CRD42023454520). STUDY ELIGIBILITY CRITERIA: Inclusion criteria comprised RCTs comparing early amniotomy with delayed amniotomy in individuals undergoing cervical ripening by Foley balloon. Early amniotomy was defined as amniotomy soon after cervical ripening. Delayed amniotomy was defined as withholding amniotomy until after the onset of the active phase of labor, until at least 4 hours from either initiation of oxytocin or Foley balloon removal/expulsion, or until achieving >4 cm of dilation. Participants included nulliparous or multiparous individuals with singleton pregnancies undergoing labor induction at 37 weeks or later. STUDY APPRAISAL AND SYNTHESIS: A systematic literature search was conducted using defined search terms including "early amniotomy," "delayed amniotomy," "induction of labor," "cervical ripening," and "Foley balloon," and "Foley catheter." The quality of the included trials was assessed using the Cochrane Risk of Bias Tool for randomized controlled trials. The primary outcome was cesarean delivery. Secondary outcomes included outcomes related to labor duration and neonatal outcomes. Pooled relative risks (RR) and weighted mean differences (WMD) with 95% confidence intervals were calculated. RESULTS: Five trials involving 849 participants undergoing induction and cervical ripening by Foley balloon were included. The rate of cesarean delivery did not differ between individuals randomly assigned to the early amniotomy group compared with those assigned to the delayed amniotomy group (22.9% vs. 23.3%; RR 1.00; 95% CI 0.65-1.55). Early amniotomy compared to delayed amniotomy was associated with a higher proportion of delivery within 24 hours (79.9% vs. 67.1%; RR 1.19; 95% CI 1.04-1.36). Early amniotomy compared with delayed amniotomy was associated with a shorter interval from oxytocin to delivery (WMD -1.5 hours; 95% CI -2.1 to -0.8), from Foley expulsion to vaginal delivery (WMD -2.5 hours; 95% CI -4.8 to -0.1), and from the start of oxytocin to vaginal delivery (WMD -1.8 hours; 95% CI -3.2 to -0.4). Other outcomes were not significantly different. CONCLUSION: Early amniotomy following cervical ripening by Foley balloon in individuals with singleton pregnancies did not impact rates of cesarean delivery compared with delayed amniotomy but led to shorter duration for various labor progress outcomes.

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BACKGROUND: Induction of labor (IOL) is recommended following prelabor rupture of membranes (PROM). The optimal method for IOL and need for cervical ripening in those with PROM and an unfavorable cervical examination is unclear. OBJECTIVE: To determine if oxytocin or oral misoprostol results in a shorter time to delivery among nulliparous patients with an unfavorable cervical examination and PROM diagnosis and to evaluate patient satisfaction with both methods. STUDY DESIGN: This is a randomized clinical trial conducted at an urban tertiary care center from 2019 to 2023. Subjects were nulliparas ≥36 weeks with an unfavorable starting cervical exam (≤2 cm and Bishop <8). The primary outcome was time from IOL to delivery in hours compared between oxytocin vs oral misoprostol. Secondary outcomes included suspected intraamniotic infection, cesarean delivery, composite maternal and neonatal morbidity, and patient satisfaction (assessed by Birth Satisfaction Scale-Revised). Sub-group analyses for those with BMI ≥ 30 kg/m2 and cervical dilation ≥1 cm were performed. We required 148 subjects to have 80% power to detect a 2-hour difference in time to delivery. The study was stopped early by the data safety monitoring board due to feasibility concerns in recruiting desired sample size. RESULTS: A total of 108 subjects were randomized: 56 oxytocin; 52 oral miso. The median gestational age at induction was 39.5 weeks; the mean starting cervical dilation was 1.1 cm. There was no statistical difference in time to delivery between groups overall: 14.9 hours oxytocin vs 18.1 hours oral misoprostol (P=.06). In sub-group analyses, there was a 5 hours shorter time to delivery with oxytocin for those with a BMI ≥ 30 kg/m2 (16.6 hours oxytocin vs 21.8 hours oral misoprostol, P .04) and 4.5 hours shorter time to delivery with oxytocin for those with cervix ≥1 cm (12.9 hours oxytocin vs 17.3 hours oral misoprostol, P .04). There were no differences in intraamniotic infection, cesarean delivery, maternal or neonatal morbidity between the groups. Patient satisfaction was higher for those receiving oxytocin compared to misoprostol (29.0 vs 26.3, P=.03). CONCLUSION: Among nulliparas with PROM and an unfavorable cervix, there was no difference in overall time to delivery between oxytocin and oral misoprostol. This result should be interpreted with caution given early study discontinuation and inadequate power. However, a shorter time to delivery with oxytocin was noted in obese patients and those with cervical dilation of at least 1 cm. Furthermore, patient satisfaction was higher in the oxytocin group, and there was no increased risk of neonatal or maternal morbidity with oxytocin.

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Introduction: Rupture of the gestational membranes often precedes major pregnancy complications, including preterm labor and preterm birth. One major cause of inflammation in the gestational membranes, chorioamnionitis (CAM) is often a result of bacterial infection. The commensal bacterium Streptococcus agalactiae, or Group B Streptococcus (GBS) is a leading infectious cause of CAM. Obesity is on the rise worldwide and roughly 1 in 4 pregnancy complications is related to obesity, and individuals with obesity are also more likely to be colonized by GBS. The gestational membranes are comprised of several distinct cell layers which are, from outermost to innermost: maternally-derived decidual stromal cells (DSCs), fetal cytotrophoblasts (CTBs), fetal mesenchymal cells, and fetal amnion epithelial cells (AECs). In addition, the gestational membranes have several immune cell populations; macrophages are the most common phagocyte. Here we characterize the effects of palmitate, the most common long-chain saturated fatty acid, on the inflammatory response of each layer of the gestational membranes when infected with GBS, using human cell lines and primary human tissue. Results: Palmitate itself slightly but significantly augments GBS proliferation. Palmitate and GBS co-stimulation synergized to induce many inflammatory proteins and cytokines, particularly IL-1ß and matrix metalloproteinase 9 from DSCs, CTBs, and macrophages, but not from AECs. Many of these findings are recapitulated when treating cells with palmitate and a TLR2 or TLR4 agonist, suggesting broad applicability of palmitate-pathogen synergy. Co-culture of macrophages with DSCs or CTBs, upon co-stimulation with GBS and palmitate, resulted in increased inflammatory responses, contrary to previous work in the absence of palmitate. In whole gestational membrane biopsies, the amnion layer appeared to dampen immune responses from the DSC and CTB layers (the choriodecidua) to GBS and palmitate co-stimulation. Addition of the monounsaturated fatty acid oleate, the most abundant monounsaturated fatty acid in circulation, dampened the proinflammatory effect of palmitate. Discussion: These studies reveal a complex interplay between the immunological response of the distinct layers of the gestational membrane to GBS infection and that such responses can be altered by exposure to long-chain saturated fatty acids. These data provide insight into how metabolic syndromes such as obesity might contribute to an increased risk for GBS disease during pregnancy.

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INTRODUCTION: The optimal protocol for serial amnioinfusions to maintain amniotic fluid in pregnancies with early-onset fetal renal anhydramnios before 22 weeks is not known. We compared the performance of two different approaches. METHODS: A secondary analysis was conducted of serial amnioinfusions performed by a single center during the external pilot and feasibility phases of the Renal Anhydramnios Fetal Therapy (RAFT) trial. During the external pilot, higher amnioinfusion volumes were given less frequently; in the feasibility study, smaller volume amnioinfusions were administered more frequently. Procedural details, complications, and obstetric outcomes were compared between the two groups using Pearson's χ2 or Fisher's exact tests for categorical variables and Student's t tests or Wilcoxon rank-sum tests for continuous variables. The adjusted association between procedural details and chorioamniotic separation was obtained through a multivariate repeated measure logistic regression model. RESULTS: Eleven participants underwent 159 amnioinfusions (external pilot: 3 patients, 21 amnioinfusions; feasibility: 8 patients, 138 amnioinfusions). External pilot participants had fewer amnioinfusions (7 vs. 19.5 in the feasibility group, p = 0.04), larger amnioinfusion volume (750 vs. 500 mL, p < 0.01), and longer interval between amnioinfusions (6 [4-7] vs. 4 [3-5] days, p < 0.01). In the external pilot, chorioamniotic separation was more common (28.6% vs. 5.8%, p < 0.01), preterm prelabor rupture of membranes (PPROM) occurred sooner after amnioinfusion initiation (28 ± 21.5 vs. 75.6 ± 24.1 days, p = 0.03), and duration of maintained amniotic fluid between first and last amnioinfusion was shorter (38 ± 17.3 vs. 71 ± 19 days, p = 0.03), compared to the feasibility group. While delivery gestational age was similar (35.1 ± 1.7 vs. 33.8 ± 1.5 weeks, p = 0.21), feasibility participants maintained amniotic fluid longer. CONCLUSION: Small volume serial amnioinfusions performed more frequently maintain normal amniotic fluid volume longer because of delayed occurrence of PPROM.