Azithromycin Dosing and Preterm premature rupture of membranes Treatment (ADAPT): A randomized controlled Phase I trial.

BACKGROUND: Seven days of antibiotics are recommended in the setting of preterm premature rupture of membranes (PPROM) to promote latency. Azithromycin has generally replaced a seven-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. Based on limited pharmacokinetic studies in pregnancy, 1g one time dose of azithromycin may not maintain local (amniotic fluid) drug concentrations above minimum inhibitory concentrations (MIC50) for common genitourinary pathogens (50-500ng/ml). OBJECTIVE: We aim to compare the pharmacokinetics of one-time vs daily dosing of azithromycin in the setting of preterm pre-labor rupture of membranes (PPROM) STUDY DESIGN: This is a randomized clinical trial of singletons with PPROM randomized to 1gram oral azithromycin once or 500mg oral azithromycin daily x7 days. Primary outcome was amniotic fluid azithromycin concentrations over 8 days. Secondary outcomes included plasma azithromycin trough concentrations. Plasma was collected at time points 1-4hrs and 12-24hrs after first dose, and then every 24hrs 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 compared with Mann Whitney U test and relationship between azithromycin concentration and time assessed with linear regression. RESULTS: The study was halted after N=6 enrolled due to lagging enrollment, with 3 in each group. The mean gestational age of enrollment was 27.1±1.7weeks in the 1g group and 31.0±1.4 weeks in the 500mg daily group. One participant in each group had latency to delivery >7days. Regarding amniotic fluid azithromycin concentration, there was a difference in change in amniotic fluid azithromycin concentration over time between groups (p<0.001). Amniotic fluid concentration of azithromycin was relatively stable in the 1g once group (B=-0.07 (-0.44 - 0.31), p=0.71), in contrast, amniotic fluid concentration (ng/ml) increased over time (hours) in the 500mg daily group (B=1.3 (0.7 - 1.9), p<0.001). By ≥96hours median amniotic fluid levels of azithromycin were lower in the 1g once dosing group (median 11[7-56]) compared to 500mg daily (median 46 [23-196]), with a median difference -27 (-154 to -1), p=0.03. In plasma, there was higher azithromycin concentration during the first 24hrs with 1g once vs 500mg daily (median difference 637ng/ml (101-1547), p=0.01), however by ≥96hrs plasma azithromycin declined and was virtually undetectable in the 1g once group, while trough plasma levels in the 500mg remained elevated (median difference -207ng/ml (-271 to -155), p=0.03). CONCLUSION: 500mg daily dosing of azithromycin maintains higher amniotic fluid concentrations, and more consistently greater than common MICs, over eight days compared to 1g once in the setting of PPROM.

A comparison of Mersilene tape versus braided suture in transvaginal cervical cerclage: A retrospective case-control study.

OBJECTIVE: Previous studies have indicated that there is an association between cervical cerclage and type of suture material. However, it is still unclear which suture material can provide the greatest benefit to patients who have undergone cerclage. This study investigated the effect of two different suture materials (Mersilene tape vs braided suture) used for transvaginal cervical cerclage placement on maternal outcomes of women with cervical insufficiency. METHODS: In this retrospective case-control study, 170 women who underwent history-, ultrasound-, or physical examination-indicated transvaginal cervical cerclage were categorized according to suture materials used for cerclage: a total of 96 received Mersilene tape and 74 received braided suture. Study participants received a transvaginal cervical cerclage before 28 weeks and were followed up until delivery to assess pregnancy and neonatal outcomes. The primary outcome was gestational age at delivery. Secondary outcomes included preterm premature rupture of membranes (PPROM), premature rupture of membranes (PROM), chorioamnionitis, neonatal survival rate, and neonatal morbidity. RESULTS: Out of 170 eligible women, 74 (43.5%) received braided suture while 96 (56.5%) received Mersilene tape. Baseline characteristics were similar between the two groups. The group that received braided suture had a lower incidence of gestational age at delivery <37 weeks (29.2% vs 54.2%, P = 0.046), PPROM (9.5% vs 21.9%, P = 0.029) and PROM (17.6% vs 32.3%, P = 0.028) compared to the group that received Mersilene tape. However, there were no significant differences between the two groups in average gestational age at delivery, the rate of gestational age at delivery <24, <28, <32, and < 34 weeks, chorioamnionitis, and neonatal survival rate, as well as neonatal morbidity. CONCLUSION: Compared to Mersilene tape, the utilization of braided suture has been significantly associated with a reduction in the incidence of gestational age at delivery <37 weeks, as well as a decreased risk of PPROM and PROM. However, the use of braided sutures did not result in discernible differences in the rates of chorioamnionitis or adverse neonatal outcomes.

[Impact of the mode of follow-up of preterm premature rupture of membranes before 36 weeks of gestation on the latency period]. / Impact du mode de suivi des ruptures prématurées des membranes avant 36 SA sur la durée de latence.

INTRODUCTION: Preterm premature rupture of membranes (PPROM) is the main cause of premature delivery, complicating 1-3% of all pregnancies. Conventional hospitalization (CH) is the most frequent mode of follow-up, but homecare (HC) seems to be an alternative. OBJECTIVES: Study of the impact of the monitoring mode on the duration of the latency period and on the latency ratio after PPROM, and analysis of the risk factors modifying this ratio. METHODS: This was a bicentric retrospective cohort study here-abouts including patients who presented a PPROM between 24 and 36weeks of gestation from 2016 to 2018. Patients had a follow-up in HC at Lille University Hospital center (UHC) and in CH at Nantes UHC according to two different follow-up protocols. The latency ratio corresponded to the real latency period divided by the latency period to theoretical term. RESULTS: We included 154 patients: 102 in HC and 52 in CH. The mean latency period was significantly higher in HC: 36.9±21.8 days, corresponding to an 85.5±23.7% latency ratio versus 20.2±12 days, corresponding to an 66.9±29.8% latency ratio in CH (P<0.001). The latency ratio in CH was correlated with term at PPROM (P=0.001). CONCLUSIONS: The duration of the latency period seems prolonged for PPROM followed by HC management versus CH in selected populations. This study suggests a benefit to HC in stable patients.

Outcome of prelabor rupture of membranes before or at the limit of viability: systematic review and meta-analysis.

OBJECTIVE: Counseling of pregnancies complicated by pre- and periviable premature rupture of membranes to reach shared decision-making is challenging, and the current limited evidence hampers the robustness of the information provided. This study aimed to elucidate the rate of obstetrical and neonatal outcomes after expectant management for premature rupture of membranes occurring before or at the limit of viability. DATA SOURCES: Medline, Embase, CINAHL, and Web of Science databases were searched electronically up to September 2023. STUDY ELIGIBILITY CRITERIA: Our study included both prospective and retrospective studies of singleton pregnancies with premature rupture of membranes before and at the limit of viability (ie, occurring between 14 0/7 and 24 6/7 weeks of gestation). METHODS: Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale for cohort studies. Moreover, our study used meta-analyses of proportions to combine data and reported pooled proportions. Given the clinical heterogeneity, a random-effects model was used to compute the pooled data analyses. This study was registered with the International Prospective Register of Systematic Reviews database (registration number: CRD42022368029). RESULTS: The pooled proportion of termination of pregnancy was 32.3%. After the exclusion of cases of termination of pregnancy, the rate of spontaneous miscarriage or fetal demise was 20.1%, whereas the rate of live birth was 65.9%. The mean gestational age at delivery among the live-born cases was 27.3 weeks, and the mean latency between premature rupture of membranes and delivery was 39.4 days. The pooled proportion of cesarean deliveries was 47.9% of the live-born cases. Oligohydramnios occurred in 47.1% of cases. Chorioamnionitis occurred in 33.4% of cases, endometritis in 7.0%, placental abruption in 9.2%, and postpartum hemorrhage in 5.3%. Hysterectomy was necessary in 1.2% of cases. Maternal sepsis occurred in 1.5% of cases, whereas no maternal death was reported in the included studies. When focusing on neonatal outcomes, the mean birthweight was 1022.8 g in live-born cases. The neonatal intensive care unit admission rate was 86.3%, respiratory distress syndrome was diagnosed in 66.5% of cases, pulmonary hypoplasia or dysplasia was diagnosed in 24.0% of cases, and persistent pulmonary hypertension was diagnosed in 40.9% of cases. Of the surviving neonates, the other neonatal complications included necrotizing enterocolitis in 11.1%, retinopathy of prematurity in 27.1%, and intraventricular hemorrhage in 17.5%. Neonatal sepsis occurred in 30.2% of cases, and the overall neonatal mortality was 23.9%. The long-term follow-up at 2 to 4 years was normal in 74.1% of the available cases. CONCLUSION: Premature rupture of membranes before or at the limit of viability was associated with a great burden of both obstetrical and neonatal complications, with an impaired long-term follow-up at 2 to 4 years in almost 30% of cases, representing a clinical challenge for both counseling and management. Our data are useful when initially approaching such patients to offer the most comprehensive possible scenario on short- and long-term outcomes of this condition and to help parents in shared decision-making. El resumen está disponible en Español al final del artículo.

Evidence of brain injury in fetuses of mothers with preterm labor with intact membranes and preterm premature rupture of membranes.

BACKGROUND: Brain injury and poor neurodevelopment have been consistently reported in infants and adults born before term. These changes occur, at least in part, prenatally and are associated with intra-amniotic inflammation. The pattern of brain changes has been partially documented by magnetic resonance imaging but not by neurosonography along with amniotic fluid brain injury biomarkers. OBJECTIVE: This study aimed to evaluate the prenatal features of brain remodeling and injury in fetuses from patients with preterm labor with intact membranes or preterm premature rupture of membranes and to investigate the potential influence of intra-amniotic inflammation as a risk mediator. STUDY DESIGN: In this prospective cohort study, fetal brain remodeling and injury were evaluated using neurosonography and amniocentesis in singleton pregnant patients with preterm labor with intact membranes or preterm premature rupture of membranes between 24.0 and 34.0 weeks of gestation, with (n=41) and without (n=54) intra-amniotic inflammation. The controls for neurosonography were outpatient pregnant patients without preterm labor or preterm premature rupture of membranes matched 2:1 by gestational age at ultrasound. Amniotic fluid controls were patients with an amniocentesis performed for indications other than preterm labor or preterm premature rupture of membranes without brain or genetic defects whose amniotic fluid was collected in our biobank for research purposes matched by gestational age at amniocentesis. The group with intra-amniotic inflammation included those with intra-amniotic infection (microbial invasion of the amniotic cavity and intra-amniotic inflammation) and those with sterile inflammation. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture and/or positive 16S ribosomal RNA gene. Inflammation was defined by amniotic fluid interleukin 6 concentrations of >13.4 ng/mL in preterm labor and >1.43 ng/mL in preterm premature rupture of membranes. Neurosonography included the evaluation of brain structure biometric parameters and cortical development. Neuron-specific enolase, protein S100B, and glial fibrillary acidic protein were selected as amniotic fluid brain injury biomarkers. Data were adjusted for cephalic biometrics, fetal growth percentile, fetal sex, noncephalic presentation, and preterm premature rupture of membranes at admission. RESULTS: Fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes showed signs of brain remodeling and injury. First, they had a smaller cerebellum. Thus, in the intra-amniotic inflammation, non-intra-amniotic inflammation, and control groups, the transcerebellar diameter measurements were 32.7 mm (interquartile range, 29.8-37.6), 35.3 mm (interquartile range, 31.2-39.6), and 35.0 mm (interquartile range, 31.3-38.3), respectively (P=.019), and the vermian height measurements were 16.9 mm (interquartile range, 15.5-19.6), 17.2 mm (interquartile range, 16.0-18.9), and 17.1 mm (interquartile range, 15.7-19.0), respectively (P=.041). Second, they presented a lower corpus callosum area (0.72 mm2 [interquartile range, 0.59-0.81], 0.71 mm2 [interquartile range, 0.63-0.82], and 0.78 mm2 [interquartile range, 0.71-0.91], respectively; P=.006). Third, they showed delayed cortical maturation (the Sylvian fissure depth-to-biparietal diameter ratios were 0.14 [interquartile range, 0.12-0.16], 0.14 [interquartile range, 0.13-0.16], and 0.16 [interquartile range, 0.15-0.17], respectively [P<.001], and the right parieto-occipital sulci depth ratios were 0.09 [interquartile range, 0.07-0.12], 0.11 [interquartile range, 0.09-0.14], and 0.11 [interquartile range, 0.09-0.14], respectively [P=.012]). Finally, regarding amniotic fluid brain injury biomarkers, fetuses from mothers with preterm labor with intact membranes or preterm premature rupture of membranes had higher concentrations of neuron-specific enolase (11,804.6 pg/mL [interquartile range, 6213.4-21,098.8], 8397.7 pg/mL [interquartile range, 3682.1-17,398.3], and 2393.7 pg/mL [interquartile range, 1717.1-3209.3], respectively; P<.001), protein S100B (2030.6 pg/mL [interquartile range, 993.0-4883.5], 1070.3 pg/mL [interquartile range, 365.1-1463.2], and 74.8 pg/mL [interquartile range, 44.7-93.7], respectively; P<.001), and glial fibrillary acidic protein (1.01 ng/mL [interquartile range, 0.54-3.88], 0.965 ng/mL [interquartile range, 0.59-2.07], and 0.24 mg/mL [interquartile range, 0.20-0.28], respectively; P=.002). CONCLUSION: Fetuses with preterm labor with intact membranes or preterm premature rupture of membranes had prenatal signs of brain remodeling and injury at the time of clinical presentation. These changes were more pronounced in fetuses with intra-amniotic inflammation.

Role of NF-κB p65/TNF-α in Cell Apoptosis in the Fetal Membranes of Pregnant Women with Preterm Premature Rupture of Membranes.

OBJECTIVE: This study aimed to investigate the roles of nuclear factor-kappa B p65 (NF-[Formula: see text]B p65) and tumor necrosis factor-α (TNF-α) in cell apoptosis occurring in the fetal membranes of pregnant women who experience preterm premature rupture of membranes (PPROM). METHODS: This was a case-control study involving 57 pregnant women who delivered in the obstetric department of Affiliated Loudi Hospital, Hengyang Medical School, University of South China, from June 2021 to June 2022. Samples of fetal membrane tissue were collected from pregnant women with PPROM (n=27) and pregnant women who had normal deliveries (control group; n=30). The membrane tissue morphology of both groups was observed, and the expression of NF-[Formula: see text]B p65, p-NF-[Formula: see text]B p65, TNF-α, and caspase-3 was detected. Apoptosis in fetal membranes was examined. RESULTS: Morphological evaluation of the fetal membrane tissues obtained from patients with PPROM revealed an abnormal structure with a thin collagen fiber layer and cells with a largely vacuolar cytoplasm. There was a positive correlation between the expression of p-NF-[Formula: see text]B p65/NF-[Formula: see text]B p65 and cell apoptosis (r1 =0.89, R2 =0.805, P=0.00). Furthermore, TNF-α was positively correlated with fetal membrane cell apoptosis (r2 =0.93, R2=0.881, P=0.00). CONCLUSION: NF-[Formula: see text]B p65 is involved in the occurrence of PPROM by promoting the expression of TNF-α, which upregulates caspase-3 to cause apoptosis of fetal membrane cells.

Rescue Cerclage by McDonald's Technique at 18 Weeks for Cervical Insufficiency With Intravaginal Amniotic Sac: A Case Report.

Recurrent pregnancy loss, premature birth, and associated complications exhibit a multifactorial etiology and persist as substantial challenges during pregnancy, despite the notable advancements in the medical field. Among several factors, cervical insufficiency or incompetence emerges as a prominent causal factor, characterized by painless softening and shortening of the cervix associated with absent contractions. The implementation of emergency cerclage represents a pivotal intervention in mitigating preterm birth among individuals with advanced cervical insufficiency. By extending gestational age, this procedure increases the likelihood of neonatal survival without elevating the risk of chorioamnionitis or preterm rupture of the membranes. In this study, an antenatal woman presented with advanced changes in the cervix along with intravaginal bulging amniotic membranes at 18 weeks and underwent a rescue cervical cerclage, resulting in a successful pregnancy.

Prenatal exposure to intra-amniotic infection with Ureaplasma species increases the prevalence of bronchopulmonary dysplasia.

OBJECTIVES: The present study investigated the relationship between bronchopulmonary dysplasia (BPD) and intra-amniotic infection with Ureaplasma species. METHODS: This was a single-center, retrospective cohort study. Patients with singleton pregnancies who underwent inpatient management at our department for preterm premature rupture of membranes (PPROM), preterm labor, cervical insufficiency, and asymptomatic cervical shortening at 22-33 gestational weeks were included. Amniocentesis was indicated for patients with PPROM or an elevated maternal C-reactive protein level (≥0.58 mg/dL). Patients with an amniotic fluid IL-6 concentration ≥3.0 ng/mL were diagnosed with intra-amniotic inflammation, while those with positive aerobic, anaerobic, M. hominis, and Ureaplasma spp. cultures were diagnosed with microbial invasion of the amniotic cavity (MIAC). Patients who tested positive for both intra-amniotic inflammation and MIAC were considered to have intra-amniotic infection. An umbilical vein blood IL-6 concentration >11.0 pg/mL indicated fetal inflammatory response syndrome (FIRS). The maternal inflammatory response (MIR) and fetal inflammatory response (FIR) were staged using the Amsterdam Placental Workshop Group Consensus Statement. RESULTS: Intra-amniotic infection with Ureaplasma spp. was diagnosed in 37 patients, intra-amniotic infection without Ureaplasma spp. in 28, intra-amniotic inflammation without MIAC in 58, and preterm birth without MIR/FIR and FIRS in 86 as controls. Following an adjustment for gestational age at birth, the risk of BPD was increased in patients with intra-amniotic infection with Ureaplasma spp. (adjusted odds ratio: 10.5; 95% confidence interval: 1.55-71.2), but not in those with intra-amniotic infection without Ureaplasma spp. or intra-amniotic inflammation without MIAC. CONCLUSION: BPD was only associated with intra-amniotic infection with Ureaplasma species.

Autophagy Determines Distinct Cell Fates in Human Amnion and Chorion Cells.

Human fetal membranes (amniochorion) that line the intrauterine cavity consist of two distinct cell layers; single-layer amnion epithelial cells (AEC) and multilayer chorion trophoblast cells (CTC). These layers are connected through a collagen-rich extracellular matrix. Cellular remodeling helps support membrane growth and integrity during gestation and helps to maintain pregnancy. Preterm prelabor rupture of the human amniochorionic (fetal) membrane (pPROM) is antecedent to 40% of all spontaneous preterm birth. Oxidative stress (OS) induced activation of the p38 MAPK due to various maternal risk exposures and the amniochorion cells' senescence are reported pathological features of pPROM. Our transcriptomics analysis implicated dysregulated autophagy and epithelial-mesenchymal transition (EMT) in fetal membranes from pPROM. The molecular interplay between OS-induced p38 MAPK activation, autophagy, and EMT was investigated in AECs and CTCs to better understand the involvement of autophagy and EMT. We report the differential impact of OS on the autophagic machinery in AECs and CTCs, resulting in distinct cell fates. In AECs, OS-induced p38 MAPK activation causes autophagosome accumulation and reduced autophagic flux mediated by decreased ULK1 activity and kinase activity, leading to senescence. In CTCs, induction of autophagy has a limited effect; however, inhibition of autophagy led to SQSTM1-mediated EMT of trophoblast cells. Autophagy, EMT, and senescence were associated with proinflammatory changes. Thus, AECs and CTCs respond differently to OS via differential autophagy response, partly mediated via p38 MAPK. Besides senescence, OS-induced autophagy dysregulation in amniochorion cells may play a mechanistic role in pPROM pathophysiology.

Maternal biomarkers in predicting neonatal sepsis after preterm premature rupture of membranes in preterm infants.

AIM: This retrospective cohort study aimed to assess the utility of maternal C-reactive protein (CRP) and leukocyte levels in predicting neonatal sepsis after preterm premature rupture of membranes (pPROM). METHODS: We conducted a retrospective cohort study (2009-2021), encompassing preterm infants born ≤29 + 6 weeks of gestation following pPROM. The primary outcome was early-onset neonatal sepsis within the initial 72 h of life. RESULTS: We analysed data from 706 patients with a median gestational age at pPROM of 25.1 weeks and a median gestational age at birth of 26.4 weeks. Overall survival rate was 86.1%, with 65.7% survival without severe morbidities. These rates were significantly worse in preterm infants with sepsis. Maternal CRP and leukocyte levels correlated significantly with neonatal infection markers and sepsis. However, their predictive values, correlation coefficients, and area under the curve values were generally low. Using maternal CRP ≥2 mg/dL to predict neonatal sepsis yielded a positive predictive value of 18.5%, negative predictive value of 91.5%, AUC of 0.589, 45.5% sensitivity, and 74.5% specificity. CONCLUSION: Maternal CRP and leukocyte levels were ineffective as a tool for predicting early-onset neonatal sepsis following early pPROM. Consequently, these biomarkers lack the reliability required for clinical decision-making in this context.

Statement of the Obstetrics and Prenatal Medicine Working Group (AGG - Preterm Birth Section) on "Outpatient Management for Pregnant Women with Preterm Premature Rupture of Membranes (PPROM)".

Preterm premature rupture of membranes (PPROM) is one of the leading causes of perinatal morbidity and mortality. After a PPROM, more than 50% of pregnant women are delivered within 7 days. Fetal and maternal risks are primarily due to infection and inflammation, placental abruption, umbilical cord complications and preterm birth. Standard care usually consists of an expectant approach. Management includes the administration of antenatal steroids and antibiotic therapy. Patients with PPROM require close monitoring. The management of pregnant women with PPROM (inpatient vs. outpatient) is still the subject of controversial debate. The international guidelines also do not offer a clear stance. The statement presented here discusses the current state of knowledge.

Potential of plasma inflammatory and angiogenic mediators for predicting spontaneous preterm delivery, intraamniotic infection/inflammation, and composite neonatal morbidity/mortality in women with early preterm premature rupture of membranes.

PROBLEM: To assess the potential of five inflammatory and six angiogenic/antiangiogenic plasma proteins for predicting imminent spontaneous preterm delivery (SPTD; ≤14 days of sampling), microbial invasion of the amniotic cavity and/or intraamniotic inflammation (MIAC/IAI), and composite neonatal morbidity and mortality (CNMM) in women with early preterm premature rupture of membranes (PPROM). METHODS OF STUDY: This retrospective cohort study included 76 singleton pregnant women with early PPROM (23-30 weeks). Amniotic fluid obtained via amniocentesis was cultured for microorganism detection and assayed for interleukin-6 to define IAI (≥2.6 ng/mL). Plasma C4a, endoglin, endostatin, IGFBP-1, IGFBP-2, MMP-9, PlGF, S100A8, S100A9, S100 A8/A9, and VEGFR-1 levels were determined using ELISA. RESULTS: Multivariate logistic regression analyses revealed significant associations between (i) high levels of plasma S100A8/A9, SPTD ≤14 days after sampling, and shorter sampling-to-delivery intervals; (ii) elevated plasma MMP-9, S100A9, and S100A8/A9 levels and MIAC/IAI, and (iii) decreased plasma endoglin levels and increased CNMM risk, while adjusting for gestational age at sampling (or delivery) and tocolytic use. The area under the curves of the aforementioned proteins ranged from 0.655 to 0.731 for each outcome. Notably, the SPTD risk increased significantly with increasing plasma S100A8/A9 levels (P for trend < .05). CONCLUSIONS: Plasma S100A8/A9, MMP-9, S100A9, and endoglin may represent valuable biomarkers associated with SPTD, MIAC/IAI, and CNMM in women with early PPROM. Owing to their less invasive nature, repeatability, and fair-to-moderate diagnostic accuracy, these biomarkers may contribute to risk stratification of PPROM-related complications in the clinical setting.

Soluble urokinase plasminogen activator receptor in vaginally collected amniotic fluid predicting fetal inflammatory response syndrome: a prospective cohort study.

BACKGROUND: Improving noninvasive antenatal diagnosis of fetal inflammatory response syndrome (FIRS) can assist in the evaluation of prenatal risk and reduce perinatal outcomes. This study aimed to determine whether soluble urokinase-type plasminogen activator receptor (suPAR) in vaginally collected amniotic fluid is significant in identifying FIRS after preterm premature rupture of membranes before 34 weeks of gestation. METHODS: This was a prospective cohort study of 114 pregnant women and their newborns after preterm premature rupture of membranes at 22-34+6 weeks of gestation. SuPAR was evaluated using an enzyme-linked immunosorbent assay in vaginally collected amniotic fluid. Patients were classified according to the presence or absence of FIRS. FIRS was defined by umbilical cord blood interleukin-6 level > 11 pg/mL or histological funisitis. The data were analyzed using the R package (R-4.0.5). RESULTS: SuPAR was detected in all amniotic fluid samples with a median of 26.23 ng/mL (interquartile range (IQR), 15.19-51.14). The median level of suPAR was higher in the FIRS group than in the non-FIRS group, 32.36 ng/mL (IQR, 17.27-84.16) vs. 20.46 ng/mL (IQR, 11.49-36.63) (P = 0.01), respectively. The presence of histological chorioamnionitis significantly increased the suPAR concentration in the FIRS group (P < 0.001). The areas under the curve for FIRS and FIRS with histological chorioamnionitis were 0.65 and 0.74, respectively, with an optimum cutoff value of 27.60 ng/mL. Controlling for gestational age, the cutoff of suPAR more than 27.60 ng/mL predicted threefold higher odds for FIRS and sixfold higher odds for FIRS with histologic chorioamnionitis. CONCLUSION: Soluble urokinase-type plasminogen activator receptor in vaginally obtained amniotic fluid may assist in evaluating prenatal risk of FIRS in patients after preterm premature rupture of membranes before 34 weeks of gestation.

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.

The Importance of Tissue Doppler Imaging and M-Mode Ultrasonography in Fetuses With Preterm Premature Rupture of Membranes: A Case-Control Study.

OBJECTIVE: To compare the cardiac functions of fetuses with preterm premature rupture of membranes (PPROM) between their control groups and investigate its relationship with perinatal outcomes. METHODS: This prospective study was conducted with 102 pregnant women. Pregnant women with PPROM were divided into two subgroups Group A, between 26 and 30 weeks, and Group B, between 30 and 34 weeks. A control group was formed by randomly including one healthy pregnant woman for each study patient. Sociodemographic, obstetric data, tissue Doppler imaging, and M-mode imaging results were compared. The relationship between echocardiographic parameters and perinatal outcomes was also investigated. RESULTS: Tricuspid annular plane systolic excursion (TAPSE), S', and ET' of systolic cardiac parameters were shortened in both groups compared with their controls. Diastolic function indicator E'/A', and global function indicator myocardial performance index' increased in both groups. Isovolumetric contraction time' did not change between groups. A correlation was found between myocardial performance index', and the length of neonatal intensive care unit stay in Group A and TAPSE and duration of respiratory support and length of neonatal intensive care unit stay in Group B. CONCLUSIONS: The fetal cardiac function seems to be affected by PPROM, and these changes are associated with neonatal outcomes. Therefore, administering fetal cardiac function evaluation in pregnancies complicated by PPROM may help physicians establish more appropriate clinical management protocols in this special population.

Vaginal Microbial Colonization after Antibiotic Treatment in Women with Preterm Premature Rupture of Membranes: An Observational Cohort Study.

Preterm premature rupture of membranes (pPROM) stands as a primary contributor to preterm deliveries worldwide, closely linked to consequential infectious peripartum complications, including chorioamnionitis and early-onset neonatal sepsis. As a prophylactic measure, individuals following pPROM routinely undergo antibiotic treatment. The aim of this study was to evaluate changes in the vaginal microbial colonization after antibiotic treatment following pPROM. Therefore, we retrospectively assessed the impact of antibiotic treatment on the maternal vaginal microbial colonization in 438 post-pPROM patients delivering before 29 gestational weeks. Vaginal samples were collected for microbiological analysis before and after antibiotic administration and analysed for seventeen pre-defined microbial groups. We observed eradication in eleven microbial groups, including beta-hemolytic streptococci group B and Gardnerella vaginalis. No significant reduction was found for the remaining groups, including Escherichia (E.) coli. Moreover, we found a notable increase in resistant bacteria after antibiotic treatment. In conclusion, broad-spectrum antimicrobial treatment exhibited substantial efficacy in eradicating the majority of pathogens in our cohort. However, certain pathogens, notably E. coli, showed resilience. Given E. coli's prominent role in infectious peripartum complications, our findings underline the challenges in antibiotic management post-pPROM and the need to establish international guidelines, particularly regarding emerging concerns about antibiotic resistances.

Antibiotic administration reduced intra-amniotic inflammation 7 days after preterm premature rupture of the membranes with intra-amniotic infection.

OBJECTIVE: Intra-amniotic infections increase the risk of preterm delivery and short- and long-term fetal morbidity; however, no consensus exists on the choice of antimicrobial agents as treatment for these infections. We aimed to examine the efficacy of intravenous administration of sulbactam/ampicillin (SBT/ABPC) and azithromycin (AZM) for intra-amniotic infection in patients with preterm premature rupture of membranes (PPROM). METHODS: This study followed a single-centered retrospective cohort design. We compared changes in interleukin 6 (IL-6) levels and the load of Ureaplasma species DNA in the amniotic fluid between singleton pregnancy patients with intra-amniotic infection (Group A) and without either intra-amniotic inflammation (IAI) or microbial invasion of the amniotic cavity (MIAC) (Group B) who developed PPROM between week 22, day 0 and week 33, day 6 of gestation and maintained pregnancy for ≥7 d after diagnosis (August 2014 to April 2020). Patients in Group A were treated with SBT/ABPC and AZM, whereas those in Group B were treated with ABPC and AZM or clarithromycin. RESULTS: Thirty-one patients with IAI and 48 patients without either IAI or MIAC at diagnosis of PPROM underwent pregnancy/delivery management at our hospital. Following the study population selection, we evaluated six patients in Group A and 13 patients in Group B. Amniotic fluid IL-6 concentrations at the initial amniocentesis were high, ranging from 11.7 ng/mL to 139.2 ng/mL, indicating a state of severe IAI in all six patients in Group A. In five of the six patients in Group A, the amniotic fluid cultures during the first amniocentesis included Ureaplasma species only. In both groups, the amniotic fluid IL-6 concentration at the follow-up amniocentesis was lower than that at the initial amniocentesis (Group A: follow-up median 3.06 ng/mL [quartiles, 1.75-6.74], initial median 30.53 ng/mL [quartiles, 15.60-67.07], p＝.03; Group B: follow-up median 0.40 ng/mL [quartiles, 0.18-0.69], initial median 0.96 ng/mL [quartiles, 0.65-1.42], p＝.005); Group A showed a greater decrease than Group B (p < .001). No difference was found between the microbial loads of Ureaplasma species DNA in the initial and follow-up amniocentesis (p = .13). CONCLUSIONS: In patients with PPROM and intra-amniotic infection, IL-6 levels in the amniotic fluid decreased significantly from before antimicrobial administration to day 7. This decrease is thought to be mainly due to the effects of intravenous AZM. The efficacy of AZM in patients with PPROM needs to be further confirmed via randomized controlled studies in the future.

Association between light rare earth elements in maternal plasma and the risk of spontaneous preterm birth: a nested case-control study from the Beijing birth cohort study.

BACKGROUND: Parental exposure to rare earth elements (REEs) could increase the risk of premature rupture of membranes, a major cause of spontaneous preterm birth (SPB). In addition, different subtypes of SPB, such as spontaneous preterm labor (SPL) and preterm premature rupture of membranes (PPROM), may have different susceptibility to environmental exposure. Therefore, we investigated the potential associations between REE exposure in different trimesters and SPB and its subtypes. METHODS: A nested case-control study was performed. We included 244 women with SPB as cases and 244 women with full-term delivery as controls. The plasma concentrations of light REEs were measured in the first and third trimesters. Logistic regression was used to analyze the associations between single REE levels and SPB, and Bayesian kernel machine regression (BKMR) was used to analyze the mixed-exposure effect. RESULTS: Exposure to light REEs was associated with SPB and its subtypes only in the third trimester. Specifically, the intermediate- and highest-tertile concentration groups of La and the highest-tertile concentration group of Sm were associated with an increased risk of SPL, with adjusted odds ratios (AORs) of 2.00 (95% CIs: 1.07-3.75), 1.87 (95% CIs: 1.01-3.44), and 1.82 (95% CIs: 1.00-3.30), respectively. The highest-tertile concentration group of Pr was associated with an increased risk of PPROM, with an AOR of 1.69 (95% CIs: 1.00-2.85). Similar results were also found in BKMR models. CONCLUSIONS: La and Sm levels in plasma may be associated with the risk of SPL, and Pr levels in plasma may be associated with the risk of PPROM.

Vaginal probiotics as an adjunct to antibiotic prophylaxis in the management of preterm premature rupture of membranes: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To investigate the efficacy of vaginal probiotics administration in combination with prophylactic antibiotics versus antibiotic prophylaxis only on perinatal outcomes in women with preterm premature rupture of membrane (PPROM). METHODS: Four different databases were searched from inception till March 2023. We selected randomized controlled trials (RCTs) that compared vaginal probiotics along with antibiotics versus antibiotics only among pregnant women who were presented with PPROM between 24 and 34 weeks of gestation. We performed the meta-analysis using Revman software. Our primary outcomes were gestational age at birth and latency period duration. Our secondary outcomes were the rate of admission in the neonatal intensive care unit (NICU), infant birth weight, length of stay in the NICU, and neonatal complications. RESULTS: Four RCTs, involving a total of 339 patients, were included in the meta-analysis. The gestational age at the time of delivery and latency period duration were significantly higher among probiotics + antibiotics group (p = 0.01 & p < 0.001). There was a significant reduction in the rate of NICU admission and length of NICU stay among the probiotics + antibiotics group compared to the antibiotics only group. A significant improvement in the infant birth weight after delivery was demonstrated among the probiotics + antibiotics group (p = 0.002). Although there was a decrease in the incidence of neonatal sepsis and respiratory distress syndrome within probiotics + antibiotics group versus antibiotics only group, these differences were not statistically significant (p > 0.05). CONCLUSIONS: The combination of vaginal probiotics and antibiotic prophylaxis has been shown to effectively improve perinatal outcomes in women with PPROM. Further trials are needed to validate our findings.