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

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

[Box: see text].

Duration of rupture of membranes and microbiome transmission to the newborn: A prospective study.

OBJECTIVE: To assess whether labour variables (i.e. individuals characteristics, labour characteristics and medical interventions) impact maternal and newborn microbiomes. DESIGN: Prospective monocentric study. SETTING: Saint-Joseph Hospital tertiary maternity unit, in Paris, France. POPULATION: All consecutive primiparous women with a physiological pregnancy and term labour from 15 April to 1 June 2017. METHODS: 16S ribosomal RNA gene sequencing of the maternal vaginal, newborn skin and newborn oral microbiomes from 58 mother-baby dyads. MAIN OUTCOME MEASURES: Analysis of the effects of 19 labour variables on the composition and diversity of these microbiomes. RESULTS: The 19 labour variables explained a significant part of the variability in the vaginal, newborn oral and skin microbiomes (44%-67%). Strikingly, duration of rupture of membranes was the single factor that explained the greatest variability (adjusted R2: 7.7%-8.4%, p ≤ 0.002) and conditioned, by itself, the compositions of the three microbiomes under study. Long duration of rupture of membranes was specifically associated with a lower relative abundance of the Lactobacillus genus (1.7-fold to 68-fold reduction, p < 0.0001) as well as an increase in microbiome diversity, including genera implicated in nosocomial infections. The effects of duration of rupture of membranes were also present in newborns delivered by non-elective caesarean section. CONCLUSIONS: Maternal and newborn microbiomes were greatly affected by labour variables. Duration of rupture of membranes, even in non-elective caesarean sections, should be considered in epidemiological and microbiological studies, as well as in vaginal seeding practices.

The change of inflammatory status and vaginal flora in pregnant women with premature rupture of membranes.

Introduction. Premature rupture of the membrane (PROM) can trigger significant maternal complications, even maternal and fetal morbidity or mortality.Hypothesis. Inflammatory status and vaginal flora might be utilized to predict the occurrence of PROM.Aim. To explore the association between the occurrence of PROM and vaginal flora and inflammatory status alteration.Methodology. A case-control cross-sectional study was carried out on 140 pregnant women with or without PROM. Socio-demographic characteristics, vaginal flora assessment, pregnant outcomes and Apgar score information were retrieved.Results. Pregnant women with PROM showed an increased incidence of vulvovaginal candidiasis (VVC), trichomonas vaginitis (TV) and bacterial vaginitis (BV) with dysregulated vaginal flora and diminished fetal tolerance of labour indicated by down-regulated Apgar score. The increased rate of prematurity, puerperal infection and neonatal infection could be detected in PROM patients with imbalanced vaginal flora compared with PROM patients with normal vaginal flora. ROC analysis suggested IL-6 and TNF-α yielded the best discrimination for the prediction of PROM.Conclusion. Altered vaginal and inflammatory status are associated with PROM, and IL-6 and TNF-α can predict the occurrence of PROM.

Alterations in the vaginal microbiota of patients with preterm premature rupture of membranes.

Background: Preterm premature rupture of membranes (PPROM) is a common pregnancy complication. Yet, the main cause of PPROM remains poorly understood. In this study, we used 16S rRNA gene sequencing technology to identify the differences in vaginal microbiota between pregnant women with PPROM and those who delivered at term. Methods: Vaginal samples were collected from 48 patients with PPROM and 54 age- and gestational age-matched pregnant women who delivered at term (controls). The vaginal microbiota of the two groups was compared using 16S rRNA gene sequencing of the V3-V4 regions. Results: The vaginal microbial composition of the PPROM group was significantly different from that of the control group. Our results showed that the diversity of vaginal microbiota in patients with PPROM increased compared with controls. The relative abundance of Lactobacillus iners, Gardnerella vaginalis, Prevotella bivia, Ochrobactrum sp., Prevotella timonensis, and Ureaplasma parvum were more abundant in patients with PPROM, while Lactobacillus crispatus and Lactobacillus gasseri were more abundant in controls. Ochrobactrum sp., Prevotella timonensis, and Gardnerella vaginalis, could serve as biomarkers for PPROM. Finally, we proposed several metabolic pathways, including PWY-6339, PWY-6992, and PWY-7295. Conclusion: PPROM is characterized by vaginal microbial dysbiosis. The dysbiotic vaginal microbiota signatures in patients with PPROM include a higher bacterial diversity, decreased autochthonous bacteria, and increased pathogenic bacteria. These results may be beneficial for developing biomarkers for screening and early diagnosis of PPROM and may provide effective preventative treatments.

Estimated time to emergence of secondary intra-amniotic infection or inflammation since the onset of the preterm premature rupture of membranes.

OBJECTIVE: Prematurity is the most important prognostic factor for infants born following preterm premature rupture of membranes (PPROM). Therefore, when PPROM occurs between 22 and 33 weeks of gestation, prolonging pregnancy is recommended. Determination of management strategies requires screening for the presence of intra-amniotic infection or inflammation at the time of PPROM diagnosis. If intra-amniotic infection/inflammation is not detected, it is important to monitor the patient to diagnose any new infection/inflammation. We examined the period from PPROM to secondary intra-amniotic infection/inflammation and associated factors. MATERIALS AND METHODS: This retrospective study was conducted at a single facility. We examined 26 patients who experienced PPROM between 26 and 33 weeks of gestation and were negative for intra-amniotic infection/inflammation at the time of diagnosis and underwent serial amniocentesis. Antibiotic therapy comprising ampicillin, amoxicillin, and clarithromycin for 7 days was started after the first amniocentesis. The period from PPROM to secondary intra-amniotic infection/inflammation was analyzed using a Kaplan-Meier survival curve. The onset of intra-amniotic infection/inflammation was considered as the time at which amniotic fluid bacterial culture results became positive, the time when amniotic fluid Interleukin (IL)-6 increased beyond 2.6 ng/mL, or the day of delivery if histological chorioamnionitis was observed in the delivered placenta. Patients were treated as censored if no intra-amniotic infection/inflammation could be confirmed in the amniotic fluid and delivered placenta. RESULTS: The median time from PPROM to secondary intra-amniotic infection/inflammation was 18 days. Six patients developed intra-amniotic infection/inflammation, while 13 patients without intra-amniotic infections/inflammation delivered fewer than 7 days after PPROM. No confounding factors at the time of PPROM diagnosis were associated with the time from PPROM until secondary intra-amniotic infection/inflammation. CONCLUSIONS: The time between PPROM and onset of secondary intra-amniotic infection/inflammation appears prolonged. Treatments other than antimicrobial agents may need to be added to prolong pregnancy.

Calprotectin levels in amniotic fluid in relation to intra-amniotic inflammation and infection in women with preterm labor with intact membranes: A retrospective cohort study.

OBJECTIVE: To evaluate the concentrations of calprotectin in amniotic fluid with respect to intra-amniotic inflammation and infection and to assess the presence or absence of bacteria in the amnio-chorionic niche with respect to presence or absence of intra-amniotic inflammation. STUDY DESIGN: Seventy-nine women with singleton pregnancies and preterm labor with intact membranes (PTL) were included in the study. Amniotic fluid was collected at the time of admission by amniocentesis and calprotectin levels were analyzed from frozen/thawed samples using ELISA. Interleukin (IL)-6 concentration was measured by point-of-care test. Samples from amniotic fluid and the amnio-chorionic niche (space between amniotic and chorionic membranes) were microbiologically analyzed. Microbial invasion of the amniotic cavity (MIAC) was diagnosed based on a positive PCR result for Ureaplasma species, Mycoplasma hominis, 16S rRNA or positive culture. Intra-amniotic inflammation (IAI) was defined as amniotic fluid point-of-care IL-6 concentration ≥ 745 pg/mL. The cohort of included women was divided into 4 subgroups based on the presence or absence of IAI/MIAC; i) intra-amniotic infection, ii) sterile IAI, iii) intra-amniotic colonization and iv) neither MIAC nor IAI. RESULTS: Women with intra-amniotic infection had a significantly higher intra-amniotic calprotectin concentration (median; 101.6 µg/mL) compared with women with sterile IAI (median; 9.2 µg/mL), women with intra-amniotic colonization (median; 2.6 µg/mL) and women with neither MIAC nor IAI (median 4.6 µg/mL) (p = 0.001). Moreover, significantly higher amniotic fluid calprotectin concentration was seen in women who delivered within 7 days (p = 0.003). A significant negative correlation was found between amniotic fluid calprotectin and gestational age at delivery (rho = 0.32, p = 0.003). Relatively more bacteria in the amnio-chorionic niche were found in the sterile IAI group compared with the other groups. CONCLUSIONS: Calprotectin concentrations in amniotic fluid were significantly higher in the intra-amniotic infection group compared with the other groups. Moreover, the bacterial presence in the amnio-chorionic niche was higher in IAI group.

Differential impact of abnormal vaginal colonization on perinatal outcome and association with early-onset neonatal sepsis: preterm labor vs. preterm premature rupture of membrane.

OBJECTIVE: The purpose of this study was to check whether the impact of abnormal vaginal colonization on perinatal outcomes would be different in patients with preterm labor (PTL) and premature membrane rupture (PPROM). We also sought to determine the concordance rate of microorganisms isolated from the maternal vagina and neonatal blood in cases of early-onset neonatal sepsis (EONS) in PTL and PPROM. METHODS: This retrospective study included 996 singleton pregnancies who were admitted to the high risk care unit of our institution due to PTL (n = 519) or PPROM (n = 477) and underwent vaginal culture examination at admission between January 2005 and April 2019. Abnormal vaginal colonization was defined upon isolation of aerobic microorganisms. The maternal baseline characteristics, delivery, and neonatal outcomes were compared according to the presence or absence of abnormal vaginal flora, both in PTL and PPROM. RESULTS: The rate of abnormal vaginal colonization in PTL and PPROM was 17.0 and 21.4%, respectively. Both in PTL and PPROM, the gestational age at admission was lower in the abnormal vaginal colonization group (PTL, 27.2 ± 3.5 vs. 28.2 ± 3.5 weeks, p = .024; PPROM, 26.1 ± 5.3 vs. 27.5 ± 4.5 weeks, p = .007). Multivariable analysis demonstrated that the group with abnormal bacteria in PPROM but not in PTL had a significantly higher rate of EONS than the group without abnormal bacteria after adjustment for confounders including gestational age at admission (PPROM, odds ratio, OR [95% confidence interval, CI]: 4.172 [1.426-12.206]; PTL, OR [95% CI]: 0.661 [0.079-5.505]). Concordance analysis showed that the maternal vaginal bacteria colonization by Escherichia coli (5.9 vs. 0.5%, p = .033) and Staphylococcus aureus (14.3 vs. 0.2%, p = .032) in PPROM was significantly correlated with the microorganisms from the neonatal blood culture EONS cases. In PTL, no specific microorganisms showed concordance between maternal vaginal bacteria and microorganisms causing EONS. CONCLUSION: Our data showed that maternal vaginal colonization in PPROM, but not in PTL, is an independent risk factor for EONS.

A global perspective on management of bacterial infections in pregnancy: a systematic review of international guidelines.

INTRODUCTION: Maternal sepsis is a leading cause of maternal and neonatal mortality. Despite the availability of management protocols, there is disparity in case fatality rates for pregnancy-related sepsis compared to other maternity-related complications. The main aim of this systematic review was to assess concordance between international evidence-based guidelines for the prevention and management of childbirth-related bacterial infections. MATERIAL AND METHODS: The PRISMA statement was followed during the conduct and reporting of this review. PubMed was searched electronically from 2009 to November 2019 for clinical guidelines covering the topic of childbirth-related infections and specific searches for relevant guidelines on the websites of the top five international professional bodies most commonly identified by our searches. We did not apply any language restrictions. Guidelines were included if they provided any information about the prevention or management of childbirth-related bacterial infections irrespective of whether the guideline stated a recommendation or not. Two independent reviewers undertook study selection, decisions about inclusion of selected guidelines and data extraction. Extracted information was synthesized under the following topics: Asymptomatic bacteriuria; group B streptococcal infection (GBS); preterm premature rupture of membranes (P-PROM); intrauterine infection; procedures; maternal sepsis; miscellaneous. Concordance was defined as absence of contradictory information between the different guidelines with regards to a specific topic, subtopic or recommendation. Quality of included guidelines was assessed against the AGREE II guideline reporting domains. RESULTS: A total of 43 guidelines were selected of which 11 were excluded leaving 32 guidelines that fulfilled our inclusion criteria. None of the guidelines fulfilled all the quality assessment domains and 11 (34%) of the guidelines satisfied 1-2 of domains only. Two guidelines covered the topic of asymptomatic bacteriuria, nine for GBS, five for P-PROM and three covered each of intra-amniotic infections maternal sepsis, obstetric procedures and interventions topics. The remaining guidelines covered miscellaneous topics. CONCLUSIONS: There was concordance between guidelines with regards to several aspects in the prophylaxis and treatment of bacteriological infections in pregnancy. Nevertheless, there were several areas of discordance, some of which reached the extent of contradictory information as in the case of antenatal screening for GBS.

Intra-amniotic infection and sterile intra-amniotic inflammation in women with preterm labor with intact membranes are associated with a higher rate of Ureaplasma species DNA presence in the cervical fluid.

OBJECTIVE: To determine the prevalence of Ureaplasma spp. DNA and its load in the cervical fluid in women with preterm labor with intact membranes (PTL) complicated by intra-amniotic infection (the presence of both microbial invasion of the amniotic cavity and intra-amniotic inflammation) or sterile intra-amniotic inflammation (the presence of intra-amniotic inflammation alone). METHODS: Overall, 115 women with singleton pregnancies complicated by PTL between gestational ages of 22 + 0 and 34 + 6 weeks were included in this study. Paired amniotic and cervical fluid samples were collected at the time of admission via transabdominal amniocentesis using a Dacron polyester swab. Microbial invasion of the amniotic cavity was diagnosed based on a combination of culture and molecular biology methods. Intra-amniotic inflammation was determined based on the concentration of interleukin-6 in the amniotic fluid. Bacterial and Ureaplasma spp. DNA loads were assessed in the cervical fluid using PCR. RESULTS: Intra-amniotic infection and sterile inflammation were identified in 14% (16/115) and 25% (29/115) of the women, respectively. Ureaplasma spp. DNA in the cervical fluid was identified in 51% (59/115) of women. The presence of Ureaplasma spp. DNA in the cervical fluid was higher in women with intra-amniotic infection (75% (12/16)) and sterile intra-amniotic inflammation (76% (22/29)) than in women without intra-amniotic inflammation (36% (25/70); p = .0002). Concurrent presence of Ureaplasma spp. and Mycoplasma hominis DNA was higher in women with intra-amniotic infection (42% (5/12)) than women with sterile intra-amniotic inflammation (7% (2/29)) and women without intra-amniotic inflammation (7% (5/70); p = .001). There were no differences in the load of Ureaplasma spp. DNA in the cervical fluid among women with intra-amniotic infection, sterile intra-amniotic inflammation, and those without intra-amniotic inflammation (median values; infection: 1.2 × 104 copies DNA/mL; sterile: 5.0 × 105 copies DNA/mL; without: 8.4 × 104 copies DNA/mL; p = .18). CONCLUSIONS: In PTL , both forms of intra-amniotic inflammation were associated with a higher prevalence of Ureaplasma spp. DNA in the cervical fluid. The presence of intra-amniotic infection was related to a higher rate of concurrent Ureaplasma spp. and M. hominis DNA in the cervical fluid.

Streptococcus agalactiae do not penetrate human chorioamniotic membranes in vitro but alter their biomechanical properties.

INTRODUCTION: Vaginal colonization with Streptococcus agalactiae (group B streptococci) is hypothesized to constitute a risk factor for preterm prelabor rupture of membranes. In vitro studies have shown that S. agalactiae strains isolated from infants with neonatal sepsis adhere to chorion cells of the human chorioamniotic membrane. However, it is still unknown whether S. agalactiae strains penetrate the chorioamniotic membranes and whether S. agalactiae colonization affects the biomechanical properties of the membranes and thus contributes to increased risk of preterm prelabor rupture. The aim of this in vitro study was to explore if different strains of S. agalactiae penetrate and affect the biomechanical properties of human chorioamniotic membranes. MATERIAL AND METHODS: Three different strains of S. agalactiae were obtained, one from an early-onset neonatal infection, one from a case of preterm prelabor rupture of membranes and one from a healthy pregnant carrier. Chorioamniotic membranes from elective cesarean deliveries were either incubated with S. agalactiae or mounted in a two-chamber incubation cell generating a "maternal" and a "fetal" chamber and incubated with S. agalactiae in the maternal chamber. Subsequently the membranes were examined to evaluate S. agalactiae attachment, penetration and the effect on the biomechanical properties. RESULTS: At 5 h after incubation, S. agalactiae adhered to the chorioamniotic membranes with increased number at 20 h. Streptococcus agalactiae did not penetrate the membranes even after 20 h of incubation. Streptococcus agalactiae increased the ultimate tensile stress needed to rupture the membranes and increased the work needed to rupture the membranes as well as the elastic modulus. CONCLUSIONS: Human chorioamniotic membranes constitute a physical barrier against S. agalactiae infections. Moreover, S. agalactiae infection leads to increased strength of the membranes.

Vaginal bacterial load in the second trimester is associated with early preterm birth recurrence: a nested case-control study.

OBJECTIVE: To assess the association between vaginal microbiome (VMB) composition and recurrent early spontaneous preterm birth (sPTB)/preterm prelabour rupture of membranes (PPROM). DESIGN: Nested case-control study. SETTING: UK tertiary referral hospital. SAMPLE: High-risk women with previous sPTB/PPROM <34+0 weeks' gestation who had a recurrence (n = 22) or delivered at ≥37+0 weeks without PPROM (n = 87). METHODS: Vaginal swabs collected between 15 and 22 weeks' gestation were analysed by 16S rRNA gene sequencing and 16S quantitative PCR. MAIN OUTCOME MEASURE: Recurrent early sPTB/PPROM. RESULTS: Of the 109 high-risk women, 28 had anaerobic vaginal dysbiosis, with the remainder dominated by lactobacilli (Lactobacillus iners 36/109, Lactobacillus crispatus 23/109, or other 22/109). VMB type and diversity were not associated with recurrence. Women with a recurrence, compared to those without, had a higher median vaginal bacterial load (8.64 versus 7.89 log10 cells/mcl, adjusted odds ratio [aOR] 1.90, 95% CI 1.01-3.56, P = 0.047) and estimated Lactobacillus concentration (8.59 versus 7.48 log10 cells/mcl, aOR 2.35, (95% CI 1.20-4.61, P = 0.013). A higher recurrence risk was associated with higher median bacterial loads for each VMB type after stratification, although statistical significance was reached only for L. iners domination (aOR 3.44, 95% CI 1.06-11.15, P = 0.040). Women with anaerobic dysbiosis or L. iners domination had a higher median vaginal bacterial load than women with a VMB dominated by L. crispatus or other lactobacilli (8.54, 7.96, 7.63, and 7.53 log10 cells/mcl, respectively). CONCLUSIONS: Vaginal bacterial load is associated with early sPTB/PPROM recurrence. Domination by lactobacilli other than L. iners may protect women from developing high bacterial loads. Future PTB studies should quantify vaginal bacteria and yeasts. TWEETABLE ABSTRACT: Increased vaginal bacterial load in the second trimester may be associated with recurrent early spontaneous preterm birth.

Cervical Gardnerella vaginalis in women with preterm prelabor rupture of membranes.

OBJECTIVE: To determine the association between microbial invasion of the amniotic cavity (MIAC) and/or intra-amniotic inflammation (IAI) and the cervical prevalence of Gardnerella vaginalis DNA in pregnancies with preterm prelabor rupture of membrane (PPROM). METHOD: In total, 405 women with singleton pregnancies complicated with PPROM were included. Cervical fluid and amniotic fluid samples were collected at the time of admission. Bacterial and G. vaginalis DNA were assessed in the cervical fluid samples using quantitative PCR technique. Concentrations of interleukin-6 and MIAC were evaluated in the amniotic fluid samples. Loads of G. vaginalis DNA ≥ 1% of the total cervical bacterial DNA were used to define the cervical prevalence of G. vaginalis as abundant. Based on the MIAC and IAI, women were categorized into four groups: with intra-amniotic infection (both MIAC and IAI), with sterile IAI (IAI without MIAC), with MIAC without IAI, and without either MIAC or IAI. RESULTS: The presence of the abundant cervical G. vaginalis was related to MIAC (with: 65% vs. without: 44%; p = 0.0004) but not IAI (with: 52% vs. without: 48%; p = 0.70). Women with MIAC without IAI had the highest load of the cervical G. vaginalis DNA (median 2.0 × 104 copies DNA/mL) and the highest presence of abundant cervical G. vaginalis (73%). CONCLUSIONS: In women with PPROM, the presence of cervical G. vaginalis was associated with MIAC, mainly without the concurrent presence of IAI.

A specific bacterial DNA signature in the vagina of Australian women in midpregnancy predicts high risk of spontaneous preterm birth (the Predict1000 study).

BACKGROUND: Intrauterine infection accounts for a quarter of the cases of spontaneous preterm birth; however, at present, it is not possible to efficiently identify pregnant women at risk to deliver preventative treatments. OBJECTIVE: This study aimed to establish a vaginal microbial DNA test for Australian women in midpregnancy that will identify those at increased risk of spontaneous preterm birth. STUDY DESIGN: A total of 1000 women with singleton pregnancies were recruited in Perth, Australia. Midvaginal swabs were collected between 12 and 23 weeks' gestation. DNA was extracted for the detection of 23 risk-related microbial DNA targets by quantitative polymerase chain reaction. Obstetrical history, pregnancy outcome, and demographics were recorded. RESULTS: After excluding 64 women owing to losses to follow-up and insufficient sample for microbial analyses, the final cohort consisted of 936 women of predominantly white race (74.3%). The overall preterm birth rate was 12.6% (118 births); the spontaneous preterm birth rate at <37 weeks' gestation was 6.2% (2.9% at ≤34 weeks' gestation), whereas the preterm premature rupture of the membranes rate was 4.2%. No single individual microbial target predicted increased spontaneous preterm birth risk. Conversely, women who subsequently delivered at term had higher amounts of Lactobacillus crispatus, Lactobacillus gasseri, or Lactobacillus jensenii DNA in their vaginal swabs (13.8% spontaneous preterm birth vs 31.2% term; P=.005). In the remaining women, a specific microbial DNA signature was identified that was strongly predictive of spontaneous preterm birth risk, consisting of DNA from Gardnerella vaginalis (clade 4), Lactobacillus iners, and Ureaplasma parvum (serovars 3 and 6). Risk prediction was improved if Fusobacterium nucleatum detection was included in the test algorithm. The final algorithm, which we called the Gardnerella Lactobacillus Ureaplasma (GLU) test, was able to detect women at risk of spontaneous preterm birth at <37 and ≤34 weeks' gestation, with sensitivities of 37.9% and 44.4%, respectively, and likelihood ratios (plus or minus) of 2.22 per 0.75 and 2.52 per 0.67, respectively. Preterm premature rupture of the membranes was more than twice as common in GLU-positive women. Adjusting for maternal demographics, ethnicity, and clinical history did not improve prediction. Only a history of spontaneous preterm birth was more effective at predicting spontaneous preterm birth than a GLU-positive result (odds ratio, 3.6). CONCLUSION: We have identified a vaginal bacterial DNA signature that identifies women with a singleton pregnancy who are at increased risk of spontaneous preterm birth and may benefit from targeted antimicrobial therapy.

Detection of Vaginal Metabolite Changes in Premature Rupture of Membrane Patients in Third Trimester Pregnancy: a Prospective Cohort Study.

Premature rupture of membranes (PROM) is usually associated with pregnant and neonatal complications. Most of the PROM cases are caused by ascending asymptomatic genital infection. In China, PROM (15.3%) is more common than spontaneous preterm labor (7.3%) and leads to more adverse pregnancy outcomes. Here, we designed a prospective cohort study to measure the metabolomics changes in vaginal swab samples and explored their potential contribution to PROM. A total of 260 differentially expressed metabolites were identified and further analyzed. In the PROM group, N-acetyl-D-galactosamine and sucrose were downregulated (P = 0.0025, P = 0.0195, respectively), both of which are the upstream metabolites of the glycolysis pathway. Furthermore, estriol 3-sulfate 16-glucuronide (P = 0.0154) and 2-methoxy-17beta-estradiol 3-glucosiduronic acid (P = 0.004), two final metabolites in steroid hormone biosynthesis, were both downregulated in the PROM group. Finally, we found two catechin metabolites (epigallocatechin-7-glucuronide, P = 0.0009; 4'-methyl-epigallocatechin-7-glucuronide, P = 0.01) as well as DL-citrulline (P = 0.0393) were also significantly downregulated in the PROM group compared with the healthy control (HC) group, which are related to important antioxidant and anti-inflammatory activities in the human body. Altogether, metabolite changes in glycolysis, steroid hormone biosynthesis, and antioxidant/anti-inflammatory pathways may contribute to (or be a consequence of) vaginal dysbiosis and PROM. Metabolite pathway analysis is a new and promising approach to further investigate the mechanism of PROM and help prevent its unfavorable pregnant outcomes at a functional level. Trial registration number: ChiCTR2000034721.

Erythromycin compared to amoxicillin and azithromycin for antimicrobial prophylaxis for preterm premature rupture of the membranes: a retrospective study.

Antimicrobial prophylaxis is widely recommended for pregnant women who have preterm premature rupture of the membranes. Erythromycin prophylaxis was used during an initial period (control) and then changed to intravenous amoxicillin for 48 h, followed by 5 days of oral amoxicillin along with a single dose of azithromycin (case). Healthcare records were reviewed retrospectively. The primary outcome was latency (between membrane rupture and delivery) and the secondary outcomes were mode of delivery, maternal high dependency unit (HDU) admission, and several laboratory parameters. There were 78 women in the case group (amoxicillin and azithromycin) and controls were selected on a 1:1 ratio. There was no statistically significant difference between cases and controls with respect to group B Streptococcus or E.coli carriage, previous preterm birth, assissted fertility and parity. No babies had a positive blood culture with Group B Streptococcus. There was a longer latency to delivery for those prescribed amoxicillin and azithromycin (median = 5.5 days), compared with controls on erythromycin (median = 2 days, p < .001). There was no difference in the mode of delivery or maternal HDU admission. Given the potential sequelae of preterm birth, this warrants further prospective investigation in a randomised control trial.IMPACT STATEMENTWhat is already known on this subject? Antimicrobial prophylaxis is recommended for women who have preterm premature rupture of the membranes (PPROM). It has been shown to increase latency of delivery. However there are different regimens recommended in North America (amoxicillin and a macrolide) and the United Kingdom (macrolide monotherapy).What do the results of this study add? This study has shown that in our population, women who were prescribed the PPROM regimen of amoxicillin with azithromycin had a longer median latency from time of rupture of membranes to delivery, than women in a historical control group who were prescribed erythromycin monotherapy.What are the implications of these findings for clinical practice and/or further research? This retrospective study has shown that there may be a difference in latency between different antimicrobial prophylaxis regimens for PPROM. A randomised control trial, with sufficient patient numbers, is needed to determine the best regimen for prophylaxis, and would allow harmonisation of international guidelines.

Vaginal Microbiome in Preterm Rupture of Membranes.

There is an association between vaginal microbiota dysbiosis and preterm premature rupture of membranes (PPROM). In PPROM, reduced Lactobacillus spp abundance is linked to the emergence of high-risk vaginal microbiota, close to the time of membrane rupture. Although PPROM itself can change vaginal microbial composition, antibiotic therapy profoundly effects community structure. Erythromycin may have a beneficial effect in women deplete in Lactobacillus spp but damages a healthy microbiome by targeting Lactobacillus spp. Increased rates of chorioamnionitis and early-onset neonatal sepsis are associated with vaginal microbiota dysbiosis close to the time of delivery.

Antibiotics for Prophylaxis in the Setting of Preterm Prelabor Rupture of Membranes.

"For many years, providers have been using antibiotics to prevent infection in women who present with preterm prelabor rupture of membranes (PPROM). Given the polymicrobial nature of intra-amniotic infection, the recommended regimen includes a 7-day course of ampicillin and erythromycin, although many substitute of azithromycin. This regimen is used from viability to 34 weeks, independent of the number of fetuses present. Meta-analyses have shown that antibiotics for this indication are associated with lower rates of maternal and fetal infection, as well as longer pregnancy latency. Thus, latency antibiotics are recommended for all women with PPROM through 34 weeks of gestation."

The impact of Ureaplasma infections on pregnancy complications.

The aim of this study was to assess if ureaplasmas are associated with pregnancy complications and diseases in newborns. Pregnant women with complaints and threatening signs of preterm delivery were included. A sample, taken from the endocervical canal and from the surface of the cervical portion, was sent to the local microbiology laboratory for DNA detection of seven pathogens: Chlamydia trachomatis, Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma parvum, Ureaplasma urealyticum, Neisseria gonorrhoeae, and Trichomonas vaginalis. The Pearson Chi-Square test was used to determine the difference in unpaired categorical data. A two-sided p value <0.05 was considered to be statistically significant. In all, 50 pregnant women with complaints and threatening signs of preterm delivery were included. Premature rupture of uterine membranes was found in 23 (46%) of the patients and 38 women (76%) had preterm delivery. Ureaplasma infections were associated with a premature rupture of membranes (p < 0.004), the placental inflammation (p < 0.025), a newborn respiratory distress syndrome (p < 0.019). Ureaplasmas could have affected the preterm leakage of fetal amniotic fluid and are associated with the placental inflammation and a newborn respiratory distress syndrome.

Effect of Chlamydia trachomatis on adverse pregnancy outcomes: a meta-analysis.

PURPOSE: To analyze the effect of Chlamydia trachomatis (C. trachomatis) on adverse pregnancy outcomes based on the currently available evidence. METHODS: Multiple databases were comprehensively searched from the available date of inception through December 9, 2019. The effect of C. trachomatis on adverse pregnancy outcomes was assessed using pooled odds rations (ORs) and 95% confidence intervals (CIs). Egger's test was used for publication bias. RESULTS: Fifty studies involving 502,141 participants were identified. C. trachomatis infection was found to be associated with preterm birth in antibody detection [OR (95% CI): 1.571 (1.112-2.220), P = 0.010] and high-quality assessment [OR (95% CI): 1.734 (1.295-2.321), P < 0.001], preterm premature rupture of membranes (PPROM) in culture detection [OR (95% CI): 4.339 (1.806-10.424), P = 0.001] and high-quality assessment [OR (95% CI): 2.822 (1.333-5.973), P = 0.007], stillbirth [OR (95% CI): 1.585 (1.219-2.062), P = 0.001], low-birthweight babies [OR (95% CI): 2.205 (1.137-4.274), P = 0.019], and babies small for gestational age [OR (95% CI): 1.193 (1.091-1.305), P < 0.001]. No publication bias was exhibited in miscarriage (P = 0.170), preterm birth (P = 0.303), PPROM (P = 0.341), stillbirth (P = 0.533), and low-birthweight babies (P = 0.535). CONCLUSIONS: C. trachomatis infection during pregnancy is associated with a higher risk of preterm birth, PPROM, stillbirth, low-birthweight babies, and babies small for gestational age.

MicroRNA Signature of Epithelial-Mesenchymal Transition in Group B Streptococcal Infection of the Placental Chorioamniotic Membranes.

BACKGROUND: Infection-induced preterm birth is a major cause of neonatal mortality and morbidity and leads to preterm premature rupture of placental chorioamniotic membranes. The loss of amniotic epithelial cells and tensile strength preceding membrane rupture is poorly understood. We hypothesized that intrauterine bacterial infection induces changes in microRNA (miRNA) expression, leading to amniotic epithelial cell loss and membrane weakening. METHODS: Ten pregnant pigtail macaques received choriodecidual inoculation of either group B Streptococcus (GBS) or saline (n = 5/group). Placental chorioamniotic membranes were studied using RNA microarray and immunohistochemistry. Chorioamniotic membranes from women with preterm premature rupture of membranes (pPROM) and normal term pregnancies were studied using transmission electron microscopy. RESULTS: In our model, an experimental GBS infection was associated with changes in the miRNA profile in the chorioamniotic membranes consistent with epithelial to mesenchymal transition (EMT) with loss of epithelial (E-cadherin) and gain of mesenchymal (vimentin) markers. Similarly, loss of desmosomes (intercellular junctions) was seen in placental tissues from women with pPROM. CONCLUSIONS: We describe EMT as a novel mechanism for infection-associated chorioamniotic membrane weakening, which may be a common pathway for many etiologies of pPROM. Therapy based on anti-miRNA targeting of EMT may prevent pPROM due to perinatal infection.