Treatment of classic mid-trimester preterm premature rupture of membranes (PPROM) with oligo/ anhydramnion between 22 – 26 weeks’ gestation by means of continuous amnioinfusion: a randomized multicentric prospective controlled TRIAL

Background: The classic mid-trimester preterm premature rupture of membranes (PPROM), is defined as rupture of fetal membranes prior to 28 weeks’ gestation (WG) with oligo/ anhydramnion, complicates approximately 0.4-0.7% of all pregnancies and is associated with very high neonatal mortality and morbidity.Antibiotics have limited success to prevent bacterial growth, chorioamnionitis and fetal inflammation. The repetitive amnioinfusion doesn’t work because of immediately fluid lost after the intervention. The continuous amnioinfusion through the transabdomianal port system or catheter in patients with classic PPROM shows promise by flush out of bacteria and inflammatory components from the amniotic cavity, replacing amniotic fluid and thus prolonging PPROM-to-delivery interval.Aim: This multicenter trial tests the effect of continuous amnioinfusion on the neonatal survival without the typical major morbidities, like severe bronchopulmonary dysplasia, intraventricular hemorrhage, cystic periventricular leukomalacia and necrotizing enterocolitis one year after the delivery.Methods/Design: randomized multicenter trial; two-arm parallel design. Control group: PPROM patients between 22/0 (20/0) -26/0 WG treated with antibiotics and corticosteroids in accordance to guidelines of German Society of Obstetrics and Gynecology (standard PPROM therapy). In the interventional group the standard PPROM therapy will be complemented by “Amnion Flush Method” with the amnioinfusion of artificial amniotic fluid (up to 100 ml/h, 2400 ml/day).Subjects: 68 patients with classic PPROM between 22/0 (20/0)-26/0 WG.TRIAL-registration: ClinicalTrials.gov ID: NCT04696003 and German Clinical Trials Register: DRKS00024503, January 2021.The trial is approved by the Ethic committee of the Martin-Luther University Halle-Wittenberg (2020-185, January 25, 2021).

Minimally Invasive Precise Application of Bioadhesives to Prevent IPPROM on a Pregnant Sheep Model

<b><i>Introduction:</i></b> Iatrogenic preterm premature rupture of the membrane remains the Achille’s heel of fetoscopy. The aim of this study was to show in vivo feasibility of fetal membrane (FM) defect sealing by the application of tissue glues with umbrella-shaped receptors. <b><i>Methods:</i></b> First, we adapted our previously described ex vivo strategy and evaluated the adhesion strength of different tissue glues, Histoacryl® and Glubran2®, by bonding polytetrafluoroethylene or silicone encapsulated nitinol glue receptor to human FM. Then, we exposed pregnant sheep uterus through a laparotomy and placed a 10-French trocar into the amniotic cavity through which the umbrella-shaped glue receptor (<i>n</i> = 9) was inserted and fixated onto the FM with the tissue glues (<i>n</i> = 8). The tightness of the sealed defects was assessed 4 h post-surgery. <b><i>Results:</i></b> Both tissue glues tested resulted in adhesion of the glue receptors to the FM ex vivo. In vivo, all glue receptors opened in the amniotic cavity (<i>n</i> = 9) and all successfully placed glue receptors sealed the FM defect (<i>n</i> = 8). Four hours post-surgery, 2 treatment sites showed minimal leakage whereas the negative control without glue (<i>n</i> = 1) showed substantial leakage. <b><i>Discussion:</i></b> This in vivo study confirms that fetoscopically induced FM defects can be sealed by the application of tissue adhesives.

Treatment of mid-trimester preterm premature rupture of membranes (PPROM) with multi-resistant bacteria-colonized anhydramnion with continuous amnioinfusion and meropenem: a case report and literature review

Purpose Treatment of mid-trimester classic preterm premature rupture of membranes (PPROM) with systemic antibiotics has limited success in the prevention of chorioamnionitis, funisitis and fetal inflammatory response syndrome because of very low transplacental passage. Methods Here we report a case of PPROM at 18 weeks gestation with anhydramnion colonized by multi-resistant Escherichia coli (E. coli). A catheter system was implanted at 23/2nd weeks gestation, enabling long-term continuous lavage of the amniotic cavity with Amnion Flush Solution (100 ml/h combined with intraamniotic meropenem application). Results The patient gave birth to a preterm male infant at 28/3rd without any signs of infection. In a follow-up examination at 24 months, there was no neurological disturbance or developmental delay. Conclusion The classic PPROM with multi-resistant E. coli colonization could be treated with continuous amnioinfusion and meropenem.

When a vesicular placenta meets a live fetus: case report of twin pregnancy with a partial hydatidiform mole

Background Hydatidiform moles exhibit a distinctive gross appearance of multiple vesicles in the placenta. The advances in cytogenetic technologies have helped uncover novel entities of hydatidiform moles and enabled elaborate diagnoses. However, management of a vesicular placenta with a coexistent live fetus poses a bigger challenge beyond hydatidiform moles. Case presentation A 33-year-old woman was referred to our department for suspected hydatidiform mole coexistent with a live fetus at 24 weeks’ gestation. The patient had conceived through double embryo transplantation, and first-trimester ultrasonography displayed a single sac. Mid-trimester imaging findings of normal placenta parenchyma admixed with multiple vesicles and a single amniotic cavity with a fetus led to suspicion of a singleton partial molar pregnancy. After confirmation of a normal diploid by amniocentesis and close surveillance, the patient delivered a healthy neonate. Preliminary microscopic examination of the placenta failed to clarify the diagnosis until fluorescence in situ hybridization showed a majority of XXY sex chromosomes. The patient developed suspected choriocarcinoma and achieved remission for 5 months after chemotherapy, but relapsed with suspected intermediate trophoblastic tumor. Conclusion We report a rare case of twin pregnancy comprising a partial mole and a normal fetus that resembled a singleton partial molar pregnancy. Individualized care is important in conditions where a vesicular placenta coexists with a fetus. We strongly recommend ancillary examinations in addition to traditional morphologic assessment in such cases.

The alarmin S100A12 causes sterile inflammation of the human chorioamniotic membranes and preterm birth and neonatal mortality in mice†

Sterile inflammation is triggered by danger signals or alarmins released upon cellular stress or necrosis. Sterile inflammation occurring in the amniotic cavity (i.e. sterile intra-amniotic inflammation) is frequently observed in women with spontaneous preterm labor resulting in preterm birth, the leading cause of neonatal morbidity and mortality worldwide, and is associated with increased amniotic fluid concentrations of alarmins. However, the mechanisms whereby alarmins induce sterile intra-amniotic inflammation are still under investigation. Herein, we investigated the mechanisms whereby the alarmin S100A12 induces inflammation of the human chorioamniotic membranes in vitro and used a mouse model to establish a causal link between this alarmin and adverse perinatal outcomes. We report that S100A12 initiates sterile inflammation in the chorioamniotic membranes by upregulating the expression of inflammatory mediators such as pro-inflammatory cytokines and pattern recognition receptors. Importantly, S100A12 induced the priming and activation of inflammasomes, resulting in the activation of caspase-1 and the subsequent release of mature IL-1β by the chorioamniotic membranes. This alarmin also caused the activation of the chorioamniotic membranes by promoting MMP-2 activity and collagen degradation. Lastly, the ultrasound-guided intra-amniotic injection of S100A12 at specific concentrations observed in the majority of women with sterile intra-amniotic inflammation induced preterm birth (rates: 17% at 200 ng/sac; 25% at 300 ng/sac; 25% at 400 ng/sac) and neonatal mortality (rates: 22% at 200 ng/sac; 44% at 300 ng/sac; 31% at 400 ng/sac), demonstrating a causal link between this alarmin and adverse perinatal outcomes. Collectively, our findings shed light on the inflammatory responses driven by alarmins in the chorioamniotic membranes, providing insight into the immune mechanisms leading to preterm birth in women with sterile intra-amniotic inflammation.

Engineered neuron-targeting, placental mesenchymal stromal cell-derived extracellular vesicles for in utero treatment of myelomeningocele

This study investigated the feasibility and efficiency of neuron-targeting hybrid placental mesenchymal stromal cell-derived extracellular vesicles (PMSC-EVs), engineered by membrane fusion with Targeted Axonal Import (TAxI) peptide modified, TrkB agonist 7,8-DHF-loaded liposomes for treatment of myelomeningocele (MMC) via intra-amniotic cavity administration. The prepared TAxI modified liposomes with 7,8-DHF were used to fuse with PMSC-EVs. Different fusion approaches were investigated and freeze-thaw-extrude method was found to be the optimal. The engineered PMSC-EVs had a uniform particle size and efficiently loaded 7,8-DHF. It also had typical markers of native EVs. Freeze-thaw-extrude process did not change the release profile of 7,8-DHF from engineered EVs compared to TAxI modified, 7,8-DHF loaded liposomes. The engineered EVs could elicit TrkB phosphorylation depending on the incorporation of 7,8-DHF while native EVs did not. The engineered EVs increased neurite outgrowth of apoptotic cortical neurons induced by staurosporine, suggesting that they exhibited neuroprotective function. In a rodent model of MMC, neuron-targeting, engineered EVs became an active targeting delivery system to MMC defect sites. Pups treated with engineered EVs had the lowest density of apoptotic cells and displayed a therapeutic outcome. The study suggests the potential use of engineered hybrid, active neuron-targeting EVs for the in utero treatment of MMC.

Bacteria in the amniotic fluid without inflammation: early colonization vs. contamination

Objectives Intra-amniotic infection, defined by the presence of microorganisms in the amniotic cavity, is often accompanied by intra-amniotic inflammation. Occasionally, laboratories report the growth of bacteria or the presence of microbial nucleic acids in amniotic fluid in the absence of intra-amniotic inflammation. This study was conducted to determine the clinical significance of the presence of bacteria in amniotic fluid samples in the absence of intra-amniotic inflammation. Methods A retrospective cross-sectional study included 360 patients with preterm labor and intact membranes who underwent transabdominal amniocentesis for evaluation of the microbial state of the amniotic cavity as well as intra-amniotic inflammation. Cultivation techniques were used to isolate microorganisms, and broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was utilized to detect the nucleic acids of bacteria, viruses, and fungi. Results Patients whose amniotic fluid samples evinced microorganisms but did not indicate inflammation had a similar perinatal outcome to those without microorganisms or inflammation [amniocentesis-to-delivery interval (p=0.31), spontaneous preterm birth before 34 weeks (p=0.83), acute placental inflammatory lesions (p=1), and composite neonatal morbidity (p=0.8)]. Conclusions The isolation of microorganisms from a sample of amniotic fluid in the absence of intra-amniotic inflammation is indicative of a benign condition, which most likely represents contamination of the specimen during the collection procedure or laboratory processing rather than early colonization or infection.