Effect of acute histologic chorioamnionitis on bronchopulmonary dysplasia and mortality rate among extremely low gestational age neonates: A retrospective case-control study.

OBJECTIVE: To evaluate whether acute histologic chorioamnionitis (HCA) diagnosed in the placenta may be associated with an increased occurrence of bronchopulmonary dysplasia (BPD) or death among extremely low gestational age neonates (ELGAN). METHODS: This Italian single-center case-control retrospective study involved ELGAN admitted to the neonatal intensive care unit between January 2019 and June 2022. Infants born from pregnant women with acute and severe HCA, identified as stage ≥2 and grade 2 HCA, (HCA-infants) were compared with infants of pregnant women without chorioamnionitis or with stage 1, grade 1 chorioamnionitis (no-HCA-infants). RESULTS: Among 101 eligible ELGAN, 63 infants had complete clinical and histologic data relevant to the study: thirty infants were included in the HCA-infants group and 33 in the no-HCA-infants group. Neonatal and maternal demographic and clinical characteristics were similar between the two groups. Infants born from mothers with acute and severe HCA had significantly higher occurrence of composite BPD or death (18 [60%] vs. 9 [27%]; P = 0.012), as well as higher incidence of severe forms of BPD (6 [30%] vs. 2 [6%]; P = 0.045). In multiple logistic regression analysis, after adjustment for confounding covariates, HCA was an independent risk factor for BPD or death (OR, 4.49; 95% CI: 1.47-13.71). CONCLUSIONS: This is the first study showing that in utero exposure to acute and severe HCA is an independent risk factor for the occurrence of composite BPD or death among ELGAN.

FIGO good practice recommendations: Bundle of care to reduce neonatal mortality and improve outcomes after preterm and term delivery.

An integrated approach is lacking for the management of childbirth and newborn care, even though their codependence is critical for improving maternal and newborn outcomes. FIGO's Prep-for-Labor rapid triage methods for women arriving at a clinical facility are addressed in earlier papers in this Supplement, but do not include newborn care. Immediate postpartum rapid triage using established Apgar score helps determine whether standard of care can be followed on site with available staff/tools. If not, newborn transfer alone or with the mother to a higher-level center as soon as feasible may be required. Updated newborn management tools with special emphasis on pragmatic steps that are applicable for any clinical setting including low- and middle-income countries (LMICs) are presented in this article. Given that more than 80% of newborn care can be managed at the birthing facility, transfer to a higher-level center for care is required only in selected cases. Management steps for healthy newborns are described and the actions needed for those requiring resuscitation are summarized. The simple noninvasive kangaroo mother care approach-universally applicable for both term and preterm newborns-is associated with a significant reduction in morbidity and mortality. Kangaroo mother care involves continuous maternal skin-to skin contact from birth, exclusive breastfeeding, and home support after discharge. Hence, hypothermia, hypoglycemia, and acquired infections are frequently prevented. It is anticipated that implementing simple noninvasive management steps will have a substantial positive impact on improving maternal and newborn outcomes.

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

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

Prep-for-Labor: Overview of FIGO's labor and delivery triage bundles of care to optimize maternal and newborn outcomes.

Childbirth is an intense event in which decisions may need to be made in seconds to guarantee the health of both mother and newborn. Despite health systems and care approaches varying widely according to real-life scenarios, availability of facilities, beliefs, resources, staff, and geography, among others, optimal outcomes should be ensured worldwide. Triaging low-risk pregnancies from high-risk pregnancies is the first step to ensure proper allocation of resources. From this need, we developed FIGO's Prep-For-Labor triage methods, a series of 2-minute labor and delivery bundles of care, with special regard given to low- and middle-income countries and rural settings. Around 80% of women, once properly triaged, can pursue vaginal delivery with minimal intervention, while those at risk can either be managed on site or transferred promptly to an advanced care site. FIGO's bundles of care and good practice recommendations for labor and delivery and immediate newborn triage cover four clinical scenarios: (1) preterm labor; (2) induced or spontaneous labor at term; (3) cesarean delivery; and (4) newborn care. From rapid triage of the mother (low vs high risk) to the list of required equipment, description of skilled staff, and coordination of resources, the recommendations for care are introduced across these four areas in this overview article. Implementing the proposed management steps described in each summary can improve maternal and neonatal outcomes.

FIGO good practice recommendations for cesarean delivery: Prep-for-Labor triage to minimize risks and maximize favorable outcomes.

Cesarean delivery is an abdominal surgical procedure performed for child delivery when the vaginal route is not feasible or desired due to maternal/fetal indications. All childbirth facilities should be able to safely perform a cesarean, which is not the current reality. For planned cesarean delivery, the facility must be prepared for the patient. In contrast, for unplanned arrivals at the facility, FIGO's Prep-for-Labor triage method allows rapid decision-making on whether cesarean delivery can be safely performed on site or whether transfer to an advanced care center is needed. A checklist of staff/tools for safe on-site cesarean delivery is provided to enable timely decision-making. Maternal complications following cesarean are three-fold higher than vaginal delivery. To prevent nonmedically indicated cesarean by favoring vaginal delivery, up-to-date safe and effective guidance is provided, defining labor, second stage length, and status before an arrested labor is confirmed. Whether cesarean delivery is planned or emergency, the Misgav Ladach simplified procedure is proposed as it is suitable for both low- and high-risk cases, including twins, thereby reducing both operative morbidity and postoperative recovery. A trial of labor after first cesarean (TOLAC) should be pursued when feasible, for which the indications, contraindications, safeguards, and steps of safe labor induction are delineated. Implementation of these good practice recommendations will improve childbirth by reducing excessive nonindicated cesareans, while precisely defining the resources and postoperative care required for safe performance on site. Enabling safe childbirth by cesarean and TOLAC, even at sites with low rates currently, will significantly improve maternal and fetal outcomes.

FIGO good practice recommendations for induced or spontaneous labor at term: Prep-for-Labor triage to minimize risks and maximize favorable outcomes.

The goal of induced or spontaneous labor is childbirth by vaginal delivery. Delivery after 37 weeks is desirable and associated with favorable maternal and newborn outcomes. Delivery facilities should have suitable staff and resources on site for antenatal services and delivery care. FIGO's Prep-for-Labor triage method provides rapid diagnostic tools that help define patients as high or low risk to determine whether transfer to a higher-level center is needed. There is often a disconnect between a facility's designation and its ability to achieve safe deliveries. For preplanned labor induction, the designated clinical facility must have the right set-up and prenatal records available to achieve a successful outcome. However, this is often not the case if a patient arrives in labor or needs an induction and the facility has limited patient information and resources, thus requiring rapid management decisions. The practical guidance checklist in this article defines maternal and/or fetal risk factors and delineates approaches and safe practices for labor induction and management, including when antenatal information is limited to maximize safe delivery practices. Guidelines on using the Bishop score (>6 or <6) to manage labor are presented. Evidence supporting successful safe labor induction at 41-42 weeks of gestation in low-risk cases is described. This practice will increase the rate of spontaneous labor and delivery, minimizing intervention and thereby diverting limited clinical resources to those patients in need. In the right setting, this could lead to around 80% of women delivering spontaneously, which remains a desired goal.

Murine glial progenitor cells transplantation and synthetic PreImplantation Factor (sPIF) reduces inflammation and early motor impairment in ALS mice.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuronal disorder characterized by neuronal degeneration and currently no effective cure is available to stop or delay the disease from progression. Transplantation of murine glial-restricted precursors (mGRPs) is an attractive strategy to modulate ALS development and advancements such as the use of immune modulators could potentially extend graft survival and function. Using a well-established ALS transgenic mouse model (SOD1G93A), we tested mGRPs in combination with the immune modulators synthetic PreImplantation Factor (sPIF), Tacrolimus (Tac), and Costimulatory Blockade (CB). We report that transplantation of mGRPs into the cisterna magna did not result in increased mice survival. The addition of immunomodulatory regimes again did not increase mice lifespan but improved motor functions and sPIF was superior compared to other immune modulators. Immune modulators did not affect mGRPs engraftment significantly but reduced pro-inflammatory cytokine production. Finally, sPIF and CB reduced the number of microglial cells and prevented neuronal number loss. Given the safety profile and a neuroprotective potential of sPIF, we envision its clinical application in near future.

The voltage-gated potassium channel KV1.3 regulates neutrophil recruitment during inflammation.

AIMS: Neutrophil trafficking within the vasculature strongly relies on intracellular calcium signalling. Sustained Ca2+ influx into the cell requires a compensatory efflux of potassium to maintain membrane potential. Here, we aimed to investigate whether the voltage-gated potassium channel KV1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca2+ signalling. METHODS AND RESULTS: Using in vitro assays and electrophysiological techniques, we show that KV1.3 is functionally expressed in human neutrophils regulating sustained store-operated Ca2+ entry through membrane potential stabilizing K+ efflux. Inhibition of KV1.3 on neutrophils by the specific inhibitor 5-(4-Phenoxybutoxy)psoralen (PAP-1) impaired intracellular Ca2+ signalling, thereby preventing cellular spreading, adhesion strengthening, and appropriate crawling under flow conditions in vitro. Using intravital microscopy, we show that pharmacological blockade or genetic deletion of KV1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified KV1.3 as a critical component for neutrophil extravasation into the inflamed peritoneal cavity. Finally, we also revealed impaired phagocytosis of Escherichia coli particles by neutrophils in the absence of KV1.3. CONCLUSION: We show that the voltage-gated potassium channel KV1.3 is critical for Ca2+ signalling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of KV1.3 for sustained calcium signalling in neutrophils affecting key functions of these cells, they also open up new therapeutic approaches to treat inflammatory disorders characterized by overwhelming neutrophil infiltration.

Corrigendum: Editorial: Immunological role of the maternal microbiome in pregnancy.

[This corrects the article DOI: 10.3389/fimmu.2021.703009.].

Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2.

Failed or altered gliogenesis is a major characteristic of diffuse white matter injury in survivors of premature birth. The developmentally regulated long noncoding RNA (lncRNA) H19 inhibits S-adenosylhomocysteine hydrolase (SAHH) and contributes to methylation of diverse cellular components, such as DNA, RNA, proteins, lipids, and neurotransmitters. We showed that the pregnancy-derived synthetic PreImplantation Factor (sPIF) induces expression of the nuclear receptor corepressor 2 (NCOR2) via H19/SAHH-mediated DNA demethylation. In turn, NCOR2 affects oligodendrocyte differentiation markers. Accordingly, after hypoxic-ischemic brain injury in rodents, myelin protection and oligodendrocytes' fate are in part modulated by sPIF and H19. Our results revealed an unexpected mechanism of the H19/SAHH axis underlying myelin preservation during brain recovery and its use in treating neurodegenerative diseases can be envisioned.

Assessment of Immunological Potential of Glial Restricted Progenitor Graft In Vivo-Is Immunosuppression Mandatory?

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease, causing motor neuron and skeletal muscle loss and death. One of the promising therapeutic approaches is stem cell graft application into the brain; however, an immune reaction against it creates serious limitations. This study aimed to research the efficiency of glial restricted progenitors (GRPs) grafted into murine CNS (central nervous system) in healthy models and the SOD1G93A ALS disease model. The cellular grafts were administered in semiallogenic and allogeneic settings. To investigate the models of immune reaction against grafted GRPs, we applied three immunosuppressive/immunomodulatory regimens: preimplantation factor (PiF); Tacrolimus; and CTLA-4, MR1 co-stimulatory blockade. We tracked the cells with bioluminescence imaging (BLI) in vivo to study their survival. The immune response character was evaluated with brain tissue assays and multiplex ELISA in serum and cerebrospinal fluid (CSF). The application of immunosuppressive drugs is disputable when considering cellular transplants into the immune-privileged site/brain. However, our data revealed that semiallogenic GRP graft might survive inside murine CNS without the necessity to apply any immunomodulation or immunosuppression, whereas, in the situation of allogeneic mouse setting, the combination of CTLA-4, MR1 blockade can be considered as the best immunosuppressive option.

Preimplantation factor modulates trophoblastic invasion throughout the decidualization of human endometrial stromal cells.

BACKGROUND: Successful human embryo implantation requires the differentiation of endometrial stromal cells (ESCs) into decidual cells during a process called decidualization. ESCs express specific markers of decidualization, including prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1), and connexin-43. Decidual cells also control of trophoblast invasion by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases. Preimplantation factor (PIF) is a recently identified, embryo-derived peptide with activities at the fetal-maternal interface. It creates a favorable pro-inflammatory environment in human endometrium and directly controls placental development by increasing the human trophoblastic cells' ability to invade the endometrium. We hypothesized that PIF's effects on the endometrium counteract its pro-invasive effects. METHODS: We tested sPIF effect on the expression of three decidualization markers by RT-qPCR and/or immunochemiluminescence assay. We examined sPIF effect on human ESC migration by performing an in vitro wound healing assay. We analyzed sPIF effect on endometrial control of human trophoblast invasion by performing a zymography and an invasion assay. RESULTS: Firstly, we found that a synthetic analog of PIF (sPIF) significantly upregulates the mRNA expression of IGFBP-1 and connexin-43, and prolactin secretion in ESCs - suggesting a pro-differentiation effect. Secondly, we showed that the HTR-8/SVneo trophoblastic cell line's invasive ability was low in the presence of conditioned media from ESCs cultured with sPIF. Thirdly, this PIF's anti-invasive action was associated with a specifically decrease in MMP-9 activity. CONCLUSION: Taken as a whole, our results suggest that PIF accentuates the decidualization process and the production of endometrial factors that limit trophoblast invasion. By controlling both trophoblast and endometrial cells, PIF therefore appears to be a pivotal player in the human embryo implantation process.

Don't forget eclampsia in the efforts to reduce maternal morbidity and mortality.

Hypertensive disorders are a leading cause of maternal morbidity and mortality worldwide. Despite advances in prevention and clinical management, women in low-resource countries continue to bear the burden of the sequelae of severe pre-eclampsia-eclampsia. Sustainable strategies to improve the care of women with hypertensive disease, to identify those at risk for hypertensive disease, and to reduce the risk of eclampsia will require partnerships between clinicians and health policy makers. Resources are needed to scale up healthcare access and infrastructure, establish evidence-based protocols for care, and ensure an adequate supply of equipment and drugs. Additionally, efforts for a sustained workforce of perinatal clinicians and staff trained in the assessment and management of hypertensive disease are needed. Effective postpartum care and monitoring are essential to prevent morbidity and mortality due to cardiovascular disease. Culturally appropriate strategies are needed to educate women and their families on the symptoms of pre-eclampsia to address delays in seeking care during pregnancy and postpartum. With targeted, sustained efforts and resources, eclampsia and its associated co-morbidities can be preventable.

From fragmented levels of care to integrated health care: Framework toward improved maternal and newborn health.

Worldwide, health systems and care approaches vary widely due to local reality, distance to facilities, cultural norms, resources, staff availability, geography, and politics. Consequently, globally maternal-newborn dyad care and outcomes are highly variable, leading to approximately 800 maternal deaths daily with a 100-fold difference among high- and low-resource countries. Irrespective of where care is received, maternal safety and wellbeing should be preserved. Despite ongoing efforts, however, this is not the case. Large gaps exist between spending and clinical outcomes. Segmented health care, coupled with poor planning and inadequate resource distribution, results in failure to provide essential life-saving treatment. The proposed solution is a regional integrated care model from midwife to advanced level III/IV care and the newborn unit, achieved through effective coordination by site, staff, and clinicians. This model has been successfully implemented in high- to low-resource countries in the past 20 years. In the large diverse population of the United States, constructive steps have been implemented to reduce high maternal mortality in black and rural communities. The COVID-19 pandemic demonstrates the feasibility of rapid resources coordination to provide effective advanced care. The proposed integration of resources will have a major positive impact on the maternal-newborn dyad.

FIGO position paper on reference charts for fetal growth and size at birth: Which one to use?

Publication of the Intergrowth-21st and WHO growth charts raises the question of which growth data prenatal providers should use in clinical practice. Is it better to use a universal chart applied globally, or metrics based on local or regional growth patterns? And what about customized charts versus local charts? FIGO has reviewed the different growth charts and studies assessing their reproducibility and predictive values for small- and large-for-gestational age newborns and, where available, adverse fetal outcomes. It concludes that local or regional charts are likely to be best for identifying the 10th percentile of newborns at highest risk. However, international standards for growth may also be used when coupled with locally appropriate thresholds for risk interpretation.

FIGO Statement: Vaccination in pregnancy.

Pregnant women and their fetuses are among the vulnerable populations that can be severely affected by communicable diseases. As such, some vaccines such as the influenza and the Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccines are strongly recommended in each pregnancy, with generally safe profiles. Other vaccines can be offered based on risk factors, and only when the benefits of receiving them outweigh the risks. Development of vaccines against group B streptococcus infection and respiratory syncytial virus infection are of great importance. In this paper, the recommendations for administration of each vaccine during pregnancy are discussed. The FIGO Committee for Safe Motherhood and Newborn Health Committee endorses the recommendations to vaccinate all pregnant women against influenza during the influenza season at any time during the pregnancy and against Tdap preferably between the 27th and 36th weeks of pregnancy in each pregnancy.

Synthetic PreImplantation Factor (sPIF) reduces inflammation and prevents preterm birth.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy.

PreImplantation Factor immunohistochemical expression correlates with prostate cancer aggressiveness.

BACKGROUND: The PreImplantation Factor (PIF)-a peptide secreted by viable embryos-exerts autotrophic protective effects, promotes endometrial receptivity and controls trophoblast invasion. Synthetic PIF (sPIF) has both immune-protective and regenerative properties, and reduces oxidative stress and protein misfolding. PIF is detected by immunohistochemistry (IHC) in hyperplastic endometriotic lesions and advanced uterine cancer. sPIF reduces graft-versus-host disease while maintaining a graft-versus-leukemia effect. METHODS: PIF detection in prostate cancer was assessed in 50 human prostate samples following radical prostatectomy using tumor-microarray-based IHC correlating PIF immune staining with Gleason score (GS) and cancer aggressiveness. RESULTS: PIF was detected in moderate-to-high risk prostate cancer (GS 4+3 and beyond, prognostic groups 3 to 5). In prostate cancer (GS (WHO Grade Group (GG)5), PIF was detected in 50% of cases; in prostate cancer (GS 4+4 GG4), PIF was observed in 62.5% of cases; in prostate cancer (GS 4+3 GG3), PIF immunostaining was observed in 57.1% of cases. In prostate cancer, (GS 3+4 GG2) and (GS 3+3 GG1) cases where PIF staining was negative to weak, membranous staining was observed in 20% of cases (staining pattern considered negative). High-grade prostate intraepithelial neoplasia PIF positive stain in 28.57% of cases (6 of 21) was observed. In contrast, PIF was not detected in normal prostate glands. Importantly, sPIF added to the PC3 cell line alone or combined with prostate cancer fibroblast feeder-cells did not affect proliferation. Only when peripheral blood mononuclear cells were added to the culture, a minor increase in cell proliferation was noted, reflecting local proliferation control. CONCLUSIONS: Collectively, PIF assessment could be a valuable, simple-to-use immunohistochemical biomarker to evaluate aggressiveness/prognosis in specimens from prostate cancer patients.

Synthetic PreImplantation Factor (sPIF) induces posttranslational protein modification and reverses paralysis in EAE mice.

An autoimmune response against myelin protein is considered one of the key pathogenic processes that initiates multiple sclerosis (MS). The currently available MS disease modifying therapies have demonstrated to reduce the frequency of inflammatory attacks. However, they appear limited in preventing disease progression and neurodegeneration. Hence, novel therapeutic approaches targeting both inflammation and neuroregeneration are urgently needed. A new pregnancy derived synthetic peptide, synthetic PreImplantation Factor (sPIF), crosses the blood-brain barrier and prevents neuro-inflammation. We report that sPIF reduces paralysis and de-myelination of the brain in a clinically-relevant experimental autoimmune encephalomyelitis mice model. These effects, at least in part, are due to post-translational modifications, which involve cyclic AMP dependent protein kinase (PKA), calcium-dependent protein kinase (PKC), and immune regulation. In terms of potential MS treatment, sPIF was successfully tested in neurodegenerative animal models of perinatal brain injury and experimental autoimmune encephalitis. Importantly, sPIF received a FDA Fast Track Approval for first in human trial in autommuninty (completed).