Probiotic intervention as a potential therapeutic for managing gestational disorders and improving pregnancy outcomes.

Recent molecular investigations have significantly developed our knowledge of the characteristics of the reproductive microbiome and their associations with host responses to provide an ideal milieu for the development of the embryo during the peri-implantation period and throughout pregnancy as well as to provide a successful in vitro fertilization and appropriate reproductive outcomes. In this context, the establishment of microbial homeostasis in the female reproductive tract, in various physiological periods, is a substantial challenge, which appears the application of probiotics can facilitate the achievement of this goal. So that, currently, probiotics due to its safe and natural features can be considered as a novel biotherapeutic approach. In this review, we comprehensively discuss the bacterial, fungal, and viral diversity detected in the reproductive tract, and their associations with the establishment of dysbiosis/eubiosis conditions as well as we present the significant outcomes on probiotic intervention as an efficient biotherapeutic strategy for management of gestational disorders and improve pregnancy outcomes.

The maternal microbiome modulates fetal neurodevelopment in mice.

'Dysbiosis' of the maternal gut microbiome, in response to challenges such as infection1, altered diet2 and stress3 during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring4. However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain.

Determinants of adverse neonatal outcome in vaginal deliveries complicated by suspected intraamniotic infection.

PURPOSE: Intraamniotic infection, categorized into isolated maternal fever, suspected intraamniotic infection (SII), and confirmed intraamniotic infection, is associated with neonatal morbidity. However, there is paucity of data regarding the association between intraamniotic infection duration and neonatal outcomes among term singleton vaginal deliveries. We aimed to study the risk factors for adverse neonatal outcome among vaginal deliveries complicated by SII. METHODS: A retrospective observational study conducted at a tertiary medical center. All consecutive singleton term deliveries with SII were included between 2011 and 2019. Maternal and obstetrical characteristics were evaluated to identify risk factors for adverse neonatal outcome. Correlation between SII duration and neonatal adverse outcome was analyzed. RESULTS: Overall, 882 were analyzed. Most women (85.4%) were primiparous. Median gestation age at delivery was 40 2/7 weeks. Median time from SII to delivery was 170 min. Adverse neonatal outcomes occurred in 113 (12.8%) of deliveries. Duration of SII was not associated with adverse neonatal outcome. Analysis for determinants of adverse neonatal outcome revealed that oligohydramnios was more common in pregnancies with adverse neonatal outcome (7/113 (6.2%) vs. 41 (5.4%) OR [95% CI] 2.47 (1.02-5.98), p = 0.03). Duration of second stage of labor was longer in the adverse outcome group (median 179 min vs. 126 min, p = 0.008). Prolonged second stage was more common in the adverse outcome group (60 (53.1%) vs. 273 (35.5%) OR [95% CI] 2.05 (1.38-3.06), p < 0.001). On logistic regression analysis, prolonged second stage was the only modifiable factor independently associated with adverse neonatal outcome [adjusted OR 2.09 (1.37-3.2), p = 0.001]. Other variables tested did not differ between groups. Only phototherapy and base excess ≥ 12 mmol/L were significantly associated with the duration of second stage of labor; for each additional hour of the second stage, the OR for the former increased by 0.34 (p = 0.008), and for the latter by 0.69 (p = 0.007). CONCLUSION: Duration of suspected intraamniotic infection was not associated with increased neonatal morbidity among women delivering vaginally at term. Prolonged second stage was a strong independent predictor of an adverse neonatal outcome among fetuses exposed to intraamniotic infection.

Early-Life Gut Microbiome-The Importance of Maternal and Infant Factors in Its Establishment.

The early-life microbiome is gaining appreciation as a major influencer in human development and long-term health. Multiple factors are known to influence the initial colonization, development, and function of the neonatal gut microbiome. In addition, alterations in early-life gut microbial composition is associated with several chronic health conditions such as obesity, asthma, and allergies. In this review, we focus on both maternal and infant factors known to influence early-life gut colonization. Also reviewed is the important role of infant feeding, including evidence-based strategies for maternal and infant supplementation with the goal to protect and/or restore the infant gut microbiome.

Dysbiosis and Prematurity: Is There a Role for Probiotics?

Healthy microbiota is a critical mediator in maintaining health and it is supposed that dysbiosis could have a role in the pathogenesis of a number of diseases. Evidence supports the hypothesis that maternal dysbiosis could act as a trigger for preterm birth; aberrant colonization of preterm infant gut might have a role in feeding intolerance and pathogenesis of necrotizing enterocolitis. Despite several clinical trials and meta-analyses, it is still not clear if modulation of maternal and neonatal microbiota with probiotic supplementation decreases the risk of preterm birth and its complications.

Potential Application of Bacteriophages in Enrichment Culture for Improved Prenatal Streptococcus agalactiae Screening.

Vertical transmission of Streptococcus agalactiae can cause neonatal infections. A culture test in the late stage of pregnancy is used to screen for the presence of maternal S. agalactiae for intrapartum antibiotic prophylaxis. For the test, a vaginal⁻rectal sample is recommended to be enriched, followed by bacterial identification. In some cases, Enterococcus faecalis overgrows in the enrichment culture. Consequently, the identification test yields false-negative results. Bacteriophages (phages) can be used as antimicrobial materials. Here, we explored the feasibility of using phages to minimize false-negative results in an experimental setting. Phage mixture was prepared using three phages that specifically infect E. faecalis: phiEF24C, phiEF17H, and phiM1EF22. The mixture inhibited the growth of 86.7% (26/30) of vaginal E. faecalis strains. The simple coculture of E. faecalis and S. agalactiae was used as an experimental enrichment model. Phage mixture treatment led to suppression of E. faecalis growth and facilitation of S. agalactiae growth. In addition, testing several sets of S. agalactiae and E. faecalis strains, the treatment with phage mixture in the enrichment improved S. agalactiae detection on chromogenic agar. Our results suggest that the phage mixture can be usefully employed in the S. agalactiae culture test to increase test accuracy.

Overweight and obesity status in pregnant women are related to intestinal microbiota and serum metabolic and inflammatory profiles.

BACKGROUND: Overweight and obesity may predispose women to clinical complications during their pregnancy. We hypothesize that a higher degree of overweight status is related to a range of aberrations in biomarkers already in early pregnancy. Our objective was to investigate whether intestinal microbiota, serum metabolic and inflammatory profiles differ in relation to the degree of overweight status in pregnant women. METHODS: This study investigated 52 overweight and 47 obese pregnant women in early pregnancy. Fecal samples were analyzed for intestinal microbiota composition by 16S ribosomal RNA gene sequencing and Qiime pipeline. Circulating serum metabolites, including lipids, amino acids and GlycA, a marker of low-grade inflammation, were analyzed by NMR metabolomics and hsCRP was quantified by immunoassay. Serum zonulin levels were analyzed to depict intestinal permeability by Zonulin ELISA kit and LPS activity for endotoxemia by Limulus amebocyte lysate assay. The analyses were adjusted for multiple comparisons using Benjamini-Hochberg procedure for false discovery rate controlling. RESULTS: The relative abundance of bacterial family Prevotellaceae (adjusted P = 0.19) and markers of low-grade inflammation, hsCRP (P = 0.0015) and GlycA (P < 0.001) and three branched chain amino acids (isoleucine, adjusted P = 0.024; leucine, adjusted P = 0.026; valine, adjusted P = 0.10) and one aromatic amino acid (phenylalanine, adjusted P = 0.050) and concentrations of several VLDL particles and lipid measures in several VLDL particles were higher in obese pregnant women compared to their overweight pregnant counterparts (adjusted P < 0.12). In contrast, lipid measures in a few HDL particles and many fatty acids were lower in obese compared to overweight pregnant women (adjusted P < 0.12). CONCLUSIONS: The detected alterations in intestinal microbiota and metabolic and inflammatory profiles related to obesity status may offer new alternative tools to supplement standard clinical measures to predict the risk for metabolic alterations during the early phase of pregnancy.

The impact of probiotics and n-3 long-chain polyunsaturated fatty acids on intestinal permeability in pregnancy: a randomised clinical trial.

A disruption in intestinal barrier integrity may predispose individuals to metabolic aberrations, particularly during the vulnerable period of pregnancy. We investigated whether intestinal permeability, as measured by serum zonulin concentration, changes over the duration of pregnancy and whether this change is reflected in lipopolysaccharide (LPS) activity. Second, we tested in a randomised double-blind placebo controlled clinical trial the impact of consuming dietary probiotics and/or long chain polyunsaturated fatty acid (LC-PUFA) supplements in lowering serum zonulin concentration and LPS activity. The probiotic supplement was a combination of two bacteria, Bifidobacterium animalis ssp. lactis 420 and Lactobacillus rhamnosus HN001. This study included 200 overweight pregnant women participating in an on-going study; participants were randomised to consume either (1) probiotics, (2) LC-PUFA, (3) probiotics and LC-PUFA, or (4) placebo for each supplement. Blood samples were obtained at early, the baseline, and late pregnancy (mean 14 and 35 weeks of gestation, respectively). Serum zonulin concentration increased from early (mean (standard deviation): 62.7 (12.9) ng/ml) to late pregnancy by 5.3 (95%CI 3.7-6.9) ng/ml, and LPS activity increased from (0.16 (0.04) EU/ml) by 0.04 (95%CI 0.03-0.05) EU/ml. No differences among the intervention groups were detected in the change from early to late pregnancy in serum zonulin concentration (P=0.8) or LPS activity (P=0.2). The change in serum zonulin concentration during the pregnancy was associated with the weeks of follow up (r=0.25, P<0.001). Serum LPS activity was correlated with higher maternal weight gain (r=0.19, P=0.008). As a conclusion, intestinal permeability increased with the progression of pregnancy in overweight and obese women and was reflected in LPS activity. No efficacy of supplementation with probiotics and/or LC-PUFA was demonstrated in pregnancy-induced changes in serum zonulin concentration or LPS activity.

Probiotics and pregnancy.

Complications of pregnancy are associated with adverse outcomes for mother and baby in the short and long term. The gut microbiome has been identified as a key factor for maintaining health outside of pregnancy and could contribute to pregnancy complications. In addition, the vaginal and the recently revealed placental microbiome are altered in pregnancy and may play a role in pregnancy complications. Probiotic supplementation could help to regulate the unbalanced microflora composition observed in obesity and diabetes. Here, the impact of probiotic supplementation during pregnancy and infancy is reviewed. There are indications for a protective role in preeclampsia, gestational diabetes mellitus, vaginal infections, maternal and infant weight gain and allergic diseases. Large, well-designed randomised controlled clinical trials along with metagenomic analysis are needed to establish the role of probiotics in adverse pregnancy and infancy outcomes.

The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery.

BACKGROUND: Breast milk is recognized as the most important postpartum element in metabolic and immunologic programming of health of neonates. The factors influencing the milk microbiome and the potential impact of microbes on infant health have not yet been uncovered. OBJECTIVE: Our objective was to identify pre- and postnatal factors that can potentially influence the bacterial communities inhabiting human milk. DESIGN: We characterized the milk microbial community at 3 different time points by pyrosequencing and quantitative polymerase chain reaction in mothers (n = 18) who varied in BMI, weight gain, and mode of delivery. RESULTS: We found that the human milk microbiome changes over lactation. Weisella, Leuconostoc, Staphylococcus, Streptococcus, and Lactococcus were predominant in colostrum samples, whereas in 1- and 6-mo milk samples the typical inhabitants of the oral cavity (eg, Veillonella, Leptotrichia, and Prevotella) increased significantly. Milk from obese mothers tended to contain a different and less diverse bacterial community compared with milk from normal-weight mothers. Milk samples from elective but not from nonelective mothers who underwent cesarean delivery contained a different bacterial community than did milk samples from individuals giving birth by vaginal delivery, suggesting that it is not the operation per se but rather the absence of physiological stress or hormonal signals that could influence the microbial transmission process to milk. CONCLUSIONS: Our results indicate that milk bacteria are not contaminants and suggest that the milk microbiome is influenced by several factors that significantly skew its composition. Because bacteria present in breast milk are among the very first microbes entering the human body, our data emphasize the necessity to understand the biological role that the milk microbiome could potentially play for human health.

Tratamiento de la infección genital por virus del papiloma humano durante la gestación / Treatmentof genital infections by human papiloma virus during pregnancy

La infección genital por Virus del Papiloma Humano (VPH) puede afectar mujeres, varones e incluso estos. En algunos sitios es incluso la enfermedad de transmisión sexual más frecuente. En las últimas dos décadas ha tomado crecimiento importancia por la posibilidad de afectar al bebé a su paso por el canal del parto infectado provocándole Papilomatosis Laríngea Juvenil así como lesiones virales en conjuntiva e incluso en genitales. Se ha propuesto que la realización de operación cesárea evita dicho riesgo. Información reciente muestra que este abordaje no solo es insuficiente, sino que es exagerado en la mayoría de los casos. Se propone como alternativa efectuar un abordaje integral que incluya realización de colposcopía y biopsia de las lesiones sospechosas, seguido de tratamiento de las zonas infectadas y seguimiento estrecho. Los recursos terápeuticos más valiosos con la crioterapia, laser, electrocauterio y ácido tricoloroacético. La realización de operación cesárea se limitaría entonces a los casos refractarios a tratamiento, aquellos diagnosticados tardíamente o en los que las lesiones voluminosas provoquen distocia. El manejo debe inclir valoración diagnóstica de la(s) pareja(s) sexual(es) de la mujer así como del neonato, con tratamiento subsecuente -de ser necesario- según el caso

[Antibacterial therapy of pyelonephritis in pregnant women]. / Antibakterial'naia terapiia pielonefrita beremennykh.

To determine the optimal schemes of rational antibacterial therapy of pyelonephritis gravidarum with ampicillin and cephuroxim, assays of the patient urine and studies on the pharmacokinetics of the drugs were performed. The bacteriurea levels were estimated in 264 women with Gould's method in modification of Ryabinsky and Rodoman. The causative agents of the disease were isolated from the urine of 92 pregnant women. Sensitivity of the isolates to 9 antibiotics was tested with the use of standard paper disks and the method of serial dilutions in solid media. The pharmacokinetics of ampicillin and cephuroxim in the blood and urine of 97 patients was studied for 6-8 hours after parenteral administration of the antibiotics in doses of 500 mg. Comparative analysis of the pharmacokinetic parameters of the antibiotics in the blood and urine of the patients, the antibiotic MICs for the disease causative agents and the clinical course of the disease suggests that pyelonephritis gravidarum should be treated with ampicillin and cephuroxim on doses of 500 mg injected intramuscularly 4 and 3 times a day respectively for 7-8 days in combination with antiinflammatory therapy.