Analysis of cervicovaginal fluid metabolome and microbiome in relation to preterm birth.

The biochemical activities and resultant metabolic by-products of the vaginal microbial community during gestation can provide useful insight into the pathophysiology of preterm birth (PTB), as well as help in identifying women at risk. These metabolic changes leave specific signature fingerprints that can be investigated by Magnetic resonance spectroscopy (MRS). Therefore, we hypothesised that women who ultimately deliver prematurely will have significantly different vaginal microbiota metabolite signatures compared to their term counterparts even in the absence of clinical infection. In order to characterise and validate the cervicovaginal fluid (CVF) metabolite profiles and determine their predictive capacities for PTB, high-vaginal swabs were obtained from asymptomatic and symptomatic pregnant women sub-classified depending on a previous history of PTB and/or short cervix (< 25 mm) into: asymptomatic low risk (ALR) women with no prior PTB nor short cervix, 20-22 gestational weeks (w), n = 183; and asymptomatic high risk (AHR) women with prior history of PTB and/or short cervix, 20-22 w, n = 186. A subset of these women were assessed again at 26-28 w (due to their high-risk status), n = 129. The fourth cohort comprised women presenting with symptoms of threatened preterm labour (PTL) 24-36 w, n = 89 (SYM). CVF dissolved in phosphate buffered saline was analysed with a 9.4T MR spectrometer. Metabolites were identified, integrated for peak area and normalised to the total spectrum integral (excluding water signal). Acetate concentrations (AceConc) were also determined from a randomly selected subset of SYM women (n = 57), by a spectrophotometric technique. Additionally, clinical parameters such as cervical length (CL), fetal fibronectin (FFN), and vaginal pH were recorded and correlated to the metabolites. Furthermore, the 16S rDNA of vaginal bacterial species were PCR-amplified and the vaginal cytology was also determined by Gram, Hematoxylin and eosin, and Papanicolaou staining methods. We observed that acetate normalised integral (N.I.) (P = 0.002), and acetate/lactate ratio (P = 0.002) were higher in the SYM women who delivered preterm. These were also predictive of PTB < 37 w (AUROC: acetate N.I. = 0.75; acetate/lactate ratio = 0.76), < 32 w (AUROC: acetate N.I. = 0.73; acetate/lactate ratio = 0.79), and within 2 weeks of the index assessment (AUROC: acetate N.I. = 0.77; acetate/lactate ratio = 0.78), whilst glutamine/glutamate N.I.s was predictive of PTB < 32 w (AUROC = 0.71), and within 2 weeks of the index assessment (AUROC = 0.68) only. Also, in the AHR20-22w and ALR women, acetate (AUROC = 0.61) and branched chain amino acids N.I.s (AUROC = 0.75) were predictive of PTB < 37 w respectively. Normalised integrals of succinate, formate, lactate, and glucose did not differ in relation to PTB in any of the groups. Like the acetate N.I.s, AceConc in the SYM women was higher (P = 0.006) in the preterm-delivered women and was predictive of PTB 0.53 g/l. AceConc also correlated with acetate N.I. (r = 0.69; P < 0.0001). PCR revealed a higher prevalence of potentially pathogenic anaerobic bacteria species in the preterm-delivered women across the groups except the ALR women. Apart from correlating with clinical parameters, the prediction of PTB was improved especially in the SYM women when metabolite N.I.s, CL and FFN were combined. In conclusion, elevated CVF acetate showed clinically useful discriminative propensity for preterm delivery and delivery within 2 weeks of presentation in symptomatic women. A ratio of acetate to lactate showed similar discriminatory capacity in symptomatic women, whilst branched chain amino acids appeared predictive of preterm delivery in asymptomatic women at low risk of PTB. These metabolite differences were supported with the association of higher prevalence of mixed anaerobes in the vaginal melieu and preterm birth

Placental microbial–metabolite profiles and inflammatory mechanisms associated with preterm birth

There is growing emphasis on the potential significance of the placental microbiome and microbiome–metabolite interactions in immune responses and subsequent pregnancy outcome, especially in relation to preterm birth (PTB). This review discusses in detail the pathomechanisms of placental inflammatory responses and the resultant maternal–fetal allograft rejection in both microbial-induced and sterile conditions. It also highlights some potential placental-associated predictive markers of PTB for future investigation. The existence of a placental microbiome remains debatable. Therefore, an overview of our current understanding of the state and role of the placental microbiome (if it exists) and metabolome in human pregnancy is also provided. We critical evaluate the evidence for a placental microbiome, discuss its functional capacity through the elaborated metabolic products and also describe the consequent and more established fetomaternal inflammatory responses that stimulate the pathway to preterm premature rupture of membranes, preterm labour and spontaneous PTB

Identifying metabolite markers for preterm birth in cervicovaginal fluid by magnetic resonance spectroscopy

Introduction Preterm birth (PTB) may be preceded by changes in the vaginal microflora and metabolite profiles. Objectives We sought to characterise the metabolite profile of cervicovaginal fluid (CVF) of pregnant women by 1H NMR spectroscopy, and assess their predictive value for PTB. Methods A pair of high-vaginal swabs was obtained from pregnant women with no evidence of clinical infection and grouped as follows: asymptomatic low risk (ALR) women with no previous history of PTB, assessed at 20–22 gestational weeks, g.w., n = 83; asymptomatic high risk (AHR) women with a previous history of PTB, assessed at both 20–22 g.w., n = 71, and 26–28 g.w., n = 58; and women presenting with symptoms of preterm labor (PTL) (SYM), assessed at 24–36 g.w., n = 65. Vaginal secretions were dissolved in phosphate buffered saline and scanned with a 9.4 T NMR spectrometer. Results Six metabolites (lactate, alanine, acetate, glutamine/glutamate, succinate and glucose) were analysed. In all study cohorts vaginal pH correlated with lactate integral (r = -0.62, p\0.0001). Lactate integrals were higher in the term ALR compared to the AHR (20–22 g.w.) women (p = 0.003). Acetate integrals were higher in the preterm versus term women for the AHR (20–22 g.w.) (p = 0.048) and SYM (p = 0.003) groups; and was predictive of PTB\37 g.w. (AUC 0.78; 95 % CI 0.61–0.95), and delivery within 2 weeks of the index assessment (AUC 0.84; 95 % CI 0.64–1) in the SYM women, whilst other metabolites were not. Conclusion High CVF acetate integral of women with symptoms of PTL appears predictive of preterm delivery, as well as delivery within 2 weeks of presentation

Interventions for the prevention of spontaneous preterm birth : a scoping review of systematic reviews

BACKGROUND: Globally, 11% of babies are born preterm each year. Preterm birth (PTB) is a leading cause of neonatal death and under-five mortality and morbidity, with lifelong sequelae in those who survive. PTB disproportionately impacts low/middle-income countries (LMICs) where the burden is highest. OBJECTIVES: This scoping review sought to the evidence for interventions that reduce the risk of PTB, focusing on the evidence from LMICs and describing how context is considered in evidence synthesis. DESIGN: We conducted a scoping review, to describe this wide topic area. We searched five electronic databases (2009-2020) and contacted experts to identify relevant systematic reviews of interventions to reduce the risk of PTB. We included published systematic reviews that examined the effectiveness of interventions and their effect on reducing the risk of PTB. Data were extracted and is described narratively. RESULTS: 139 published systematic reviews were included in the review. Interventions were categorised as primary or secondary. The interventions where the results showed a greater effect size and consistency across review findings included treatment of syphilis and vaginal candidiasis, vitamin D supplementation and cervical cerclage. Included in the 139 reviews were 1372 unique primary source studies. 28% primary studies were undertaken in LMIC contexts and only 4.5% undertaken in a low-income country (LIC) Only 10.8% of the reviews sought to explore the impact of context on findings, and 19.4% reviews did not report the settings or the primary studies. CONCLUSION: This scoping review highlights the lack of research evidence derived from contexts where the burden of PTB globally is greatest. The lack of rigour in addressing contextual applicability within systematic review methods is also highlighted. This presents a risk of inappropriate and unsafe recommendations for practice within these contexts. It also highlights a need for primary research, developing and testing interventions in LIC settingsNIHR (National Institute for Health and Care Research)http://bmjopen.bmj.comObstetrics and Gynaecolog