Preterm birth prediction in asymptomatic women at mid-gestation using a panel of novel protein biomarkers: the Prediction of PreTerm Labor (PPeTaL) study

Abstract

BACKGROUND: Accurate prediction of spontaneous preterm labor/preterm birth in asymptomatic women remains an elusive clinical challenge because of the multi-etiological nature of preterm birth. OBJECTIVE: The aim of this study was to develop and validate an immunoassay-based, multi-biomarker test to predict spontaneous preterm birth. MATERIALS AND METHODS: This was an observational cohort study of women delivering from December 2017 to February 2019 at 2 maternity hospitals in Melbourne, Australia. Cervicovaginal fluid samples were collected from asymptomatic women at gestational week 16 þ0 À24 þ0 , and biomarker concentrations were quantified by enzymelinked immunosorbent assay. Women were assigned to a training cohort (n ¼ 136) and a validation cohort (n ¼ 150) based on chronological delivery dates. RESULTS: Seven candidate biomarkers representing key pathways in utero-cervical remodeling were discovered by high-throughput bioinformatic search, and their significance in both in vivo and in vitro studies was assessed. Using a combination of the biomarkers for the first 136 women allocated to the training cohort, we developed an algorithm to stratify term birth (n ¼ 124) and spontaneous preterm birth (n ¼ 12) samples with a sensitivity of 100% (95% confidence interval, 76À100%) and a specificity of 74% (95% confidence interval, 66À81%). The algorithm was further validated in a subsequent cohort of 150 women (n ¼ 139 term birth and n ¼ 11 preterm birth), achieving a sensitivity of 91% (95% confidence interval, 62À100%) and a specificity of 78% (95% confidence interval, 70À84%). CONCLUSION: We have identified a panel of biomarkers that yield clinically useful diagnostic values when combined in a multiplex algorithm. The early identification of asymptomatic women at risk for preterm birth would allow women to be triaged to specialist clinics for further assessment and appropriate preventive treatment.

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

“…This is due to technical difficulties in safely monitoring the biochemical processes ongoing in the uterine space. However, processes causing brain injury in the preterm born infants certainly begin before delivery, as indicated by a small study of brain functional connectivity in fetuses who went on to be born preterm ( 11 ) and an increasingly number of studies showing predictive biomarkers in maternal blood months before preterm birth ( 12 – 14 ). Numerous events and antenatal exposures have also been associated with preterm birth and EoP via epidemiological study and verified with preclinical studies.…”

Development of risk prediction models for preterm delivery in a rural setting in Ethiopia

“…Genetic factors, immunological biomarkers and protein expression show promising results. 49,50 However, there may be value in exploring the use of 'omics' no biomarker(s) predictive of preterm birth have yet been identified. 51 In addition, preterm birth is thought to be multifactorial and related to infection and inflammation processes.…”

Identification of potential therapeutic intervening targets by in-silico analysis of nsSNPs in preterm birth-related genes

“…Total numbers of nsSNPs were observed with much reduced in numbers as compared to the previous exonic counts in each gene. The nsSNPs were highest in ROBO1 gene (13,235) and IL4 has the lowest numbers of nsSNPs, i.e., 467 (Fig 2 ).…”

“…A case-control has reported the higher concentrations of CRP (C-reactive protein), and Complement C3 levels in the first trimester that were associated with increased risk of PTB [ 12 ]. Recently, a study is performed that focused on the early identification of asymptomatic women at mid-gestation with the aid of novel protein biomarkers as preventive management to reduce the global maternal mortality burden in women with spontaneous PTB [ 13 ]. Recently, a research finding shared that placental STOX1 (STORKHEAD-BOX PROTEIN 1) transcription factor mutation (Y153H, C allele) is a contributing factor in PTB and placental preeclampsia due to defects in early utero-placental development [ 14 ].…”

“…A case-control has reported the higher concentrations of CRP (C-reactive protein), and Complement C3 levels in the first trimester that were associated with increased risk of PTB [12]. Recently, a study is performed that focused on the early identification of asymptomatic women at mid-gestation with the aid of novel protein biomarkers as preventive management to reduce the global maternal mortality burden in women with spontaneous PTB [13].…”