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Biochemical markers for the prediction of preterm birth American Journal of Obstetrics and Gynecology 2005 May, S36-46 산부인과 조인호 Introduction Preterm birth is the most responsible for poor pregnancy outcome in the US and many other developed countries. 70% of neonatal death. ½ of preterm birth : long-term neurologic disability Definition: before 37wks of GA -> spontaneous onset of labor or rupture of the fetal membranes. Reasons of Prediction of preterm labor Initiate appropriate risk-specific treatment Define a population of women who are at risk, -> we can study a particular treatment. Being able to predict the Preterm labor which ma allow us to gain important insights Source of biologic fluid Amniotic fluid, urine, cervical mucus, vaginal secretion, serum or plasma, saliva Consideration Biologically plausible Ease of collection Costs Safety Timing Time that the sample is collected. ALP, ferritine in plasma level <20wks of gestation : little value in the prediction of a preterm labor 24wks of gestation : highly predictive of preterm birth. Fetal fibronection >24wks of gestation : less predictive value Timing Matrix metalloproteinase-9 24 hours before the Initiation of Labor or PPROM -> turn positive The time between test turn positive and the beginning of labor or PPROM is so little. Timing Bacterial vaginosis : strong predictor of of prematurity ->sufficiently early in gestational age and intervention. Fetal fibronectin test : 22-24wks of gestation The time of day of the sample collection may also be important. Salivary estriol predicts late preterm births quite well, but 36wks birth is not important. Predictive value Any preterm predictive test and positive prdictive values generally should be high for the test to be useful. Some investigators have found negative predictive value (ie, the ability to predict who will not haver a preterm birth) to be useful and cost saving. Fetal fibronectin : high negative predictive value Classification of types of biologic marker Placental proteins A-fetoprotein, major basic protein, placental isoferritin Placental protein hormones CRH, adrenocorticotropin, prolactin, hCG Non-protein hormones Estrogens, progestines Non-hormonal proteins ALP, ferritin in placental site or extrauterine sites Infection-related factors In the last decade, it has become clear Infection/inflammation has a strong association with preterm delivery. Define markers of inflammation: C-reative protein : ferritin, interleukins, chemokines, cytokines, defensins, bacteria and bacterial products. y Cervical and vaginal fluid Many of substances have been found in cervical or vaginal fluids for their ability to predict spontaneous preterm birth. Gonococcus, Chlamydia, group Bstreptococcus, herpes virus … Baterial vaginosis : 2-fold increased risk of spontaneous preterm birth. Associated with an increased risk for intrauterine infection. Cervical and vaginal fluid Various cytokines associated with preterm birth. IL-6, monocyte chemotactic protein 1, IGF binding protein 1, WBC, collagen synthesis and degradation Fetal fibronectin Produced by fetal membranes and trophoblasts Before 20wks : not found in the cervix and vagina (>50ng/mL) 22-24wks : positive이면 very powerful predictor 24wks : postive이면 4wks 후 preterm birth가 올 확 률이 60배 증가 Amniotic fluid Generally is not obtained from asymptomatic women GA 16-18wks Increased IL-6 Wenstrom et al : associated with fetal loss within next 4wks Presence of Ureaplasma Symptomatic women Marker of infection in amniotic fluid Various cytokines [IL-1, IL-6, TNF-a], WBC, defensins, various metalloproteinases, low glucose levels Urine Various hormones and various organisms -> useful marker Urine DNA examination (Chlamydia, gonorrhea) -> prediction of vaginal or cervical colonization Saliva Ultrafiltrate of plasma Easiest fluid to collect Recently, estriol has potential relationship to preterm labor Unconjugated steroid hormones -> saliva (diffusion) But, estriol was better marker for late preterm labor Limitation Patient activity/posture, food consumtion Oral lesions, abrasions, gingivitis Serum/Plasma Over the last several decades, hundreds of publications have attempted to evaluate various plasma (or serum) components for predict preterm birth G-CSF, ferritin level (strongest) High a-fetoprotein, ALP, high CRH (useful marker) Multiple markers Powerful predictor A-fetoprotein, ALP, G-CSF (maternal serum) Fetal fibronectin (cervicovaginal mucus) Cervical length (ultrasound) Several biologic markers together might be useful. Genomics/Proteomics Genomics Gene expression -> mRNA Relation Host genome, gene expression, phenotype Proteomics Complete protein complement, proteome Relation Disease, phenotype of interest Genomics/Proteomics Genetic study Single nucleotide polymorphism relate on preterm birth But, results have been inconsistent Research tools (available) Gene array chips, gene sequencing Protein array chips, mass spectrometry Now, these technique has only begun to explored to idendifiy gene/protein Clinical utility Identification of biomarkers Insights into the pathophysiologic condition of these pregnancy complication Identify highest risk women for targeted interventions. But, few markers have high test sensitivity, specificity, and positive predictive value Few interventions have shown to be of benefit to prevent or reduce the incidence of preterm birth Clinical utility Scenario Increased cervical/vaginal fetal fibronectin (biomarker) -> Antibiotics (intervention) Failed to prevent subsequent preterm birth. Clinical utility Recently, Progesterone use to reduce preterm birth. Target : Hx. of preterm birth/not biologic fluid marker So, define that populaton that is appropriate for treatment But, the other various markers haver the potential to better. In addintion, mid-trimester : maternal serum progesterone이 상승.-> preterm birth의 marker Comment The goal of the study Understand pathways that lead to preterm birth To define a high-risk population for future intervention studies To select a population in which a specific prevention intervention is to be used, or occasionally To select a population that is at low risk so that they may be spared various interventions. Comment Only use of marker for routine prenatal care (single or multiple marker test) -> significant reduction in preterm birth
