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.

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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 B- streptococcus, 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 : positive 이면 very powerful predictor  24wks : postive 이면 4wks 후 preterm birth 가 올 확률 이 60 배 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 progesterone 이 상승.-> preterm birth 의 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