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Biochemical markers for the prediction of preterm birth

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.

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Biochemical markers for the prediction of preterm birth

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  1. Biochemical markers for the prediction of preterm birth American Journal of Obstetrics and Gynecology 2005 May, S36-46 산부인과 조인호

  2. 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.

  3. 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

  4. Source of biologic fluid • Amniotic fluid, urine, cervical mucus, vaginal secretion, serum or plasma, saliva • Consideration • Biologically plausible • Ease of collection • Costs • Safety

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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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  12. 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.

  13. 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 확률이 60배 증가

  14. 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

  15. Urine • Various hormones and various organisms -> useful marker • Urine DNA examination (Chlamydia, gonorrhea) -> prediction of vaginal or cervical colonization

  16. 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

  17. 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)

  18. 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.

  19. Genomics/Proteomics • Genomics • Gene expression -> mRNA • Relation • Host genome, gene expression, phenotype • Proteomics • Complete protein complement, proteome • Relation • Disease, phenotype of interest

  20. 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

  21. 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

  22. Clinical utility • Scenario • Increased cervical/vaginal fetal fibronectin (biomarker) -> Antibiotics (intervention) • Failed to prevent subsequent preterm birth.

  23. 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

  24. 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.

  25. Comment • Only use of marker for routine prenatal care (single or multiple marker test) -> significant reduction in preterm birth

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