Biochemical markers for the prediction of preterm birth

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Biochemical markers for the prediction of preterm
birth

• American Journal of Obstetrics and Gynecology
• 2005 May, S36-46
• ???? ???

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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 -gt spontaneous
  onset of labor or rupture of the fetal membranes.

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Reasons of Prediction of preterm labor

• Initiate appropriate risk-specific treatment
• Define a population of women who are at risk, -gt
  we can study a particular treatment.
• Being able to predict the Preterm labor which ma
  allow us to gain important insights

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Source of biologic fluid

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

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Timing

• Time that the sample is collected.
• ALP, ferritine in plasma level
• lt20wks of gestation little value in the
  prediction of a preterm labor
• 24wks of gestation highly predictive of preterm
  birth.
• Fetal fibronection
• gt24wks of gestation less predictive value

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Timing

• Matrix metalloproteinase-9
• 24 hours before the Initiation of Labor or PPROM
  -gt turn positive
• The time between test turn positive and the
  beginning of labor or PPROM is so little.

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Timing

• Bacterial vaginosis strong predictor of of
  prematurity -gtsufficiently 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.

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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

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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

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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.

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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
  (gt50ng/mL)
• 22-24wks positive?? very powerful predictor
• 24wks postive?? 4wks ? preterm birth? ? ??? 60?
  ??

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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

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Urine

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

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Saliva

• Ultrafiltrate of plasma
• Easiest fluid to collect
• Recently, estriol has potential relationship to
  preterm labor
• Unconjugated steroid hormones -gt saliva
  (diffusion)
• But, estriol was better marker for late preterm
  labor
• Limitation
• Patient activity/posture, food consumtion
• Oral lesions, abrasions, gingivitis

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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)

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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.

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Genomics/Proteomics

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

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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

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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

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Clinical utility

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

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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? ??.-gt preterm birth? marker

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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.

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Comment

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