Transcript 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.
 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