PTB: Prediction

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PTB Prediction Management

• Leonardo Pereira MD
• Assistant Professor
• Maternal-Fetal Medicine
• Oregon Health Science University

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Prediction of PTB

• Risk Factor Assessment
• Historic
• Current pregnancy
• Biochemical markers
• Primarily fFN
• Ultrasound
• Transvaginal cervical length assessment

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Preterm Labor/PPROMRisk Factors
Historical

• Prior spontaneous preterm delivery
• Prior preterm labor/PPROM
• Prior multiple DEs
• Prior cone biopsy
• Uterine anomalies
• DES exposure

Significant myomata Pre-existing medical
conditions Social stress Maternal
life-style Lower SES Maternal age Race
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Preterm Labor/PPROM Risk Factors
Current Pregnancy

• Short inter-pregnancy interval
• Poor gestational weight gain
• Multifetal gestation
• ART
• Invasive prenatal diagnostic
• tests (Amnio, CVS, PUBS)
• Polyhydramnios/oligohydramnios
• Maternal anemia
• Placental complications
• (abruptio, previa, etc.)

Asymptomatic bacteriuria Pyelonephritis GBS
bacteriuria Infection (BV, STDs, etc) Abnormal
cervix exam (manual vs U/S) PPROM Fetal
compromise/death Fetal aneuploidy Abdominal
surgery
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Biochemical markers of PTB

• Salivary estriol
• Predictive of late preterm birth, limited utility
• CRH (corticotropin-releasing hormone)
• Neuropeptide, elevated levels associated with
  onset of labor
• Marker for early preterm birth, stress
• Increased susceptibility of infection
• Fetal fibronectin

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Fetal fibronectin

• Basement membrane glycoprotein produced by
  trophoblast
• Glue - intercellular adhesion between placenta
  and decidua
• 50 ng/ml at 18-34 weeks considered positive
• Clinically utilized between 24-34 weeks and lt 3
  cm dilated
• PPV 25-85, sens 63-93, NPV 97-99
• No clinical advantage to testing demonstrated yet
• Except possibly in symptomatic women with a
  negative fFN

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Fetal FibronectinPrediction of PTB lt 34 wks
Lockwood Am J Obstet Gynecol 1993169798-804.
Nageotte Am J Obstet Gynecol
199417020-5. Hellemans Br J Obstet Gynaecol
1995102207-12. Bittar Am J Obstet
Gynecol 1996175178-81. Goldenberg Am J Obstet
Gynecol 19971778-12.
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Fetal fibronectin

• Meta-analysis 68 studies (28 asymptomatic, 40
  symptomatic)
• fFN -fFN
• LR LR
• Asymptomatic women
• SPTB lt 34 weeks (18 studies, 24860
  women) 4.01 0.78
• Symptomatic women
• SPTB 7-10 days (17 studies, 7135 women) 5.42
  0.25
• SPTB lt 34 weeks (8 studies, 683
  women) 3.64 0.32
• SPTB lt 37 weeks (33 studies, 4106
  women) 3.27 0.48
• LR does not change between asymptomatic and
  symptomatic women
• - in vitro trophoblast produce fFN in response
  to inflammatory cytokines
• LR of a negative result in an asymptomatic women
  is weak
• Honest H. Br Med J 2002325301-11.

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Fetal Fibronectin

• Symptomatic women fFN is potentially useful if
  youre willing to wait for the result
• Positive start tocolysis, give steroids
• fFN no fFN test - fFN
• NNT 11 109 509
• number needed to treat at 32
  wk to prevent 1 case of RDS
• assuming a risk of RDS at 32
  weeks 0.53
• Negative stop intervention, discharge from
  hospital
• Cost-benefit analysis

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Fetal Fibronectin

• fFN - take home points
• Asymptomatic women fFN not clinically useful
• Serial fFN not worth repeating
• 97 of negatives stay negative
• Sensitivity improves
• Specificity worsens
• predictive values do not change

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TVU of the Cervix

• True cervical length 25-50 mm at 14-30 wks
• Cannot measure CL before 14 weeks
• Internal cervical os is indistinguishable from
  LUS
• Shortening starts at internal os after 14 wks
• Funneling lt25 not significant
• Most studies use a length lt25-35mm as abnormal

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10.7 mm
17.4 mm
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Transvaginal Ultrasound of the Cervix (lt25mm)
Prediction of PTB lt 34 wks
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TVU of the Cervix

• A short cervix, as determined by
  ultrasonography, correlates with several markers
  of infection and chorioamnionitis. Although a
  short cervix might facilitate the ascension of
  bacteria into the uterus, it is also likely that
  in some women, the cervix shortens in response to
  an upper genital tract infection that has already
  occurred. However, since an early preterm
  delivery due to infection may be
  indistinguishable from one due to a structurally
  inadequate cervix, it remains uncertain whether
  the length of the cervix shortens before or after
  a silent uterine infection.
• - Goldenberg RL

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TVU of the Cervix
TVU take home points TVU should not be used to
screen patients at low risk for PTB In patients
at high risk for PTB TVU between 16-28 can
predict those women at highest risk Whether one
time TVU or serial TVU is better is unclear if
one TVU 20-24 weeks is most predictive if
serial TVU every 2 weeks is appropriate No
clear optimal therapy for women identified with a
short cervix TVU can be helpful in triage of
women with preterm contractions
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Preterm LaborDiagnosis

• GA 20-36 6/7 weeks
• and
• Documented uterine contractions (4/20 min, or
  8/60 min.)
• and
• Rupture membrane or Intact
  membranes
• 
  and
• Documented cervical change
• or
• Cervical effacement 1cm
• or
• Cervical dilatation ³ 2 cm
• Consider TVU and fFN

Modified from Creasy and Resnik, Maternal Fetal
Medicine, 4rd ed, 1999
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Traditional Approaches to Preterm Labor Management

• Hydration No benefit
• Bed rest No benefit
• Routine antibiotics no benefit
• Role of amniocentesis
• R/O infection
• Check FLM

Pircon Am J Obstet Gynecol 1989161775-9.
Egarter Obstet Gynecol 1996,88303-9. Gibbs,
Eschenbach Am J Obstet Gynecol 1997177375-80.
Kenyon ORACLE Lancet 2001357989-94.
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Traditional Approaches to Preterm Labor Management

• Tocolysis
• Beta-mimetics (ritodrine, terbutaline)
• Stim. B2 receptor (G membrane protein)
  activates adenylate cyclase ? intracellular cAMP
  activates PKA ? inhibits myosin light chain
  phosphorylation ? intracellular calcium
• Maternal Complications cardiac-increased HR,
  BP, ischemia, pulmonary edema, hypokalemia,
  hyperglycemia
• Fetal/Neonatal complications HR, BP,
  hypocalcemia, hypoglycemia
• Efficacy PTB within 48 hours compared to
  placebo
• No changes in perinatal mortality or morbidity

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Traditional Approaches to Preterm Labor Management

• Tocolysis
• Magnesium Sulfate
• competes with Ca for calmodulin binding which
  decreases MLCK activation, blocks L-type and
  T-type voltage activated Ca channels
• Maternal Complications nausea, vasodilatation,
  blurred vision, muscle weakness, CNS changes,
  hypermagnesemia, pulmonary edema
• Fetal/Neonatal complications hypocalcemia,
  respiratory suppression
• Efficacy ? in PTB within 48 hrs compared to
  placebo as good as beta-mimetics

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Traditional Approaches to Preterm Labor Management

• Tocolysis
• Prostaglandin Synthesis Inhibitors (indomethacin)
• Competitively inhibits cyclo-oxygenase blocks
  conversion of arachodonic acid to prostaglandin
  G2 ? E2, F2a inhibits myometrial contractility
• Maternal complications GI, ? platelets,
  bronchospasm, ? urine output
• Fetal complications constriction of ductus
  arteriosus after 30 wk GA (persistent use can
  lead to pulm. HTN), ? fetal/neo. renal function,
  oligohydramnios
• Efficacy ? PTB within 48 hrs compared to placebo
• Mixed trends regarding neonatal morbidities IVH

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Traditional Approaches to Preterm Labor Management

• Tocolysis
• Calcium Channel Blockers (nifedipine)
• Blocks L-type voltage activated Ca channels
  (relaxes uterine muscle)
• Maternal complications Hypotension, HA, mild
  HR, flushing, dizziness
• Efficacy as good as beta-mimetics, less
  side-effects

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Traditional Approaches to Preterm Labor Management

• Uterine-specific therapy oxytocin receptor
  antagonist (Atosiban)
• not approved in U.S.
• Competitive inhibitor of oxytocin via blockade of
  oxytocin receptor
• Maternal complications extremely rare (headache,
  nausea 5)
• Efficacy PTB at 48 hours, RR 0.83 PTB at 7
  days, RR 0.79

Romero Am J Obstet Gynecol 20001821173-83.
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Traditional Approaches to Preterm Labor Management

• Antenatal Steroid Therapy
• Mechanism of action
• Induces surfactant production by type II
  pneumocytes
• Administration
• Betamethasone 12mg IM q24h x 2 doses (preferred)
• Dexamethasone 6mg IM q6h x 4 doses
• Between 24 34 WGA, consider between 32-34 in
  preterm PROM
• No rescue doses at this time, outside of clinical
  trials
• Complications
• No changes in infection
• Neonatal concerns with repeated doses, especially
  dexamethasone
• Efficacy
• RDS, IVH/ neurologic abnormality, NEC
• neonatal mortality

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New Perspectives on PTL and PTB

• Alternative agents novel medications in
  development
• 2 oxytocin receptor antagonists in FDA pipeline
• COX 2 inhibitors
• Combination of antibiotics and immune-modulators
  (prostaglandin synthesis inhibitors) for
  infection-mediated preterm labor

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New Perspectives on PTL and PTB
Potential roles for proteomics and genomics

• Improved understanding of human parturition/PTL
  pathways
• Positive prediction of PTB
• Improve the timing of antenatal steroid
  administration
• Arrange for appropriate transfers
• Decrease tocolytic therapy and antibiotics for
  threatened preterm birth
• Decrease adverse maternal and fetal events
• Rapid identification of different PTL pathways
• Tests to determine the specific causes of preterm
  labor could lead to a shift in treatment of PTL
  towards etiologic-specific therapy

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Pathways to Preterm Labor
Uterine Hyperdistension
Preeclampsia, IUGR
ischemia
Uterine anomalies
PTL
Abruption
fibroids
Uterine dysfunction
Maternal health conditions
FIRS fetus
PPROM
Cervical insufficiency
infection
inflammation
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Conclusions

• Impact of PTB
• The most significant problem in Obstetrics
• Prediction of PTB (traditional vs. new
  perspectives)
• Need tests with strong positive prediction
  capabilities
• Traditional approaches to PTL management
• Tocolytics side effects limited benefit no
  effect on PTB rate
• New perspectives on PTL and PTB
• Need to develop etiologic-specific therapies
• Improve prediction models
• Recognize when we shouldnt attempt to arrest PTL

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Thank you