Transcript Preterm Labor

PTB: Prediction & Management
Leonardo Pereira MD
Assistant Professor
Maternal-Fetal Medicine
Oregon Health & Science University
Prediction of PTB
• Risk Factor Assessment
– Historic
– Current pregnancy
• Biochemical markers
– Primarily fFN
• Ultrasound
– Transvaginal cervical length assessment
Preterm Labor/PPROM
Risk Factors
Historical
Prior spontaneous preterm
delivery
Prior preterm labor/PPROM
Prior multiple D&Es
Prior cone biopsy
Uterine anomalies
DES exposure
Significant myomata
Pre-existing medical
conditions
Social stress
Maternal life-style
Lower SES
Maternal age
Race
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
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
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 < 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
Fetal Fibronectin
Prediction of PTB < 34 wks
Population Studies % pos Sens Spec PPV NPV
Low-risk
7
4
50
90
25
97
High-risk
4
30
70
74
35
97
Twins
2
30
63
30
70
70
PTL
17
20
85
68
55
80
Lockwood Am J Obstet Gynecol 1993;169:798-804.
Nageotte Am J Obstet Gynecol 1994;170:20-5.
Hellemans Br J Obstet Gynaecol 1995;102:207-12.
Bittar Am J Obstet Gynecol 1996;175:178-81.
Goldenberg Am J Obstet Gynecol 1997;177:8-12.
Fetal fibronectin
Meta-analysis: 68 studies (28 asymptomatic, 40 symptomatic)
+fFN
LR
-fFN
LR
Asymptomatic women
SPTB < 34 weeks (18 studies, 24860 women):
4.01
0.78
Symptomatic women
SPTB 7-10 days (17 studies, 7135 women):
SPTB < 34 weeks (8 studies, 683 women):
SPTB < 37 weeks (33 studies, 4106 women):
5.42
3.64
3.27
0.25
0.32
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 2002;325:301-11.
Fetal Fibronectin
Symptomatic women: fFN is potentially useful if you’re
willing to wait for the result
• Positive: start tocolysis, give steroids
NNT * †
+ fFN
11
no fFN test
109
- fFN
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
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
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 <25% not significant
•
Most studies use a length <25-35mm as abnormal
10.7 mm
17.4 mm
Transvaginal Ultrasound of the Cervix (<25mm)
Prediction of PTB < 34 wks
Population Studies % pos Sens Spec PPV NPV
Low-risk
5
10
37
92
18
97
High-risk
2
25
79
70
37
92
Twins
4
15
30
92
60
80
PTL
6
45
64
85
70
80
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
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
Preterm Labor
Diagnosis
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  2 cm
Consider TVU and fFN
Modified from Creasy and Resnik, Maternal Fetal Medicine, 4rd ed, 1999
Traditional Approaches to Preterm Labor
Management
• Hydration – No benefit
Pircon Am J Obstet Gynecol 1989;161:775-9.
• Bed rest – No benefit
• Routine antibiotics – no benefit
Egarter Obstet Gynecol 1996,88:303-9.
Gibbs, Eschenbach Am J Obstet Gynecol 1997;177:375-80.
Kenyon ORACLE Lancet 2001;357:989-94.
• Role of amniocentesis
– R/O infection
– Check FLM
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
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
Traditional Approaches to Preterm Labor
Management
• Tocolysis
– Prostaglandin Synthesis Inhibitors (indomethacin)
• Competitively inhibits cyclo-oxygenase; blocks conversion of
arachodonic acid to prostaglandin G2  E2, F2α; 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
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
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 2000;182:1173-83.
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
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 infectionmediated preterm labor
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
Pathways to Preterm Labor
Uterine
Hyperdistension
Preeclampsia,
IUGR
ischemia
Uterine
anomalies
Abruption
fibroids
PTL
Maternal
health
conditions
Uterine
dysfunction
FIRS
fetus
PPROM
inflammation
infection
Cervical
insufficiency
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 shouldn’t attempt to arrest PTL
Thank you