PTB: Prediction & Management

Leonardo Pereira MDAssistant Professor

Maternal-Fetal MedicineOregon Health & Science University

Prediction of PTB

• Risk Factor Assessment– Historic– Current pregnancy

• Biochemical markers– Primarily fFN

• Ultrasound– Transvaginal cervical length assessment

Preterm Labor/PPROMRisk Factors

Prior spontaneous preterm delivery

Prior preterm labor/PPROMPrior multiple D&EsPrior cone biopsyUterine anomaliesDES exposure

Significant myomataPre-existing medical

conditionsSocial stress

Maternal life-style

Lower SESMaternal ageRace

Historical

Preterm Labor/PPROM Risk Factors

Short inter-pregnancy intervalPoor gestational weight gainMultifetal gestationARTInvasive prenatal diagnostictests (Amnio, CVS, PUBS)Polyhydramnios/oligohydramniosMaternal anemiaPlacental complications (abruptio, previa, etc.)

Asymptomatic bacteriuriaPyelonephritisGBS bacteriuriaInfection (BV, STDs, etc)Abnormal cervix exam (manual vs U/S)PPROMFetal compromise/deathFetal aneuploidyAbdominal surgery

Current Pregnancy

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 FibronectinPrediction 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 -fFN LR LR

Asymptomatic womenSPTB < 34 weeks (18 studies, 24860 women): 4.01 0.78

Symptomatic womenSPTB 7-10 days (17 studies, 7135 women): 5.42 0.25SPTB < 34 weeks (8 studies, 683 women): 3.64 0.32SPTB < 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 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

+ 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

Fetal Fibronectin

fFN - take home points

Asymptomatic women: fFN not clinically useful

Serial fFN: not worth repeating97% of negatives stay negativeSensitivity improvesSpecificity worsenspredictive 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 LaborDiagnosis

GA 20-36 6/7 weeksand

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, 1999Modified from Creasy and Resnik, Maternal Fetal Medicine, 4rd ed, 1999

• Hydration – No benefit

• Bed rest – No benefit

• Routine antibiotics – no benefit

• Role of amniocentesis– R/O infection

– Check FLM

Traditional Approaches to Preterm Labor Management

Egarter Obstet Gynecol 1996,88:303-9.Gibbs, Eschenbach Am J Obstet Gynecol 1997;177:375-80. Kenyon ORACLE Lancet 2001;357:989-94.

Pircon Am J Obstet Gynecol 1989;161:775-9.

• 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

Traditional Approaches to Preterm Labor Management

• 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

New Perspectives on PTL and PTB

New Perspectives on PTL and PTB

• 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

Potential roles for proteomics and genomics:

Pathways to Preterm Labor

PTL

inflammation

ischemia

Uterine dysfunction

fibroids

Cervical insufficiency

UterineHyperdistension

Maternal health

conditions

Preeclampsia,IUGR

FIRSfetus

infection

Uterineanomalies

Abruption

PPROM

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