1. PTB: Prediction & Management Leonardo Pereira MD Assistant Professor Maternal-Fetal Medicine Oregon Health & Science University

2. Prediction of PTB Risk Factor Assessment –Historic –Current pregnancy Biochemical markers –Primarily fFN Ultrasound –Transvaginal cervical length assessment

3. Preterm Labor/PPROM Risk Factors 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 Historical

4. Preterm Labor/PPROM Risk Factors 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 Current Pregnancy

5. 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

6. 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

7. Fetal Fibronectin Prediction of PTB < 34 wks 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.

8. Fetal fibronectin Meta-analysis: 68 studies (28 asymptomatic, 40 symptomatic) +fFN-fFN LR Asymptomatic women SPTB < 34 weeks (18 studies, 24860 women):4.010.78 Symptomatic women SPTB 7-10 days (17 studies, 7135 women):5.42 0.25 SPTB < 34 weeks (8 studies, 683 women):3.640.32 SPTB < 37 weeks (33 studies, 4106 women):3.270.48 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.

9. Fetal Fibronectin Symptomatic women: fFN is potentially useful if you’re willing to wait for the result Positive: start tocolysis, give steroids + fFNno 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

10. 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

11. 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

12. 10.7 mm 17.4 mm

13. Transvaginal Ultrasound of the Cervix (<25mm) Prediction of PTB < 34 wks

14. 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

15. 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

16. 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

17. 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.

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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:

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

27. 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

28. Thank you