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Diagnosis and Treatment of Preterm Labor How Far Have We Come?

Diagnosis and Treatment of Preterm Labor How Far Have We Come?. Siri Kjos, MD Harbor-UCLA Medical Center Good Samaritan Hospital. Objectives. State the different etiologies of indicated and spontaneous preterm birth State various tocolytic agents which are used to prevent preterm birth

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Diagnosis and Treatment of Preterm Labor How Far Have We Come?

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  1. Diagnosis and Treatment of Preterm Labor How Far Have We Come? Siri Kjos, MD Harbor-UCLA Medical Center Good Samaritan Hospital

  2. Objectives • State the different etiologies of indicated and spontaneous preterm birth • State various tocolytic agents which are used to prevent preterm birth • Give the reasons why Calcium Channel Blockers are the best option for tocolysis compared to other agents • Explain the difference between the recommendations for antibiotic therapy in preventing preterm birth in intact and ruptured membranes.

  3. Preterm Labor and Delivery: • Labor or delivery occurring after 20 and before 37 completed weeks • 10% of births are preterm • 75% of neonatal deaths, excluding malformations • Rates & complications unchanged: • ?? Including earlier gestational ages as viable (now 23+ weeks)

  4. Preterm delivery  Low birth weight Birth weight is commonly used & confused • Low birth weight (LBW): <2500g • Very-Low Birth Weight (VLBW):<1500g • Micropremie (<750g) • <29 weeks: gestational age is better predictor of survival • >29 weeks: birthweight is better predictor, • less influence of gender, ethnicity, plurality

  5. Survival by Gestational Age Creasy RK, Iams JD in ‚Maternal Fetal Medicine‘, 4th Ed, 1999

  6. Preterm Delivery • Indicated preterm delivery • Follow medical or obstetrical disorders that place mother or fetus at risk (20-30%) • hypertension, placenta previa or abruption, IUGR, cardiac disease, etc • Spontaneous preterm delivery • In absence of overt maternal or fetal illness • spontaneous labor, rupture of membranes • associated with multiple gestation, 2nd trimester bleeding, history of preterm delivery Meis PJ, Am J Obstet Gynecol 173:597, 1995

  7. Spontaneous Preterm Birth: Risk Factors • 75% of Preterm Births, Predisposing Risk Factors • Multiple gestation • Bleeding in 2nd trimester • Prior spontaneous preterm birth(s) • Low Socioeconomic status • Non-white ethnicity • Low prepregnancy weight (BMI <19.8) • Smoking, cocaine use • Lack of prenatal care • Preterm, premature rupture of membranes

  8. Spontaneous Preterm Birth: Etiology Primarily unknown: > 50% Uterine malformations • Unicorniuate or bicornuate (reduction of space for fetal growth) • Myomas (submucosal, subplacental): • Poor implantation, increased antepartum bleeding and preterm labor Cervical Incompetence: 0.1-2.0% • Prior 2nd trimester abortion • Prior gynecological surgery (cervical dilatation or conization) • Maternal exposure to DES

  9. Spontaneous Preterm Birth: Etiology Vaginal Infectious: • association but no proven etiology • Genital tract colonization & infection • Poorly defined association between chorioamnionitis and preterm labor • Sexually transmitted disease and preterm labor have common risk factors • Increased preterm delivery with colonization of: Group B streptococcus N. gonorrhoeae T. pallidum C. trachomatis G. vaginalis T. vaginalis Ureaplasma urealyticum

  10. Spontaneous Preterm Birth: Etiology Infection • Positive amniotic fluid cultures in 20-30% of cases of preterm labor •  if refractory to tocolysis •  infection with earlier gestational age •  90% of PTB <28 weeks with +culture or histological evidence of infection •  Inflammatory markers • in 2nd trimester amniotic fluid in pregnancies destined to deliver preterm Suggest subclinical infection in chorioamnion & fetus before presentation of preterm labor

  11. Spontaneous Preterm Birth: Etiology 2nd Trimester Vaginal Bleeding • PROM, RR 15.1 •  Preterm labor, RR 19.7 • Etiology • not associated with previa or abruption •  Maternal serum AFP • (consistent with placental hemorrhage) • Inflammatory markers in 2nd trimester • Decidual vascular abnormalities

  12. Risk Assessment: Can we identify women at high risk for preterm birth? Scoring Systems: • Sensitivity (ability to predict who will deliver preterm) of scoring systems: <50% • Positive predictive value (correctly identifying those pregnancies at risk): 20% • Best predictors: • History of prior preterm birth • Multiple gestation • Vaginal bleeding in 2nd trimester • Low pre-pregnancy weight

  13. Risk of Preterm Birth in Subsequent Births Bakketeig LS, Hoffman HJ, 1981

  14. Management of Preterm LaborEstablishing the Diagnosis • No universal definition of preterm labor • Frequent contractions ALONE does not define preterm labor Suggested Definition: >1 criteria meet 1. Cervical Change > 1 cm 2. Cervical Dilatation > 2 cm 3. Positive Fibronectin level If none of the above are present: transvaginal cervical length >3cm = very low risk of preterm delivery (>2%)

  15. Management of Preterm LaborAssessment • Evaluate for vaginal infection, ruptured membranes, fever, etc. • Detailed history for medical complications which may limit or prohibit tocolysis • Estimate fetal weight, position (ultrasound) • Intravenous or oral hydration • Widely used, not supported by trials1,2 1. Helfgott AW, Matern Fetal Med 3:37, 1994. 2. Guinn DA, Am J Obstet Gynecol 177:814,1997

  16. Management of Preterm LaborTocolysis • No established criteria of when to initiate • Most common criteria: • Regular uterine contractions plus • Change in dilatation or effacement • Cervical dilatation >3 cm •  rate for successful tocolysis • Goal: Delay of 24-48 hours to permit corticosteroid therapy or transport to tertiary perinatal center

  17. Management of Preterm LaborTocolysis • General Guidelines • < 34 weeks: begin tocolytics • 34-37 weeks: rarely tocolyze, must individualize • Cost benefit studies: > 33 weeks, no improvement in neonatal survival or decrease in cost with tocolysis compared with no intervention • Assess certainty of data criteria, fetal weight, maternal disease, lung maturation

  18. Contraindications toTocolysis

  19. Evaluating the Efficacy of Tocolysis • No uniform criteria to accurately establish the diagnosis of preterm labor • Heterogeneous etiology of preterm labor • More than one treatment modality likely needed • Different measures of “successful tocolysis” • Delay in delivery to 37 weeks or to 34 weeks • Delay in delivery for 48 hours (allow corticosteroids) • ↓Neonatal morbidity or mortality • Improved long-term newborn outcomes

  20. Tocolysis and Preterm Labor: The Drug Options • Magnesium Sulfate • -mimetic Agents (Ritodrine, Terbutaline) • Calcium Channel Blockers (Nifedipine) • Cyclo-oxygenase (COX) inhibitors (Indomethacin) • Oxytocin antagonists (Atosiban) • Antibiotics (Intact vs. ruptured membranes) Contraindications, Complications and Efficacy

  21. Pharmocologic Therapy for Preterm Labor Contraindications toMagnesium Sulfate Intravenous administration Load:4-6 g; 1-4 g/H--titrate to response

  22. Complications from Tocolysis with Magnesium Sulfate • Toxicity • Inhibition of myometrial contractility (5-8 mg/dl) • Loss of deep tendon reflexes (9-13 mg/dl) • Respiratory depression (>13 mg/dl) • Pulmonary edema (similar to -adrenergics) •  Twins (volume expansion);  Anemia • Urinary output (renal excretion) • Tocolysis >24 hours ( colloid oncotic pressure) • Fluid overload (overhydration) • Careful attention to fluids decreases risk: • Corticosteroids do not affect risk

  23. : Magnesium Sulphate for Preventing PTB Cochrane Meta-analysis 2002 Evaluated 23 RCTs: 9 RCTs included: Rx vs Control Conclusion “Magnesium Sulfate is ineffective at delaying or preventing preterm birth and its use is associated with increased mortality for the infant.” Crowther CA, Hiller JE Doyle LW. Cochrane Collaboration 2002

  24. : A RCT of Magnesium Sulfate for Prevention of Cerebral Palsy Conclusion “Fetal exposure to Magnesium Sulfate before anticipated Early preterm deliver did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduce in survivors.” Study: N= 2241, multi-center (20 sites), 22-31 weeks, 6 g load, 2 g/H Rouse DJ, et al. New Eng J Med 359:895-905

  25. Pharmocologic Therapy for Preterm Labor Contraindications to-mimetic Agents Intravenous administration Increase dose every 20-30 min, titrate to response

  26. Complications from Tocolysis with Ritrodrine • Cardiovascular: 1 and2 Hypotension (2 ), arrhythmias (1 ), chest pain (1 ), • Pulmonary edema (1 and2) • Twins (volume expansion); Anemia • Maternal heart rate >130 beats/min (1) • Urinary output ( renin-2) • Tocolysis >24 hours ( colloid oncotic pressure) • Fluid overload (overhydration) • Careful attention to fluids decreases risk: • Rate in Canadian trial 0.3% • Corticosteroids do not affect risk

  27. Treatment of preterm labor with Ritrodine: The Canadian Preterm Labor Investigators Group • 708 women randomized to ritodrine vs. placebo (stratified by gestational age) • No difference in Perinatal outcome: • Neonatal death (6.1% vs. 6.4%) • Delay in delivery (days or < 37 weeks) • Low birth weight infants (<2500g) or birth weight • Any neonatal morbidity • Increased maternal morbidity with ritodrine • chest pain, arrhythmias • No significant beneficial effect from ritrodrine The Canadian Preterm Labor Investigators Group, N Engl J Med 327:308, 1992

  28. : -mimetic Agents for Preventing Preterm BirthCochrane Meta-analysis 2004 Included 17 RCTs; 11 with Placebo as Control Conclusion “β-mimetics help delay preterm birth for women transferred to tertiary center or complete a course of antenatal corticosteroids. However its use is associated with multiple adverse effects.” Anotayanonth S, Subhedar NV, Neilson JP, Hargopal S. Cochrane Collaboration 2004

  29. : -mimetic Agents for Maintenance Therapy after Preterm Labor Cochrane Meta-analysis 2006Included 11 RCTs with Placebo as Control Conclusion “Available evidence does not support the use of Oral β-mimetics For Maintenance Therapy after threatened Preterm labor.” Dodd JM, Crowther CA, Middleton P. Cochrane Collaboration 2006

  30. Prophylactic Oral -mimetic Agents for preventing PTL in high-risk singleton pregnanciesCochrane Meta-analysis 2008Included 1 RCTs with Placebo as Control Conclusion “Insufficient evidence to support or refute the use of Prophylactic oral β-mimetics (prior to PTL) For Primary Prevention of Preterm Labor in Singleton pregnancies at high risk Preterm labor.” Whitworth M, Siobhan Q. Cochrane Collaboration 2008

  31. Pharmocologic Therapy for Preterm Labor Contraindications toCalcium Channel Blockers oral administration 20-40 mg po load: then 10-20 mg every 4-6 hours

  32. Treatment Protocols for Tocolysis Calcium Channel Blockers: Nifedipine • Up to 40 mg orally in 1st hour • Many loading protocols: 10 mg repeat in 15-20 minutes x‘s 3 or 4 (total 30 to 40 mg), • then 10-20 mg every 4-6 hours • Side effects less than ritodrine • Maternal flushing, vasodilation

  33. : Calcium Channel Blockers for Inhibiting Preterm Labour Cochrane Meta-analysis 2003 Included 12 RCTs; with other Tocolytics as Control King JF, Papatonis DNM, Dekka GA, Carbonne B. Cochrane Collaboration 2003

  34. : Calcium Channel Blockers for Inhibiting Preterm Labour: Cochrane Meta-analysis 2003 Included 12 RCTs; 9 used β-mimetics as Control Conclusion “When tocolysis is indicated, Calcium Channel Blockers are preferable to other tocolytic agents compared, mainly β-mimetics. Further research should address effects of different dosing regimens and formulations.” King JF, Papatonis DNM, Dekka GA, Carbonne B. Cochrane Collaboration 2003

  35. : Maintenance Therapy with Calcium Channel Blockers for preventing PRB after threatened Pretern Labor: Cochrane Meta-analysis 2004 Included 1 RCT* with placebo control; (excluded 11 trials) Conclusion “The role of maintenance therapy with Calcium Channel Blockers for preventing preterm birth is not clear. Well designed trials with sufficient size are needed.” *Carr DB, Maintenance oral nifedipin for PTL: a RCT. Am J Obstet Gynecol 1999, 181:822 Gaunekar nn, Crowther CA, Carbonne B. Cochrane Collaboration 2004

  36. Pharmocologic Therapy for Preterm Labor Contraindications toIndomethacin oral or rectal administration 50 mg rectally, then 25 mg every 6 H up to 48H

  37. Cyclo-oxygenase (COX) Inhibitors Prostaglandin Synthesis Inhibitors: e.g. Indomethacin • Rectal or oral, crosses placenta • 50-100 mg rectal suppository loading, 25 mg every 6 hours for up to 48 hours • Similar efficacy to ritrodrine in controlled trials • Fetal risk • Oligohydramnios (Urinary output) • Possible primary pulmonary hypertension, IVH • Limit to 24-32 weeks

  38. : Cyclo-oxygenase (COX) Inhibitors for Treating Preterm Labor Cochrane Meta-analysis 2005: Included 13 RCTs; 10 used Indomethacin Conclusion “There is insufficient information to base decisions about the role of COX inhibition in preterm labor Further well designed trials are needed.” Review eliminated trials which used indomethacin when 1° tocolytic therapy failed King JF, Flenady V, Cole S, Thorton S. Cochrane Collaboration 2005

  39. Effect of Antenatal Indomethacin on Neonatal Outcomes Meta-analysis 2007: Included 15 Retrospective cohort studies and 6 case-controlled studies. Inclusion: examined Neonatal outcomes • Retrospective cohort and Observational studies • Gestational age <37 weeks • Used standard diagnostic criteria for PTL • Permitted studies with indomethacin after failed 1° tocolytic therapy, permitted multiple combinations of tocolytic Rx, not matched for steroid exposure • Results ↑Risk Periventricular leukomalacia: OR 2.0 (1.3, 3.1) ↑Risk Necrotizing enterocolitis: OR 2.2 (1.1,4.2) No effect on IVH, PDA, RDS, BPD, or mortality King JF, Flenady V, Cole S, Thorton S. Cochrane Collaboration 2005

  40. Oxytocin Antagonists (Atosiban) Mechanism: Oxytocin receptor antagonists Block oxytocin receptors in myometrium→ prevent ↑[Ca+2] → relax myometrium Low incidence side effects N&V, Headache, chest pain, hypotension

  41. Oxytocin receptor antagonists for Inhibiting Preterm Labour Cochrane Meta-analysis 2005 Included 2 RCTs w/ Placebo; 4 RCT w/ βmimetic Control Conclusion “this review failed to demonstrate superiority of atosiban over βmimetics or placebo in tocolytic efficacy or perinatal outcome. The finding of increased infant death in one placebo trial warrants caution.” Papatsonis D, Flenady, Cole, Liley H. Cochrane Collaboration 2005

  42. Antibiotic Therapy To Prevent Group B Streptococcus • Should be given to prevent neonatal infection at least 4 hours before delivery • Different from prolongation of latency! Without rupture of membranes • No clear benefit demonstrated to prolong latency (time between onset of labor and delivery) with antibiotic therapy. • Antibiotics not recommended in routine preterm labor management • Cochrane Review (Feb 2002) • American College of Obstetricians & Gynecologists (2001) • ORACLE trial King J. Cochrane Database, Feb 2002

  43. ORACLE II Randomize Trial: Broad Spectrum Antibiotics for Spontaneous PTL with Intact Membranes 6295 women randomized to 4 study arms, 80% received steroids • Erythromycin 250 mg (n=1611) • Co-amoxiclav (250mg amoxicillin + 125 mg clavulanic acid) (n=1550) • Both Erythromycin + Co-amoxiclav (n=1565) • Placebo (n=1569) 1°Outcome: Composite measure: neonatal death or major adverse outcome (chronic lung disease, major cerebral abnormality) 2° Outcome: Delivery <48H, <7 d, GA @ delivery Kenyon SL, ORACLE Group, Lancet 2001, 357:981-90

  44. ORACLE II Randomize Trial: Broad Spectrum Antibiotics for Spontaneous PTL with Intact Membranes: Results 1. No evidence that any antibiotic regimen prolonged pregnancy 2. Most women did not deliver <48H (89.9%) or <7days (84.6%) 3. ↓ CD wound infection with all antibiotic groups (0.7-0.8%) c.f. placebo (1.5%) 4. No difference in median birthweight, in NICU admission 5. ↑proven/suspected NEC with any co-amoxiclav (1.4%/0.6%) c.f. placebo (0.9%/0.3%) p = 0.0.8/0.06 6. No difference in composite outcome rates: Erythro 5.6%; Co-amoxiclav 5.0%; Both 5.9%; Placebo 5.0% Conclusion “This trail provides evidence that antibiotics should not be routinely prescribed in women for spontaneous PTL without evidence of clinical infection.” Kenyon SL, ORACLE Group, Lancet 2001, 357:981-90

  45. ORACLE I Randomize Trial: Broad Spectrum Antibiotics for Spontaneous PTL with Ruptured Membranes 4826 women randomized to 4 study arms, • Erythromycin 250 mg (n=1197) • Co-amoxiclav (250mg amoxicillin + 125 mg clavulanic acid) (n=1212) • Both Erythromycin + Co-amoxiclav (n=1192) • Placebo (n=1225) • Q.i.d. dose for 10 days 1°Outcome: Composite measure: neonatal death or major adverse outcome (chronic lung disease, major cerebral abnormality) 2° Outcome: Delivery <48H, <7 d, GA @ delivery Kenyon SL, ORACLE Group, Lancet 2001, 357:979-88

  46. ORACLE I Randomize Trial: Broad Spectrum Antibiotics for Spontaneous PTL with Ruptured Membranes Any Erythro vs. placebo 1. ↓Composite outcome (singletons): 11.2% vs. 14.4% (p= 0.02) 2. ↓ Delivery <48H: 34.8% vs. 40.7% (p=0.004) 3. ↓surfactant Rx, Use of oxygen >21d, ↓cerebral abnormalities, ↓blood cultures Any Co-amoxiclav vs. placebo 1. No difference in composite outcome: 13.8% vs. 14.0% 2. ↓ Delivery <48H: 30.9% vs. 37.8% (p=0.0001) 3. ↑suspect/proven NEC: 3.8% vs. 2.4% (p=0.004) Conclusion “Erythromycin for PROM is associated with range of health benefits for neonate. Co-amoxiclav cannot be recommended due to association with NEC.” Kenyon SL, ORACLE Group, Lancet 2001, 357:979-88

  47. Childhood Outcomes: 7 year follow-up of ORACLE I Trial: Broad Spectrum Antibiotics for PROM Follow-up of 4148 children at 7 years for outcome; 3298 assessed -Child health status, functional impairment, Educational outcomes (national curriculum tests) Any Erythro (+/- Co-amoxiclav) vs. placebo 1. No difference in functional impairment: 38.3% vs. 38.1% Any Co-amoxiclav (+/- Erythro) vs. placebo 1. No difference in functional impairment: 40.6% vs. 38.1% Conclusion “The prescription of antibiotics for women with PROM seems to have little effect on health of children at 7 years of age.” Kenyon SL, ORACLE Group, Lancet 2008, 1310

  48. Glucocorticosteroid Therapy • All women at risk of preterm delivery at 24-34 weeks of gestations should receive corticosteroid therapy regardless of fetal gender, race or availablity of surfactant therapy. •  50% Reduction in: • Respiratory distress syndrome • Periventricular hemorrhage • Necrotizing enterocolitis • Neonatal mortality • If preterm rupture of membranes: 24-32 weeks NIH Consensus Conference on Antenatal Steroids 1994

  49. Evaluating the Efficacy of TocolysisSUMMARY • Calcium channel blockers are recommended for tocolytic Rx based on RCTs showing • Less deliveries <48H, <7d c.f. Β-mimetics • Less discontinuation 2° mat adverse reaction • Less RDS, IVH and neonatal jaundice • β-mimetics help delay preterm birth for women transferred to tertiary center or complete a course of antenatal corticosteroids. However its use is associated with multiple adverse effects. • No evidence that Magnesium Sulfate is effective in delaying or preventing preterm birth and its use is associated with increased mortality for the infant

  50. Evaluating the Efficacy of TocolysisSUMMARY • Insufficient evidence for COX inhibitor Rx to prevent PTL. • No evidence to support Atosiban (no advantage over β-mimetics) and may be associated with ↑infant death. • No evidence for antibiotic therapy to prevent PTL in intact membranes. • Evidence for Erythromycin to prevent PTB with PROM • No evidence that β-mimetics are effect in primary prevention of PTB in high risk women or in maintenance after threatened PTL • Insufficient evidence for Calcium channel blockers in maintenance after threatened PTL

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