1. Premature Labor and Delivery Honor M. Wolfe Associate Professor Maternal Fetal Medicine

2. Objectives: To review the To review the –Definition, frequency and consequence of preterm delivery –Modifiable and non modifiable risks for Preterm delivery –Pathogenesis of Preterm delivery –Prediction of Preterm delivery –Management of Preterm labor

3. Preterm Labor: Definition “ “Regular” uterine contractions With – –Cervical “change” or – –> 2 cm dilation or – –> 80% effacement

4. Preterm Delivery Preterm Delivery - Preterm birth:< 37completed weeks - Very Preterm birth: < 32 weeks - Very Preterm birth: < 32 weeks - Extremely Preterm birth: < 28 weeks - Extremely Preterm birth: < 28 weeks

5. Incidence/Definitions 12.5% USA (2004) 12.5% USA (2004) 2% < 32 weeks 2% < 32 weeks Fetal growth Fetal growth –Small for gestational age < 10 th % for GA Birthweight: Birthweight: –Low BWT < 2500 grams –Very low BWT < 1500 grams –Extremely low BWT < 1000 grams

6. Incidence 13% Rise in PTB since 1992 13% Rise in PTB since 1992 Multiple gestation (20% increase) Multiple gestation (20% increase) –50 % twins, 90% triplets born preterm Changes in Obstetric management Changes in Obstetric management –Ultrasound, induction Sociodemographic factors Sociodemographic factors –AMA! No improvement with physician interventions! No improvement with physician interventions!

7. Leading Causes of Neonatal Death (USA) Neonatal Neonatal deaths deaths Percentage of Percentage of neonatal deaths neonatal deaths Disorders related to prematurity and low birth weight 4,318 4,318 23.0 23.0 Congenital malformations, chromosomal abnormalities 4,144 4,144 22.1 22.1 Maternal complications 1,394 1,394 7.4 7.4 Placenta, cord, and membrane complications 1,049 1,049 5.6 5.6 Respiratory distress 929 929 4.9 4.9 Bacterial sepsis 737 737 3.9 3.9 Intrauterine hypoxia and birth asphyxia 589 589 3.1 3.1 Neonatal hemorrhage 563 563 3.0 3.0 Atelectasis 483 483 2.6 2.6 Necrotizing enterocolitis 313 313 1.7 1.7 Neonatal deaths: death within 28 days of birth. Data adapted from: the Centers for Disease Control and Prevention, 2000.

8. Significance Infant mortality Infant mortality –Over 50% of infant deaths occur among the 1.5% infants < 1500 grams –70 % of infant deaths occur among the 7.7% of infants < 2500 grams Morbidity Morbidity –60%: 26 weeks –30%: 30 weeks

12. Risk Factors for Preterm BirthNon-modifiable Prior preterm birth African-American race Age 40 years Poor nutrition/low prepregnancy weight Low socioeconomic status Cervical injury or anomaly Uterine anomaly or fibroid Premature cervical dilatation (>2 cm) or effacement (>80 percent) Over distended uterus (multiple pregnancy, polyhydramnios) ? Vaginal bleeding ? Excessive uterine activity Modifiable Cigarette smoking Substance abuse Absent prenatal care Short interpregnancy intervals Anemia Bacteriuria/urinary tract infection Genital infection ? Strenuous work ? High personal stress

13. Risk factors for preterm birth Stress Single women Single women Low socioeconomic status Low socioeconomic status Anxiety Anxiety Depression Depression Life events (divorce, separation, death) Life events (divorce, separation, death) Abdominal surgery during pregnancy Abdominal surgery during pregnancy Occupational fatigue Upright posture Upright posture Use of industrial machines Use of industrial machines Physical exertion Physical exertion Mental or environmental stress Mental or environmental stress Excessive or impaired uterine distention Multiple gestation Multiple gestation Polyhydramnios Polyhydramnios Uterine anomaly or fibroids Uterine anomaly or fibroids Diethystilbesterol Diethystilbesterol Cervical factors History of second trimester abortion History of cervical surgery Premature cervical dilatation or effacement Infection Sexually transmitted infections Pyelonephritis Systemic infection Bacteriuria Periodontal disease Placental pathology Placenta previa Abruption Vaginal bleeding

14. Risk factors for preterm birth Miscellaneous Previous preterm delivery Previous preterm delivery Substance abuse Substance abuse Smoking Smoking Maternal age ( 40) Maternal age ( 40) African-American race African-American race Poor nutrition and low body mass index Poor nutrition and low body mass index Inadequate prenatal care Inadequate prenatal care Anemia (hemoglobin <10 g/dL) Anemia (hemoglobin <10 g/dL) Excessive uterine contractility Excessive uterine contractility Low level of educational achievement Low level of educational achievement Genotype Genotype Fetal factors Congenital anomaly Congenital anomaly Growth restriction Growth restriction

15. Prior preterm birth - Increases risk in subsequent pregnancy - Risk increases with - more prior preterm births - earlier GA of prior preterm birth (s)

16. Prediction/Recurrence Prior PTD @ (23-27 wks) 27% Prior PTD @ (23-27 wks) 27% Prior PPROM 13.5% Prior PPROM 13.5%

18. Pathogenesis 80% of Preterm births are spontaneous 80% of Preterm births are spontaneous –50% Preterm labor –30% Preterm premature rupture of the membranes Pathogenic processes Pathogenic processes –Activation of the maternal or fetal hypothalamic pituitary axis –Infection –Decidual hemorrhage –Pathologic uterine distention

19. Activation of the HPA Axis Premature activation Premature activation Major maternal physical/psychologic stress Major maternal physical/psychologic stress Stress of uteroplacental vasculopathy Stress of uteroplacental vasculopathy Mechanism Mechanism –Increased Corticotropin-releasing hormone –Fetal ACTH –Estrogens (incr myometrial gap junctions)

20. Inflammation Clinical/subclinical chorioamnionitis Clinical/subclinical chorioamnionitis –Up to 50% of preterm birth < 30 wks GA Proinflammatory mediators Proinflammatory mediators –maternal/fetal inflammatory response –Activated neutrophils/macrophages –TNF alpha, interleukins (6) Bacteria Bacteria –Degradation of fetal membranes –Prostaglandin synthesis

21. Prediction of Preterm Delivery History: Current and Historical Risk Factors History: Current and Historical Risk Factors Mechanical Mechanical –Uterine contractions –Home uterine activity monitoring Biochemical Biochemical –Fetal fibronectin Ultrasound Ultrasound –Cervical length

22. Fetal fibronectin- Fetal fibronectin- Glycoprotein in amnion, decidua, cytotrophoblast Increased levels secondary to breakdown of the chorionic-decidual interface Inflammation, shear, movement

23. Fetal fibronectin as a predictor for delivery within 7 and 14 days after sampling, combined results Delivery <7 days Delivery <14 days Delivery <7 days Delivery <14 days Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity (percent), (percent), 95 (percent), 95 (percent), 95 (percent), (percent), 95 (percent), 95 (percent), 95 95 percent CI percent CI percent CI percent CI 95 percent CI percent CI percent CI percent CI Study group All studies 71 (57-84) 89 (84-93) 67 (51-82) 89 (85-94) Women with preterm labor 77 (67-88) 87 (84-91) 74 (67-82). 87 (83-92) Asymptomatic 63 (26-90)* 97 (97-98) 51 (33-70). 96 (92-100) (low risk or high-risk)women CI: confidence interval. * Only one study included in analysis.. Fixed-effects model used (homogeneity test P >0.10). Data from: Leitich, H, Kaider, A. Fetal fibronectin - how useful is it in the prediction of preterm birth? BJOG 2003; 110 (Suppl 20):66.. Fixed-effects model used (homogeneity test P >0.10). Data from: Leitich, H, Kaider, A. Fetal fibronectin - how useful is it in the prediction of preterm birth? BJOG 2003; 110 (Suppl 20):66.

24. Fetal fibronectin vs. Clinical assessment of Preterm Labor Parameter Sensitivity (percent) PPV (percent) NPV (percent) Parameter Sensitivity (percent) PPV (percent) NPV (percent) Fetal fibronectin 93 29 99 Cervical dilatation >1 cm 29 11 94 Contraction frequency 8/h 42 9 94 PPV: positive predictive value; NPV: negative predictive value. Data derived from symptomatic women and reflect the ability to predict delivery within seven days. Adapted from: Iams, JD, Casal, D, McGregor, JA, et al. Am J Obstet Gynecol 1995; seven days. Adapted from: Iams, JD, Casal, D, McGregor, JA, et al. Am J Obstet Gynecol 1995; 173:141. 173:141.

25. Sonographic assessment of cervical length - Transvaginal - Reproducible - Simple

26. (Dijkstra et al Am J Obstet Gynecol 1999)

30. Assessment of Risk: Integration of History, Cervical length Fibronectin

31. Prediction of spontaneous preterm delivery before 35 weeks gestation among asymptomatic low risk women Cervical length Fetal fibronectin Both tests Cervical length Fetal fibronectin Both tests <25mm (percent) (percent) (percent) <25mm (percent) (percent) (percent) Positive test Result 8.5 3.6 0.5 Sensitivity 39 23 16 Specificity 92.5 97 99.5 Positive predictive Value 14 20 50 Negative predictive value 98 98 94.4 Adapted from: Iams, JD, Goldenberg, RL, Mercer, BM, et al. Am J Obstet Gynecol 2001; 184:652.

32. Risk of Preterm birth < 35 weeks History of Delivery 18-2627-3132-36 > 37 FFN (-) CL < 25 CL < 2525%25%25%6% CL 26-35 CL 26-3514%14%13%3% CL > 35 CL > 357%7%7%1% FFN (+) CL < 25 CL < 2564%64%63%25% CL 26-35 CL 26-3546%45%45%14% CL > 35 CL > 3528%28%27%7%

33. Clinical Diagnosis Preterm Labor Clinical Criteria Clinical Criteria –Persistent Ctx 4 q 20 min or 8 q 60 min –Cervical change/80% effacement/> 2cm dil. Among the most common admission Dx Among the most common admission Dx Inexact diagnosis: PTL is not PTD Inexact diagnosis: PTL is not PTD –30% PTL resolves spontaneously –50% of hospitalized PTL deliver @ term

34. Management of Preterm Labor Bedrest, hydration, sedation Bedrest, hydration, sedation NO evidence to support in the literature NO evidence to support in the literature

35. Beta adrenergic receptor agonists (terbutaline) Mechanism Mechanism –Interferes w/ myosin light chain kinase –Inhibits actin myosin interaction Efficacy Efficacy –? 48 hours. No change in perinatal outcome Side Effects Side Effects –Tachycardia, palpitations,hypotension,SOB, pulmonary edema, hyperglycemia Contraindications Contraindications –Maternal cardiac disease, uncontrolled diabetes and hyperthyroidism

36. Magnesium Sulfate Mechanism of Action Mechanism of Action –Competes with Calcium at plasma memb (?) Efficacy Efficacy –Unproven Side Effects Side Effects –Diaphoresis, flushing, pulmonary edema Contraindications Contraindications –Myasthesthenia gravis, renal failure

37. Calcium Channel Blockers Mechanism of Action Mechanism of Action –Directly block influx of Ca thru cell membrane Efficacy Efficacy –Unproven Side Effects Side Effects –Nausea, flushing, HA, palpitations Contraindications Contraindications –Caution: LV dysfunction, CHF

38. Cyclooxygenase Inhibitors Mechanism of Action Mechanism of Action –Decrease prostaglandin production Efficacy Efficacy –Unproven Side Effects Side Effects –Nausea, GI reflux, spasm fetal DA, oligo Contraindications Contraindications –Platelet or hepatic dysfunction, GI ulcer –Renal dysfunction, asthma

39. Antenatal Steroids Recommended for: Recommended for: –Preterm labor 24 – 34 weeks –PPROM 24 – 32 weeks Reduction in: Reduction in: –Mortality, IVH, NEC, RDS Mechanism of action: Mechanism of action: –Enhanced maturation lungs –Biochemical maturation

40. Antenatal Steroids Dosage: Dosage: –Dexamethasone 6 mg q 12 h –Betamethasone 12.5 mg q 24 h Repeated doses - NO Repeated doses - NO Effect: Effect: –Within several hours –Max @ 48 hours

41. Progesterone for History of PTB 17 alpha OH Progesterone 17 alpha OH Progesterone –Women with prior PTB (singleton) 24 – 26 wks –(16 – 20 wks) – 36 weeks Reduces the risk of recurrent preterm birth Reduces the risk of recurrent preterm birth –< 37 wks 36% vs 55% –< 35 wks 21% vs 31% –< 32 wks 11% vs 20%

42. Case # 1 A 36 year old black female G2 P 0101 presents at 8 weeks gestation. A 36 year old black female G2 P 0101 presents at 8 weeks gestation. History: Chronic hypertension, no meds History: Chronic hypertension, no meds –Smokes 1 ppd, Drugs (-) ETOH (+) –STI – history of chlamydia, HIV positive –Surgical history : LEEP, tubal ligation