1. 8th Edition APGO Objectives for Medical Students Preterm Labor

2. Rationale Prematurity is the most common cause of neonatal mortality and morbidity. The reduction of preterm births remains an important goal in obstetric care. Understanding the causes and recognizing the symptoms of preterm labor provides the basis for management decisions.

3. Objectives The student will be able to cite: Factors predisposing to preterm labor Signs and symptoms of premature uterine contractions Causes of preterm labor Management of preterm labor, including: Tocolytics Steroids Antibiotics

4. Preterm Birth Definition - any delivery occurring prior to 37 wk. gestation Incidence - 11% of live-births 1/3 of preterm deliveries are due to spontaneous rupture of membranes 1/3 to obstetrical causes 1/3 due to idiopathic preterm labor

5. Criteria for diagnosis of preterm labor Gestational age 20-37 wk. Documented uterine contractions (4/20 min.; 8/60 min.) accompanied by one or more of the following: Documented cervical change Cervical effacement of > 80% Cervical dilation of > 2 cm

6. Etiology Subclinical infection of fetal membranes with subsequent spontaneous rupture Amniotic fluid infection Cervical factors - incompetent cervix, cervical trauma or congenital anomalies Cervicovaginal infection - bacterial vaginosis, N.gonorrhoeae Uterine factors - anomaly, hydramnios, fibroids Trauma or surgery Placenta previa or abruption Maternal factors - preeclampsia (iatrogenic prematurity) Fetal anomalies

7. Risk factors for preterm delivery Non-pregnancy related Previous preterm delivery Low socioeconomic status Non-white Pre-pregnancy weight < 50 kg and possibly prenatal weight gain < 15 lbs. Smoking Uterine malformations Vaginal infection

8. Risk factors for preterm delivery Obstetric related Placenta previa Placenta abruption Polyhydramnios Multiple gestation Cervical effacement/dilatation Maternal diseases Hypertension Diabetes Systemic lupus erythematosus Renal disease Other medical complications

9. Management Tocolytics Beta mimetics Mechanism of action Attachment of drug to β2-adrenergic receptor Activation of adenyl cyclase Increased cAMP Decreased myosin light chain kinase activity Interference with actin/myosin interaction

10. Management Tocolytics - Beta mimetics Maternal side effects Cardiac arrhythmias Pulmonary edema - predisposing factors Increased intravascular volume Decreased peripheral vascular resistance Decreased blood viscosity Increased heart rate Decreased plasma colloid oncotic pressure Increased pulmonary vascular permeability Intrapartum volume shifts Hyperglycemia

11. Management Tocolytics - Beta mimetics Fetal side effects Hypoglycemia Hypocalcemia Hypotension Ileus Mild tachycardia

12. Management Tocolytics - Beta mimetics Dosage Ritodrine (50 μg/min. increased by 50 μg/min./20 min.; maximum dose 350 μg/min.) Terbutaline (infusion of 2.5 μg/min. with increases of 2.5 μg/min. every 20 min. similar to ritodrine protocol). Another optional therapy includes 250 μg subcutaneously/3 hr.; oral terbutaline should be begun at 5 mg. every 4-6 hr. as necessary to inhibit contractions.

13. Management Tocolytics - Magnesium sulfate Mechanism of action - competitively inhibits calcium, thereby blocking actin/myosin interaction Maternal side effects Pulmonary edema Chest pain and tightness Nausea Flushing Drowsiness Blurred vision

14. Management Tocolytics - Magnesium sulfate Fetal side effects Fetal depression Lower neonatal Apgar scores Dosage - 4 gm loading dose over 20 min. followed by 1-2 gm/hr. increasing by 0.5 gm/hr. every 30 min. until cessation of contractions. Maximum dosage 3.5-4 gm/hr.

15. Management Tocolytics Prostaglandin synthetase inhibitors Mechanism of action Decreases prostaglandins Decreases intracellular calcium Decreases gap junction formation Prevents cervical connective tissue changes with overall effect of: Smooth muscle relaxation Decreased synchronization Decreased inhibition of cervical maturation

16. Management Tocolytics - Prostaglandin synthetase inhibitors Maternal side effects Abdominal pain Anorexia Aplastic anemia Diarrhea Dizziness Vertigo Frontal headaches Hepatitis and jaundice Mental confusion Nausea Neutropenia Postpartum hemorrhage Retention of sodium and fluids Thrombocytopenia Ulcerative lesions of bowel

17. Management Tocolytics - Prostaglandin synthetase inhibitors Fetal effects Intracranial hemorrhage Oliguria Premature closure of ductus arteriosus Pulmonary hypertension Dosage - 50 mg indomethacin followed by 25 mg in 2 hr. if contractions did not cease. Then 25 mg every 4 hr. for 24 hr.

18. Management Tocolytics - Prostaglandin synthetase inhibitors Calcium channel blockers Mechanism of action - smooth muscle relaxation by decreasing intracellular calcium Maternal side effects Headache Tachycardia Vasodilation Hypotension Transient facial flushing Fetal side effects - none observed Dosage - nifedipine orally 30 mg followed by 20 mg q8h.

19. Management Steroids History - used to enhance lung maturation ･ Short-term benefits Meta-analysis of 15 trials reported the following decreased: Respiratory distress syndrome (RDS)(O.R; 95% CI = 0.4- 0.6) Necrotizing enterocolitis (NEC) Intraventricular hemorrhage (IVH)(O.R. 0.5; 95% CI = 0.3- 0.9) Neonatal mortality (O.R. 0.6; 95% CI 0.5-0.8) No increase in infections

20. Management Steroids Long-term benefits Increased survival Follow-up (3-6 yr.) - no effect on Growth Physical development Motor or cognitive skills School progress

21. Management Steroids Adverse Effects Short-term - Neonatal No increase in infections No adrenal suppression (clinically)

22. Management Steroids Adverse Effects Long-term -Neonatal (follow-up 12 yr.) - no change in: Motor skills Language skills Cognitive ability No change in memory ? increase in pharyngeal and ear infections

23. Management Steroids Adverse Effects Short-term - maternal Pulmonary edema Questionable increase maternal infection, especially with PROM Worsening of diabetes control Long-term - maternal: none

24. Management Steroids Types of Corticosteroids Dexamethasone Readily crosses placenta No mineralocorticoid activity 6 mg intramuscular every 12 hr. x 4 doses

25. Management Steroids Types of Corticosteroids Betamethasone Crosses placenta No mineralocorticoid activity 12 mg intramuscular every 24 hr. x 2 doses

26. Management Steroids Timing Best if given > 24 hr. and < 7 days prior to delivery May be slight benefit if treatment given and delivery < 24 hr. Not enough data for delivery > 7 days to make judgments One round of steroids only per NIH consensus statement

27. Management Steroids Indications 24-34 wk. 24-28 wk. Decreases RDS severity Decreases mortality Decreases IVH 28-34 wk. Decreases RDS Decreases mortality

28. Management Steroids NIH Consensus Recommendations 2000 All fetuses 24-34 wk. at risk for preterm delivery Should not be influenced by race or gender of fetus If patient eligible for tocolytics, she is eligible for corticosteroids Treatment recommendations Betamethasone 12 mg intramuscular/24 hr. x 2 doses Dexamethasone 6 mg intramuscular/12 hr. x 4 doses

29. Management Antibiotics Infection may play a significant role in preterm labor in select patients Up to 25% in some series Average is 16% Common organisms include GBS, GC, Listeria, mycoplasma, bacteroides, and ureaplasma

30. Management Antibiotics Markers of infection Bacterial endotoxin (LPS) in amniotic fluid may stimulate cytokines and prostaglandins Endogenous host products - cytokines such as interleukin-1, interleukin-6, TNF, etc. These products may be the result, not the cause, of preterm labor.

31. Management Antibiotics Studies Multiple studies using various antibiotics show no benefit in management of preterm labor Ampicillin used intrapartum for prevention of neonatal GBS Some evidence that treatment of bacterial vaginosis in 2nd trimester of pregnancy may decrease likelihood of PTL/PROM in high risk women

32. References Cunningham FG, Gant NF, Leveno KJ, Gilstrap LC, Hauth JC, Wenstrom K. Williams Obstetrics 21st Ed., Chapter 27 pages 689- 727, 2001. Beckman, CRB, Ling FW, Laube DW, Smith RP, Barzansky BM, Herbert WNP. Obstetrics and Gynecology 4th ed., chapter 22, pages 304-312, 2002. Adapted from Association of Professors of Gynecology and Obstetrics Medical Student Educational Objectives, 7th edition, copyright 1997.

33. Clinical Case Preterm Labor

34. Patient presentation A 20-year-old African-American, who is 28 weeks pregnant, presents to the labor unit complaining of contractions. The contractions began 8 hours ago and have increased in frequency and duration. She notes that, for the last two days, she has had increased vaginal discharge and some lower back pain. Her prior pregnancy was complicated by preterm labor and premature ruptured membranes at 26 weeks gestation. The neonates course was complicated by intra- ventricular hemorrhage and necrotizing enterocolitis.

35. Patient presentation Past medical history Medicalneg Surgicalappendectomy age 11 Obstetricgravida 3 para 2 one preterm delivery, living children 2, one with cerebral palsy

36. Patient presentation Physical exam Vital SignsTemp 36.5 o C (97.8 o F), pulse 64, respiration 20, BP 100/60, wt 49 kg GeneralThin women of stated gestational age CardiacRegular rate and rhythm, no rubs, gallops or clicks Abdomen No hepatosplenomegaly, fundal height 27 cm Vaginal examNo fluid per os; cervix – 3cm dilated and completely effaced; vertex presentation

37. Diagnosis & Management Preterm labor at 27 weeks gestation plan for tocolysis, steroids and penicillin for Group B streptococcus prophylaxis

38. Discussion Preterm birth is one of the major health hazards of our time. It is the leading cause of neonatal morbidity and mortality. Approximately 11-12% of births occur prior to 37 wk. gestation. Roughly 1/3 is due to preterm labor, 1/3 to preterm premature ruptured fetal membranes and 1/3 to medical or fetal complications. Efforts to reduce or prevent preterm birth are largely unsuccessful.

39. Discussion Preterm birth is defined as that occurring less than 37 wk. in the presence of regular uterine contractions (4 per 20 min or 8 per 60 minutes) with cervical change or if the cervix is 2 cm dilated and 80% effaced. There are many possible causes of preterm labor, including infection, faulty placentation, uterine factors (leiomyomata, uterine didelphys), overdistension of the uterus (multifetal gestation, polyhydramnios), immunologic causes, drug use (such as cocaine), and idiopathic. Risk factors for preterm birth can be subdivided into pre-pregnancy (i.e. low maternal weight and prior preterm birth) and pregnancy-related (twins, abnormal placentation, maternal factors).

40. Discussion Management of women with preterm labor involves tocolytics to reduce or stop the contractions (evidence is weak that tocolytics works longer than 24-48 hours), corticosteroids to enhance lung maturation and decrease the likelihood of neonatal respiratory distress syndrome and penicillin intrapartum to prevent early onset neonatal GBS infection.

41. Discussion Tocolytics can be divided into major categories with various degrees of efficacy, safety, side effect profiles, costs, etc. Categories include B-sympathomimetic (ritodrine and terbutaline), magnesium sulfate, prostaglandin synthetase inhibitors (indomethacin), calcium channel blockers (nifedipine) and oxytocin inhibitors (atosiban).

42. Teaching points Preterm birth is a common pregnancy complication Risk factors for preterm labor/birth are many; however the most common risk factors are prior preterm birth and low maternal weight Diagnosis of preterm labor is difficult Management includes hydration, tocolytics (a high rate of failure to prevent preterm birth), corticosteroids and antibiotics