1. Compendium on Preterm Birth Epidemiology & Biology of Preterm Birth Produced in cooperation with: American Academy of Pediatrics The American College of Obstetricians and Gynecologists Association of Women’s Health, Obstetric and Neonatal Nurses © March of Dimes 2006

2. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Objectives  At the completion of this section, participants should be able to: –Describe the epidemiologic and economic factors associated with preterm birth –Recognize: Definitions Major risk factors Pathways leading to preterm birth Clinical diagnosis –Express the significance of preterm birth as an important public health issue

3. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  Preterm (or premature) infant –infant born before 37 completed weeks of gestation  Late preterm infant (a recently identified category) –infant born between 34 and 36 weeks gestation  Moderately preterm infant –infant born between 32 and 36 completed weeks of gestation  Very preterm infant –infant born before 32 completed weeks of gestation Definitions Sources: Iams JD, Creasy RK. Preterm labor and delivery, Chapter 34. In: Maternal-Fetal Medicine: Principles and Practice, 5th ed., 2004; Davidoff MJ et al. Semin Perinatol 2006;30:8-15.

4. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Definitions  Low birthweight (LBW) –infant who weighs less than 2,500 grams at delivery  Very low birthweight (VLBW) –infant who weighs less than 1,500 grams at delivery  Extremely low birthweight (ELBW) –infant who weighs less than 1,000 grams at delivery Source: Iams JD, Creasy RK. Preterm labor and delivery, Chapter 34. In: Maternal-Fetal Medicine: Principles and Practice, 5th ed., 2004.

5. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  < 1,000 grams 0.7% (of live births) – Most (99.3%) are preterm  1,000-2,500 grams7.2% – 63.9% are preterm  > 2,500 grams92.1% – 7.6% are preterm Prematurity & Low Birthweight, U.S., 2003 Low birthweight is less than 2,500 grams (5 1/2 pounds). Preterm is less than 37 completed weeks gestation. Source: National Center for Health Statistics, 2003 natality file Prepared by March of Dimes Perinatal Data Center, 2006.

6. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Low birthweight is less than 2,500 grams (5 1/2 pounds). Preterm is less than 37 completed weeks gestation. Source: National Center for Health Statistics, 2003 natality file. Prepared by the March of Dimes Perinatal Data Center, 2006. Overlap in LBW, Preterm & Birth Defects, U.S., 2003 Low Birthweight Births 7.9% Preterm Births 12.3% Birth Defects ~3-4% Among LBW: 2/3 are preterm Among preterm: more than 43% are LBW (some preterm are not LBW)

7. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth All Preterm Births by Gestational Age, U.S., 2003 Preterm is less than 37 completed weeks gestation. Source: National Center for Health Statistics, 2003 natality file. Prepared by the March of Dimes Perinatal Data Center, 2006. (34 Weeks) (33 Weeks) (32 Weeks) (<32 Weeks) (35 Weeks) (36 Weeks ) 71% of PTB is at 34, 35, 36 weeks

8. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Preterm & Very Preterm Births United States, 1993-2003 Preterm is less than 37 completed weeks gestation. Very preterm is less than 32 completed weeks gestation. Source: National Center for Health Statistics, final natality data. Prepared by March of Dimes Perinatal Data Center, 2006. Percent of live births Healthy People Objective

9. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Selected Leading Causes of Infant Mortality* United States, 1992 & 2002 *Deaths to infants less than one year of age. Source: National Center for Health Statistics, 1992 final mortality data and 2002 period-linked birth/infant death data. Prepared by the March of Dimes Perinatal Data Center, 2006. Rate per 100,000 live births 1 2 3 6 2002 Rank

10. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Preterm Births United States, 1983-2003 Preterm is less than 37 completed weeks gestation. Source: National Center for Health Statistics, 2003 final natality data. Prepared by March of Dimes Perinatal Data Center, 2006. Percent Healthy People Objective 28 Percent Increase

11. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Preterm Births by Maternal Age, United States, 2003 Preterm is less than 37 completed weeks gestation Source: National Center for Health Statistics, 2003 final natality data. Prepared by March of Dimes Perinatal Data Center, 2006. Percent

12. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Preterm Births by Maternal Race/Ethnicity, U.S., 1993-2003 Percent Preterm is less than 37 completed weeks gestation. Source: National Center for Health Statistics, final natality data. Prepared by March of Dimes Perinatal Data Center, 2006.

13. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Preterm Birth Rates by State United States, 2003 Note: Value in ( ) = number of states (includes District of Columbia). Value ranges are based on equal counts. Source: National Center for Health Statistics, 2003 final natality data. Prepared by March of Dimes Perinatal Data Center, 2005. U.S. Total = 12.3% Percent of Live Births Over 13.0 (16) 11.6 to 13.0 (18) Under 11.6 (17)

14. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Economic Consequences of Preterm Birth  Hospital charges for premature infants 1 totaled $18.1 billion in 2003.  Premature infants accounted for half of the hospital charges for all infants ($36.7 billion).  The average charge for the most severe stays 2 was $77,000 compared to $1,700 for an uncomplicated newborn stay. 1 Includes any diagnosis of prematurity/low birthweight 2 Defined as having a principal diagnosis of prematurity Source: Agency for Healthcare Research and Quality, 2003 Nationwide Inpatient Sample. Prepared by March of Dimes Perinatal Data Center, 2006.

15. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Average Length of Stay for Selected Inpatient Infant Hospitalizations, U.S., 2003 2.0 13.6 24.2 Agency for Healthcare Research and Quality, 2003. Nationwide Inpatient Sample. Prepared by March of Dimes Perinatal Data Center, 2006.

16. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Distribution of Hospital Stays & Hospital Charges, U.S., 2003 All other infant stays 4,301,000 ~91% Agency for Healthcare Research and Quality, 2003. Nationwide Inpatient Sample. Prepared by March of Dimes Perinatal Data Center, 2006. 12.9 Infant stays with any diagnosis of prematurity 413,000 ~9% Hospital charges for all other infant stays $18.6 billion Hospital charges for infant stays with any diagnosis of prematurity $18.1 billion

17. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Percent of Hospital Charges for Preterm Birth by Expected Payer, U.S., 2002 *Includes Medicare Source: Agency for Healthcare Research and Quality, 2002. Nationwide Inpatient Sample. Prepared by March of Dimes Perinatal Data Center, 2006. Almost half of hospital charges for premature infants, or about $7.4 billion, were billed to employers and other private insurers. Medicaid 46.3% Other* 3.6% Private/ Commercial 47.8 Uninsured/ Self Pay 2.3%

18. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Costs to Employers Based on analysis of births in 2001 followed for 12 months. Expenditures have been adjusted to 2004 dollars using the medical component of the CPI. Data largely from self-insured U.S. employers. Research conducted and underwritten by Thomson Medstat.

19. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Long-term Care Costs  Health-care costs –e.g., monetary value related to use of community health services  Educational costs –e.g., additional assistance (such as special education) required as a result of school failure & learning problems  Social service costs –e.g., utilization of developmental services such as day care programs, case management & counselling, or respite care & residential care  Out-of-pocket expenses –e.g., additional travel costs related to going to health & social care providers or accommodation expenses Sources: Petrou S et al. Child Care Health Dev. 2001;27:97-115; Petrou S et al. Early Hum Dev. 2006;82:77-84.

20. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  Many women think a baby born prematurely is “meant to be,” and its preterm birth can’t be prevented.  U.S. adults do not perceive preterm birth to be a serious public health problem. Source: Massett HA et al. Am J Prev Med 2003; 24:120-7. Public Opinion About Prematurity

21. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Preterm Birth A Common, Complex Disorder  Genetic contribution  Environmental influences  Gene-environment interactions

22. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  #1 cause of neonatal mortality (<28 days) in the U.S.  #2 cause of infant mortality (<1 year) in the U.S. –#1 cause of infant mortality for non-Hispanic black infants in the U.S. Sources: Mathews TJ, MacDorman MF. Natl Vital Stat Rep 2006;54:1-29; National Center for Health Statistics, 2003 period- linked birth/infant death data. Prepared by March of Dimes Perinatal Data Center, 2006. Preterm Birth

23. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Perinatal Mortality & Gestational Age Source: Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol 2003;101:178-93. Reproduced with permission from Lippincott Williams & Wilkins.

24. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth The Morbidity of Prematurity Neonatal  Respiratory distress syndrome (RDS)  Intraventricular hemorrhage (IVH) & periventricular leukomalacia (PVL)  Necrotizing enterocolitis (NEC)  Patent ductus arteriosus (PDA)  Infection  Metabolic abnormalities  Nutritional deficiencies Long term  Cerebral palsy  Sensory deficits  Special health care needs  Incomplete catch-up growth  School difficulties  Behavioral problems  Chronic lung disease Short term  Feeding and growth difficulties  Infection  Apnea  Neurodevelopmental difficulties  Retinopathy  Transient dystonia Source: Iams JD, Creasy RK. Preterm labor and delivery, Chapter 34. In: Maternal-Fetal Medicine: Principles and Practice, 5th ed., 2004.

25. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Perinatal Morbidity & Gestational Age Source: Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol 2003;101:178-93. Reproduced with permission from Lippincott Williams & Wilkins.

26. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth What are the conditions leading to preterm birth?  Spontaneous - 75% – Preterm labor – Preterm premature rupture of membranes (PPROM) – Multiple gestation – Cervical insufficiency – Other related diagnoses  Clinically Indicated - 25% – Mother or fetus at risk Classification of Preterm Birth Sources: Goldenberg RL et al. Am J Public Health 1998;88:233-8; Meis PJ et al. Am J Obstet Gynecol 1995;173:597-602; Meis PJ et al. Am J Obstet Gynecol 1998;178:562-7.

27. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  Clinical presentations –Preterm labor - 50-60% –Preterm premature rupture of membranes (PPROM) - 40-50%  Risk factors similar –PPROM More often smokers, 2nd trimester bleeding, low socioeconomic status (SES)  50% have no risk factors Sources: Goldenberg RL et al. Am J Public Health 1998;88:233-8; Meis PJ et al. Am J Obstet Gynecol 1995;173:597-602; Meis PJ et al. Am J Obstet Gynecol 1998;178:562-7. Spontaneous Preterm Births

28. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  Preeclampsia43%  Fetal distress28%  Inadequate intrauterine fetal growth10%  Abruption 7%  Fetal demise 7% Source: Meis PJ et al. Am J Obstet Gynecol 1998;178:562-7. Clinical Indications for Preterm Deliveries

29. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Demographic Characteristics of Populations at Risk for Preterm Birth  Maternal age ( 35 years)  Low socioeconomic status (SES)  Unmarried  African-American ancestry

30. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth –history of preterm birth –unintended pregnancy –previous fetal or neonatal death –3+ spontaneous losses –assisted reproductive technology (ART) –genetic predisposition –folic acid deficiency –environmental toxins –low pre-pregnancy weight –obesity –anemia –lack of social support –tobacco use –alcohol abuse –illicit drug use Known Risk Factors for Preterm Birth Epidemiologic Source: Iams JD, Creasy RK. Preterm labor and delivery, Chapter 34. In: Maternal-Fetal Medicine: Principles and Practice, 5th ed., 2004.

31. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth –systemic maternal disease –infections –preterm premature rupture of membranes (PPROM) –fetal / placental anomalies –bleeding –trauma Known Risk Factors for Preterm Birth (continued) Inflammation Overdistension/uterine problems –multifetal pregnancy –overdistension –uterine abnormalities –cervical abnormalities Decidual hemorrhage –stress / violence Activation of maternal hypothalamic pituitary adrenal (HPA) axis Source: Iams JD, Creasy RK. Preterm labor and delivery, Chapter 34. In: Maternal-Fetal Medicine: Principles and Practice, 5th ed., 2004.

32. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Common Risk Factors for Preterm Birth  Multiple gestation  Infection  Stress  Bleeding  Nutrition  Excessive physical activity  Prior preterm birth  Uterine factors – Cervical length – Contractions – Anomalies – Distention  Ancestry and ethnicity Source: Martin JA et al. Natl Vital Stat Rep. 2005;54:1-116; Iams JD, Creasy RK. Preterm labor and delivery, Chapter 34. In: Maternal-Fetal Medicine: Principles and Practice, 5th ed., 2004.

33. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  Multiple GestationOR 6 –compared to singleton births  Prior Preterm DeliveryOR 4 –compared to no history of preterm birth  2nd Trimester BleedingOR 2 or > –compared to no early bleeding (before 28 weeks)  Genito-Urinary (GU) Tract InfectionOR 2 –compared to no GU infection  African-American OR 2 –compared to non African-American ancestry  Body Mass Index <19.8 kg/m 2 OR 2 –compared to body mass index  19.8 kg/m 2 Epidemiology of Spontaneous PTB Source: Iams JD, Creasy RK. Preterm labor and delivery, Chapter 34. In: Maternal-Fetal Medicine: Principles and Practice, 5th ed., 2004.

34. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Preterm Births by Plurality United States, 2003 Preterm is less than 37 completed weeks gestation. Source: National Center for Health Statistics, 2003 final natality data. Prepared by March of Dimes Perinatal Data Center, 2006 Percent

35. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Multiple Birth Ratios by Race* United States, 1980-2003 Multiple births include twins, triplets, and higher order births. *Race of child from 1980-1988; race of mother from 1989-2003. Source: National Center for Health Statistics, 1980-2003 final natality data. Prepared by March of Dimes Perinatal Data Center, 2006 Ratio per 1,000 live births

36. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  Rises with increased number of preterm deliveries (PTDs)  Rises as gestational age of prior PTD declines  Most recent birth is more predictive  Risk greater in African-Americans Source: Mercer BM et al. Am J Obstet Gynecol 1999;181:1216-21. Recurrence Risk of Preterm Birth

37. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Population-based cohort study — Georgia 1980 to 1995  122,722 white women and 56,174 black women  Of 1,023 white women w/ 1st delivery @ 20-31 weeks –8.2% delivered 2nd at 20-31 weeks –20.1% delivered 2nd at 32-36 weeks 28.3% < 36 wk –Total preterm deliveries = 28.3% < 36 wk  Of 1,084 black women w/ 1st delivery @ 20-31 weeks –13.4% delivered 2nd at 20-31 weeks –23.4% delivered 2nd at 32-36 weeks 36.8% < 36 wk –Total preterm deliveries = 36.8% < 36 wk Source: Adams MM et al. JAMA 2000;283:1591-6. Recurrent Preterm Delivery

38. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Transvaginal Cervical Sonography Source: Reprinted from Ultrasonography in Obstetrics and Gynaecology, 4th ed., Callen PW, Copyright 2000, with permission from Elsevier.

39. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Cervical Effacement = T Y V U Source: Zilianti M et al. Monitoring the effacement of the uterine cervix by transperineal sonography: a new perspective. J Ultrasound Med 1995;14:719-24. Reproduced with permission from the American Institute of Ultrasound in Medicine. TY UV

40. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Relative Risk of Spontaneous Preterm Delivery < 35 Weeks by Percentile of Cervical Length at 24 Weeks Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 1996;334:567-72. Copyright 1996 Massachusetts Medical Society. All rights reserved. NICHD MFMU Network

41. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Risk of Spontaneous Preterm Delivery < 35 weeks by Cervical Length at 24 weeks Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 1996;334:567-72. Copyright 1996 Massachusetts Medical Society. All rights reserved. NICHD MFMU Network

42. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  Cervical length is a bell curve.  The risk of spontaneous preterm delivery increases as cervical length decreases.  This occurs across the entire range of cervical length, not just < 10th %. Cervical Length New Information from Ultrasound Source: Iams JD et al. N Engl J Med 1996;334:567-72; Taipale P, Hiilesmaa V. Obstet Gynecol. 1998;92:902-7; Goldenberg RL et al. Am J Public Health 1998;88:233-8.

43. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  Cervical function is variable and relative –Long cervix = Low risk of preterm birth, more likely to carry twins to term –Short cervix = Greater risk of preterm birth –Very short cervix = Greatest risk of early preterm birth  Why is the cervix short? –Individual or combined effect of: Biological variation Inflammation Contractions Surgery/procedure A Continuum of Cervical Function Source: Iams JD, Creasy RK. Preterm labor and delivery, Chapter 34. In: Maternal-Fetal Medicine: Principles and Practice, 5th ed., 2004.

44. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth  Inflammation  Infection - ~40%  Activation of the maternal-fetal hypothalamic– pituitary–adrenal (HPA) Axis  Stress - ~30%  Decidual hemorrhage  Abruption - ~20%  Uterine distension  Stretching - ~10% Pathways to Preterm Birth Sources: Lockwood CJ, Iams JD. Preterm labor and delivery. Precis: Obstetrics, 3rd ed. ACOG, 2005; Lockwood CJ, Kuczynski E. Paediatr Perinat Epidemiol 2001;15:78-89.

45. Compendium on Preterm Birth © March of Dimes 2006 Epidemiology & Biology of Preterm Birth Pathways to Preterm Birth Source: Lockwood CL. Unpublished data, 2002. proteases PTD Uterine Contractions Cervical Change Infection: - Chorion-Decidual - Systemic Decidual Hemorrhage CRH E1-E3 Thrombin Thrombin Rc Pathological Uterine Distention Multifetal Pregnancy Polyhydramnios Uterine Abnormality Inflammation Maternal-Fetal Stress Premature Onset of Physiologic Initiators Activation of Maternal-Fetal HPA Axis CRH + Chorion Decidua uterotonins Mechanical Stretch Gap jct PG synthase Oxt recep PPROM Ils, Fas L TNF + Abruption