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Causes of Preterm Birth: “The Preterm Parturition Syndrome” Roberto Romero,M.D. Chief Perinatology Research Branch Division of Intramural Research NICHD/NIH/DHHS.

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Presentation on theme: "Causes of Preterm Birth: “The Preterm Parturition Syndrome” Roberto Romero,M.D. Chief Perinatology Research Branch Division of Intramural Research NICHD/NIH/DHHS."— Presentation transcript:

1 Causes of Preterm Birth: “The Preterm Parturition Syndrome” Roberto Romero,M.D. Chief Perinatology Research Branch Division of Intramural Research NICHD/NIH/DHHS

2 Conflict of Interest Statement Official capacity (NICHD/NIH/DHHS) Division of Intramural Research Trial conducted by the Extramural Program of NICHD/NIH (17P-CT-002) Independent of PRB/NICHD No financial conflict of interest with sponsor

3 The Lancet Editorial 2006;368:339

4 Institute of Medicine of the National Academies, 2006 Richard E. Behrman, Adrienne Stith Butler, Editors Institute of Medicine Report Preterm Birth: Causes, Consequences, and Prevention

5 Magnitude of the Problem Definition (< 37 weeks) 2004: more than 500,000 neonates were born preterm Frequency: 12.5 %

6 Preterm Births as a Percentage of Live Births in the United States, 1990 to 2004 Institute of Medicine. PRETERM BIRTH: CAUSES, CONSEQUENCES, AND PREVENTION

7 Preterm Births as a Percent of Live Births, by Race and Ethnicity, 1992 to 2003 CDC Hispanic White, non- hispanic Black American Indian Asian or Pacific Islander

8 Frequency of Preterm Birth by Ethnic Group Source: CDC 2004 Births: Preliminary Data for (accessed August 30, 2005) Non-Hispanic African-American17.8% American Indians/Native Alaskans13.5% Hispanics11.9% Whites11.5% Asian and Pacific Islanders10.5%

9 Cost of Preterm Birth Medical care services: –16.9 billion ( $ 33,200 per preterm infant) - 2/3 total cost Maternal delivery cost: – 1.9 billion ( $ 3,800 per preterm infant) Special education services: –1.1 billion ( $ 2,200 per preterm infant) Lost household and labor market productivity: –5.7 billion ( $11,200 per preterm infant) Source: Institute of Medicine of the National Academies 2006, page 47

10 The Annual Societal Economic Burden associated with Preterm Birth in the United States In excess of $26.2 billion in 2005

11 © PJS The Prognosis of Preterm Neonates is a Function of Gestational Age at Birth

12 Survival by gestational age among live-born resuscitated infants Mercer BM Obstet Gynecol 2003;101:178 –93. Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee

13 Magnitude of the Problem The infant mortality rate for very preterm infants (delivered < 32 weeks of gestation) was 186.4, nearly 75 times the rate for infants born at term (2.5) (37–41 weeks of gestation) 20% all infants born <32 weeks do not survive the first year of life Mathews TJ. et al. National Vital Statistics Reports 2004;53:1-32

14 Acute morbidity by gestational age among surviving infants Mercer BM Obstet Gynecol 2003;101:178 –93. Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee

15 IOM Report – July 2006 “Babies born before 32 weeks have the greatest risk for death and poor health outcomes, however, infants born between 32 and 36 weeks, which make up the greatest number of preterm births, are still at higher risk for health and developmental problems compared to those infants born full term IOM Report page 72

16 Frequency of preterm birth by gestational age ( ) < 28 weeks : 0.82 % < 32 weeks: 2.2 % weeks: 8.9 % < 37 weeks: 11.2 IOM Report-July page 72/2006 Alexander GR et al 2006 (under review)

17 Complications of “Late Preterm or Near Term Infants” Cold Stress Hypoglycemia RDS Jaundice Sepsis IOM Report-July page 72/2006

18 Clinical Circumstances Associated with Preterm Birth Spontaneous preterm labor with intact membranes Preterm PROM Indicated preterm delivery –Maternal (e.g. pre-eclampsia) –Fetal (e.g. SGA/fetal compromise)

19 Is preterm labor simply “labor before its time” ?

20 Term Labor Preterm Labor © VR RR MM

21 Common Uterine Features of Term and Preterm Labor Increased myometrial contractility Cervical ripening (dilatation and effacement) Decidual/membrane activation Romero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414

22 Common Pathway of Parturition Anatomic, physiologic, biochemical, endocrinologic, immunologic, and clinical events in the mother and/or fetus in both term and preterm labor Romero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414

23 The “phenotypes” of spontaneous preterm parturition

24 Synchronous and Asynchronous Activation of Labor Cervical Ripening Cervical Ripening Uterine Contractility Uterine Contractility Membrane- Decidual Activation Membrane- Decidual Activation Preterm PROM Preterm PROM Preterm Contractions Preterm Contractions Cervical Insufficiency Cervical Insufficiency © VR RR MM

25 ComponentTestTreatment Myometrium Uterine MonitorTocolysis UltrasoundCerclage Cervix Approaches for the Prevention of Preterm Birth Fetal Fibronectin Antibiotics Membrane/Decidua © VR RR MM

26 Common Terminal Pathway Normal Term Labor Normal Term Labor Physiologic Activation Physiologic Activation Preterm Labor Preterm Labor Pathologic Activation Pathologic Activation © VR RR MM

27 What causes pathologic activation of the pathway ?

28 Placental Pathology in Prematurity Arias et al. Obstet Gynecol 1997;69:285. © PJS

29 Multiple etiologies Chronicity Fetal diseases Clinical manifestations are adaptive Symptomatic treatment is ineffective Genetic/environmental factors “Great Obstetrical Syndromes” © VR RR MM Romero R J Prenat Neonat Med 1996;1:8-11

30 The Preterm Parturition Syndrome UterineOverdistension Vascular Infection Cervical Disease Hormonal Immunological © VR RR MM Unknown

31 The Preterm Parturition Syndrome UterineOverdistension Vascular Infection Cervical Disease Hormonal Immunological © VR RR MM Unknown

32 Frequent: 25 % (at presentation) Sub-clinical Fetal disease FIRS Host defense Intraamniotic Infection

33 12% of preterm labor 20% of preterm PROM Sub-clinical Clinical Chorioamnionitis

34 Severe neonatal morbidity Severe neonatal morbidity Impending preterm delivery Impending preterm delivery Fetal multisystem involvement Fetal multisystem involvement FIRS © VR RR MM

35 Fetal Inflammatory Response Syndrome Hematologic Abnormalities Endocrine System Cardiac Dysfunction Pulmonary Injury Renal Dysfunction Brain Injury (PVL)

36 How common is sub- clinical intra-amniotic infection in asymptomatic midtrimester pregnancy

37 2461 midtrimester amniocenteses 9 patients with U. urealyticum (0.4%) 8 continuing pregnancies 6 spont. abortions within 4 weeks 2 preterm labor 8 histologic chorioamnionitis Infection in m id-trimester Gray DJ. Prenat Diagn 1992;12:111

38 Prevention of Preterm Labor/Delivery Important and desirable goal Only proven beneficial strategy is eradication of asymptomatic bacteriuria Limited attributable risk Patients with previous preterm birth are at increased risk for recurrence Potential beneficial effect of progesterone administration –17OHP-C and vaginal progesterone

39 The Preterm Parturition Syndrome UterineOverdistension Vascular Infection Cervical Disease Hormonal Immunological © VR RR MM Unknown

40 “Progesterone deficient state” has been proposed to be a Mechanism of Disease in Preterm Labor

41 Corpus Luteum

42 AJOG 1973;115: Prostaglandins 1973;4:421-9 AJOG 1973;115:759-65

43 What is the Effect of Luteectomy on Human Pregnancy? 64 pregnant women (< 5 weeks) Desired tubal ligation IRB approval Allocated to: –Tubal ligation (control group) –Tubal ligation + luteectomy –Tubal ligation + luteectomy + progesterone American Journal of Obstetrics and Gynecology: 1972 Prostaglandins: 1973 Ciba Symposium 47: 1977

44 Csapo AI The Fetus and Birth. Ciba Foundation Symposium 47; Pregnancy outcome after lutectomy Only tubal ligation 24+2 No Ab D  C) Days after Lutectomy Incipient Ab (curettage) ) ) Ab Luteectomy Amenorrhea Days 32+2 No Ab D  C Progesterone Plasma Progesterone (ng/ml)

45 Arpard Csapo Progesterone is “indispensable” for normal pregnancy Progesterone withdrawal is a prerequisite of normal pregnancy termination

46 Progesterone in Pregnancy Maintenance Myometrial quiescence Down-regulate gap junction formation Inhibit cervical ripening

47 A progesterone withdrawal “prepares” the uterus for the action of uterotonic agents

48 Administration of anti-progestins (RU-486 or onapristone) can induce abortion and cervical ripening Evidence that suspension of progesterone action is important in human parturition Kovacs L et al. Contraception 1984; 29: 399 Crowley WF. N EJM 1986; 18: 1607 Chwalisz K Human Reproduction 1994;9:131 Bygdeman et al. Human Reproduction 1994;9:120

49 No labor (n = 20) Labor (n = 20) Progesterone/estradiol ratio No labor (n = 20) Labor (n = 20) Progesterone/estriol ratio Romero R et al AJOG 1988;150:650-60

50 Key hormone for pregnancy maintenance “Progesterone withdrawal”: – Concentration – Receptor (A and B) Mesiano S, Chan E, Fitter JT, Kwek K, Yeo G, and Smith R. J Clin Endocrinol Metab 2002; 87:2924 – Functional (NF-kB) Allport VC, Pieber D, Slater DM, Newton R, White JO and Bennett PR. Mol Human Reprod 2001; 7:581-6 Progesterone

51 The clinical trials and meta-analysis of progesterone will be analyzed by FDA staff and the sponsor

52 Interventions for the prevention of preterm birth Efficacy Safety

53 Criteria for Efficacy Prevention of preterm birth –37 weeks –35 weeks –32 weeks Prolongation of pregnancy Neonatal morbidity and mortality

54 Safety Fetal Neonatal Infant Maternal

55 Progesterone Deficiency State Progesterone Common Terminal Pathway Preterm Labor

56 Obstet Gynecol 2003;102:1115-6

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59 Quiescence Weeks Quiescence Weeks The preparatory stage of labor

60 Progesterone Deficiency State Progesterone Common Terminal Pathway Preterm Labor Uterine Pathologic State (infection, vascular, uterine) Common Terminal Pathway Preterm Labor


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