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

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 20042 4 6 8 10 12
1990
1993
1995
1997
1999
2000
2003
2004
12.3
12.5
11.8
11.6
11.4 11 11
10.6
Institute of Medicine. PRETERM BIRTH: CAUSES, CONSEQUENCES, AND PREVENTION

7. Preterm Births as a Percent of Live Births, by Race and Ethnicity, 1992 to 20035 10 15 20
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
Black
American Indian
Hispanic
White, non- hispanic
Asian or Pacific Islander
CDC 2004.

8. Frequency of Preterm Birth by Ethnic Group
Non-Hispanic African-American
17.8%
American Indians/Native Alaskans
13.5%
Hispanics
11.9%
Whites
11.5%
Asian and Pacific Islanders
10.5%
Source: CDC 2004 Births: Preliminary Data for 2003
(accessed August 30, 2005)

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

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

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

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
Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee
Mercer BM Obstet Gynecol 2003;101:178 –93.

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 (1995-2000)
< 28 weeks : %
< 32 weeks: 2.2 %
33-36 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 2

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
Uterine
Contractility
Membrane-
Decidual
Activation
Cervical
Insufficiency
Preterm
Contractions
Preterm
PROM
© VR RR MM

25. Approaches for the Prevention of Preterm
Birth
Component
Test
Treatment
Myometrium
Uterine Monitor
Tocolysis
Cervix
Ultrasound
Cerclage
Membrane/Decidua
Fetal Fibronectin
Antibiotics
© VR RR MM

26. Common Terminal Pathway
Normal Term
Labor
Preterm
Labor
Pathologic
Activation
Physiologic
Activation
Common Terminal Pathway
© VR RR MM 4

27. What causes pathologic activation of the pathway ?

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

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

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

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

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

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

34. FIRS Impending preterm delivery Severe neonatal morbidity
Fetal multisystem
involvement
© 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. Infection in mid-trimester
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
Gray DJ. Prenat Diagn 1992;12:111 26

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
Uterine
Overdistension
Cervical Disease
Vascular
Hormonal
Immunological
Infection
Unknown
© VR RR MM

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

41. Corpus Luteum http://medstat.med.utah.edu/

42. AJOG 1973;115:759-65
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. Pregnancy outcome after lutectomy Plasma Progesterone (ng/ml)25
Luteectomy
Amenorrhea
Days
32+2
No Ab
DaC
Progesterone
Plasma Progesterone (ng/ml)
Only tubal
ligation
24+2 20
19+1 ) Ab
Incipient Ab
(curettage) )
22+1
No Ab
DaC) 15 10 5 4 8 12 16
Days after Lutectomy
Csapo AI The Fetus and Birth. Ciba Foundation Symposium 47; 1977.

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. Evidence that suspension of progesterone action is important in human parturition
Administration of anti-progestins (RU-486 or onapristone) can induce abortion and cervical ripening
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. Progesterone/estradiol ratio Progesterone/estriol ratio40 15 30 10 20 5 10
No labor
(n = 20)
Labor
(n = 20)
No labor
(n = 20)
Labor
(n = 20)
Romero R et al AJOG 1988;150:650-60

50. Progesterone 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

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. Common Terminal Pathway
Progesterone
Deficiency State
Common Terminal Pathway
Preterm Labor

56. Obstet Gynecol 2003;102:1115-6

57. Obstet Gynecol 2003;102:1115-6

59. The preparatory stage of labor
Quiescence
Weeks 36 40
Quiescence
Weeks 24 40 28 75

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