Presentation on theme: "Causes of Preterm Birth: “The Preterm Parturition Syndrome”"— Presentation transcript:
1Causes of Preterm Birth: “The Preterm Parturition Syndrome” Roberto Romero,M.D.Chief Perinatology Research BranchDivision of Intramural ResearchNICHD/NIH/DHHS
2Conflict of Interest Statement Official capacity (NICHD/NIH/DHHS)Division of Intramural ResearchTrial conducted by the Extramural Program of NICHD/NIH (17P-CT-002)Independent of PRB/NICHDNo financial conflict of interest with sponsor
4Richard E. Behrman, Adrienne Stith Butler, Editors Institute of Medicine Report Preterm Birth: Causes, Consequences, and PreventionRichard E. Behrman, Adrienne Stith Butler, EditorsInstitute of Medicine of the National Academies, 2006
5Magnitude of the Problem Definition (< 37 weeks)2004: more than 500,000 neonates were born pretermFrequency: 12.5 %
6Preterm Births as a Percentage of Live Births in the United States, 1990 to 2004 246810121990199319951997199920002003200412.312.511.811.611.4111110.6Institute of Medicine. PRETERM BIRTH: CAUSES, CONSEQUENCES, AND PREVENTION
7Preterm Births as a Percent of Live Births, by Race and Ethnicity, 1992 to 2003 5101520199219931994199519961997199819992000200120022003BlackAmerican IndianHispanicWhite, non- hispanicAsian or Pacific IslanderCDC 2004.
8Frequency of Preterm Birth by Ethnic Group Non-Hispanic African-American17.8%American Indians/Native Alaskans13.5%Hispanics11.9%Whites11.5%Asian and Pacific Islanders10.5%Source: CDC 2004 Births: Preliminary Data for 2003(accessed August 30, 2005)
9Cost of Preterm Birth Medical care services: 16.9 billion ( $ 33,200 per preterm infant) - 2/3 total costMaternal 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
10In excess of $26.2 billion in 2005 The Annual Societal Economic Burden associated with Preterm Birth in the United StatesIn excess of $26.2 billion in 2005
12Survival by gestational age among live-born resuscitated infants Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, TennesseeMercer BM Obstet Gynecol 2003;101:178 –93.
13Magnitude 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 lifeMathews TJ. et al. National Vital Statistics Reports 2004;53:1-32
14Acute morbidity by gestational age among surviving infants Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, TennesseeMercer BM Obstet Gynecol 2003;101:178 –93.
15IOM 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 termIOM Report page 72
16Frequency of preterm birth by gestational age (1995-2000) < 28 weeks : %< 32 weeks: 2.2 %33-36 weeks: 8.9 %< 37 weeks: 11.2IOM Report-July page 72/2006Alexander GR et al 2006 (under review)
17Complications of “Late Preterm or Near Term Infants” Cold StressHypoglycemiaRDSJaundiceSepsisIOM Report-July page 72/2006
18Clinical Circumstances Associated with Preterm Birth Spontaneous preterm labor with intact membranesPreterm PROMIndicated preterm deliveryMaternal (e.g. pre-eclampsia)Fetal (e.g. SGA/fetal compromise)
19Is preterm labor simply “labor before its time” ?
21Common Uterine Features of Term and Preterm Labor Increased myometrial contractilityCervical ripening (dilatation and effacement)Decidual/membrane activationRomero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414
22Common Pathway of Parturition Anatomic, physiologic, biochemical, endocrinologic, immunologic, and clinical events in the mother and/or fetus in both term and preterm laborRomero R, Mazor M, Munoz H et al: The Preterm Labor Syndrome. Ann NY Acad Sci 1994;734:414
23The “phenotypes” of spontaneous preterm parturition
36How common is sub-clinical intra-amniotic infection in asymptomatic midtrimester pregnancy
37Infection in mid-trimester 2461 midtrimester amniocenteses9 patients with U. urealyticum (0.4%)8 continuing pregnancies6 spont. abortions within 4 weeks2 preterm labor8 histologic chorioamnionitisGray DJ. Prenat Diagn 1992;12:11126
38Prevention of Preterm Labor/Delivery Important and desirable goalOnly proven beneficial strategy is eradication of asymptomatic bacteriuriaLimited attributable riskPatients with previous preterm birth are at increased risk for recurrencePotential beneficial effect of progesterone administration17OHP-C and vaginal progesterone
43What is the Effect of Luteectomy on Human Pregnancy? 64 pregnant women (< 5 weeks)Desired tubal ligationIRB approvalAllocated to:Tubal ligation (control group)Tubal ligation + luteectomyTubal ligation + luteectomy + progesteroneAmerican Journal of Obstetrics and Gynecology: 1972Prostaglandins: 1973Ciba Symposium 47: 1977
44Pregnancy outcome after lutectomy Plasma Progesterone (ng/ml) 25LuteectomyAmenorrheaDays32+2No AbDaCProgesteronePlasma Progesterone (ng/ml)Only tuballigation24+22019+1)AbIncipient Ab(curettage))22+1No AbDaC)15105481216Days after LutectomyCsapo AI The Fetus and Birth. Ciba Foundation Symposium 47; 1977.
45Arpard Csapo Progesterone is “indispensable” for normal pregnancy Progesterone withdrawal is a prerequisite of normal pregnancy termination
46Progesterone in Pregnancy Maintenance Myometrial quiescenceDown-regulate gap junction formationInhibit cervical ripening
47A progesterone withdrawal “prepares” the uterus for the action of uterotonic agents
48Evidence that suspension of progesterone action is important in human parturition Administration of anti-progestins (RU-486 or onapristone) can induce abortion and cervical ripeningKovacs L et al. Contraception 1984; 29: 399Crowley WF. N EJM 1986; 18: 1607Chwalisz K Human Reproduction 1994;9:131Bygdeman et al. Human Reproduction 1994;9:120
49Progesterone/estradiol ratio Progesterone/estriol ratio 4015301020510No labor(n = 20)Labor(n = 20)No labor(n = 20)Labor(n = 20)Romero R et al AJOG 1988;150:650-60
50Progesterone Key hormone for pregnancy maintenance “Progesterone withdrawal”:ConcentrationReceptor (A and B)Mesiano S, Chan E, Fitter JT, Kwek K, Yeo G, and Smith R.J Clin Endocrinol Metab 2002; 87:2924Functional (NF-kB)Allport VC, Pieber D, Slater DM, Newton R, White JO and Bennett PR.Mol Human Reprod 2001; 7:581-6
51The clinical trials and meta-analysis of progesterone will be analyzed by FDA staff and the sponsor
52Interventions for the prevention of preterm birth EfficacySafety
53Criteria for Efficacy Prevention of preterm birth 37 weeks35 weeks32 weeksProlongation of pregnancyNeonatal morbidity and mortality