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

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

The Lancet Editorial 2006;368:339

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

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

Preterm Births as a Percentage of Live Births in the United States, 1990 to 2004 2 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. 2006.

Preterm Births as a Percent of Live Births, by Race and Ethnicity, 1992 to 2003 5 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.

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 http://www.cdc.gov/nchs/data/nvsr/nvsr53/nvsr_09.pdf (accessed August 30, 2005)

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

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

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

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.

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

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.

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

Frequency of preterm birth by gestational age (1995-2000) < 28 weeks : 0.82 % < 32 weeks: 2.2 % 33-36 weeks: 8.9 % < 37 weeks: 11.2 IOM Report-July 2006- page 72/2006 Alexander GR et al 2006 (under review)

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

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)

Is preterm labor simply “labor before its time” ?

Term Labor Preterm Labor © VR RR MM 2

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

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

The “phenotypes” of spontaneous preterm parturition

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

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

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

What causes pathologic activation of the pathway ?

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

“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

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

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

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

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

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

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

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

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

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

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

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

Corpus Luteum http://medstat.med.utah.edu/ http://www.siumed.edu/~dking2/erg/enguide

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

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

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.

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

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

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

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. 1994 Human Reproduction 1994;9:131 Bygdeman et al. Human Reproduction 1994;9:120

Progesterone/estradiol ratio Progesterone/estriol ratio 40 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

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

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

Interventions for the prevention of preterm birth Efficacy Safety

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

Safety Fetal Neonatal Infant Maternal

Common Terminal Pathway Progesterone Deficiency State Common Terminal Pathway Preterm Labor

Obstet Gynecol 2003;102:1115-6

Obstet Gynecol 2003;102:1115-6

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

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