Causes of Preterm Birth: “The Preterm Parturition Syndrome” Roberto Romero,M.D. Chief...

Causes of Preterm Birth:

“The Preterm Parturition Syndrome”

Roberto Romero,M.D.Chief Perinatology Research

BranchDivision of Intramural

ResearchNICHD/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

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

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

Institute of Medicine. PRETERM BIRTH: CAUSES, CONSEQUENCES, AND PREVENTION. 2006.

0

2

4

6

8

10

12

1990 1993 1995 1997 1999 2000 2003 2004

10.6 11 1111.4

11.8 11.612.3 12.5

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

CDC 2004.

Hispanic

White, non-hispanic

Black

American Indian

Asian orPacific Islander

5

10

15

20

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Frequency of Preterm Birth by Ethnic Group

Source: CDC 2004 Births: Preliminary Data for 2003 http://www.cdc.gov/nchs/data/nvsr/nvsr53/nvsr_09.pdf (accessed August 30, 2005)

Non-Hispanic African-American 17.8%

American Indians/Native Alaskans 13.5%

Hispanics 11.9%

Whites 11.5%

Asian and Pacific Islanders 10.5%

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

The Annual Societal Economic Burden

associated with Preterm Birth in the United

States

In excess of $26.2 billion in 2005

© PJS

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

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

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

Mercer BM Obstet Gynecol 2003;101:178 –93.

Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee

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 72/2006Alexander 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 CircumstancesAssociated 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

Common Uterine Features of Term and Preterm Labor

•Increased myometrial

contractility

•Cervical 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

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 RipeningCervical Ripening

UterineContractility

UterineContractility

Membrane-Decidual

Activation

Membrane-Decidual

Activation

PretermPROM

PretermPROM

PretermContractions

PretermContractions

CervicalInsufficiency

CervicalInsufficiency

© VR RR MM

Component Test Treatment

Myometrium Uterine Monitor

Tocolysis

Ultrasound Cerclage Cervix

Approaches for the Prevention of Preterm

Birth

Fetal Fibronectin Antibiotics Membrane/Decidua

© VR RR MM

Common Terminal Pathway Common Terminal Pathway

Normal TermLabor

Normal TermLabor

PhysiologicActivation

PhysiologicActivation

PretermLabor

PretermLabor

PathologicActivation PathologicActivation

© VR RR MM

What causes pathologic activation of the

pathway ?

Placental Pathology in Prematurity

Arias et al. Obstet Gynecol 1997;69:285.

Acute Chorioam nionitis

42%

Chronic villitis0.8%

Villous edem a1.7%

Norm al placenta13.3%

M ixed (inflam m ation+ vascular)

20%

VascularLesions20%

© PJS

• Multiple etiologies

• Chronicity

• Fetal diseases

• Clinical manifestations are adaptive

• Symptomatic treatment is ineffective

• Genetic/environmental factors

““Great Obstetrical Great Obstetrical Syndromes”Syndromes”

““Great Obstetrical Great Obstetrical Syndromes”Syndromes”

© VR RR MM Romero R J Prenat Neonat Med 1996;1:8-11

The Preterm Parturition Syndrome

UterineUterineOverdistensioOverdistensio

nn

VascularVascular

InfectioInfectionn

Cervical Cervical DiseaseDisease

HormonalHormonal

ImmunologicalImmunological

© VR RR MM

UnknownUnknown

• Frequent: 25 % (at

presentation)

• Sub-clinical

• Fetal disease

• FIRS

• Host defense

Intraamniotic Infection

Intraamniotic Infection

• 12% of preterm labor

• 20% of preterm PROM

Sub-clinical Sub-clinical

Clinical Chorioamnionitis

Severe neonatalmorbidity

Severe neonatalmorbidity

Impending pretermdelivery

Impending pretermdelivery

Fetal multisysteminvolvement

Fetal multisysteminvolvement

FIRS FIRS

© VR RR MM

Fetal Inflammatory Response Fetal Inflammatory Response SyndromeSyndrome

Fetal Inflammatory Response Fetal Inflammatory Response SyndromeSyndrome

• 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

• 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 mid-trimester

Infection in mid-trimester

Gray DJ. Prenat Diagn 1992;12:111

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

UterineUterineOverdistensioOverdistensio

nn

VascularVascular

InfectioInfectionn

Cervical Cervical DiseaseDisease

HormonalHormonal

ImmunologicalImmunological

© VR RR MM

UnknownUnknown

“Progesterone deficient

state” has been

proposed to be a

Mechanism of Disease

in Preterm Labor

http://www.siumed.edu/~dking2/erg/enguidehttp://medstat.med.utah.edu/

Corpus Luteum

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: 1972Prostaglandins: 1973

Ciba Symposium 47: 1977

Csapo AI The Fetus and Birth. Ciba Foundation Symposium 47; 1977.

Pregnancy outcome after lutectomy

Only tuballigation24+2

No AbDC)

5

10

15

0

Days after Lutectomy8

20

25

120 4 16

Incipient Ab(curettage)

)

22+1

19+1

)

Ab

LuteectomyAmenorrheaDays32+2

No AbDC

Progesterone

Plasma Progesterone (ng/ml)

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

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: 399Crowley WF. N EJM 1986; 18: 1607

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

40

30

20

10

0No labor(n = 20)

Labor(n = 20)

Progesterone/estradiol ratio

15

10

5

0No labor(n = 20)

Labor(n = 20)

Progesterone/estriol ratio

Romero R et al AJOG 1988;150:650-60

• 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

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

ProgesteroneProgesteroneDeficiency StateDeficiency StateProgesteroneProgesterone

Deficiency StateDeficiency State

Common Terminal Common Terminal PathwayPathway


Preterm LaborPreterm LaborPreterm LaborPreterm Labor

Obstet Gynecol 2003;102:1115-6

Quiescence

Weeks 0 36 40

Quiescence

Weeks 0 24 4028

The preparatory stage of labor

The preparatory stage of labor

ProgesteroneProgesteroneDeficiency StateDeficiency StateProgesteroneProgesterone

Deficiency StateDeficiency State




Uterine Uterine Pathologic State Pathologic State

(infection, (infection, vascular, vascular, uterine)uterine)

Uterine Uterine Pathologic State Pathologic State

(infection, (infection, vascular, vascular, uterine)uterine)




Causes of Preterm Birth: “The Preterm Parturition Syndrome” Roberto Romero,M.D. Chief...

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