# Presentation: 462878

## 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

**The Lancet Editorial 2006;368:339**

## Institute of Medicine Report Preterm Birth: Causes, Consequences, and Prevention

**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.***

**10.6**

**11**

**11**

**11.4**

**11.8**

**11.6**

**12.3**

**12.5**

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

***CDC 2004.***

## 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  **

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

**© 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 72/2006**
**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” ?

## © VR  RR  MM

**© VR  RR  MM**

## 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

**Preterm**
**PROM**

**Preterm**
**Contractions**

**Cervical**
**Insufficiency**

**© VR  RR  MM**

## Approaches for the Prevention of Preterm 

**Cervix**

**Approaches for the Prevention of Preterm **
**Birth**

**Membrane/Decidua**

**© VR  RR  MM**

##  Common Terminal Pathway

** ****Normal Term**
**Labor**

** ****Physiologic**
**Activation**

**© VR  RR  MM**

## What causes pathologic  activation of the pathway ?

## Placental Pathology in Prematurity

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

**© PJS**

## “Great Obstetrical Syndromes”

**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**

## The Preterm Parturition Syndrome

**The Preterm Parturition Syndrome**

**Uterine**
**Overdistension**

**Infection**

**Cervical Disease**

**Hormonal**

**© VR  RR  MM**

**Unknown**

## The Preterm Parturition Syndrome

**The Preterm Parturition Syndrome**

**Uterine**
**Overdistension**

**Infection**

**Cervical Disease**

**Hormonal**

**© VR  RR  MM**

**Unknown**

## Intraamniotic Infection

**Sub-clinical**
**Fetal disease**
**FIRS**
**Host defense**

**Intraamniotic Infection**

## Sub-clinical 

**20% of preterm PROM**

**Sub-clinical **

**Clinical Chorioamnionitis**

## FIRS 

**FIRS **

**© VR  RR  MM**

## Hematologic Abnormalities

**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 

**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***

## 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

**The Preterm Parturition Syndrome**

**Uterine**
**Overdistension**

**Infection**

**Cervical Disease**

**Hormonal**

**© VR  RR  MM**

**Unknown**

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

## Corpus Luteum

**Corpus Luteum**

## AJOG 1973;115:759-65

***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 

**Pregnancy outcome after lutectomy **

**Only tubal**
**ligation**
**24**_**+**_**2**

**No Ab**
**D********C)**

**5**

**10**

**15**

**0**

**Days after Lutectomy**

**8**

**20**

**25**

**12**

**0**

**4**

**16**

**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: 399***
***Crowley WF. N EJM 1986; 18: 1607***
***Chwalisz K. 1994 Human Reproduction 1994;9:131***
***Bygdeman et al. Human Reproduction 1994;9:120***

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

**40**

**30**

**20**

**10**

**0**

**No labor**
**(n = 20)**

**Labor**
**(n = 20)**

**Progesterone/estradiol ratio**

**15**

**10**

**5**

**0**

**No 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 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 **

## Preterm Labor

**Deficiency State**

**Common Terminal Pathway**

**Preterm Labor**

## Obstet Gynecol 2003;102:1115-6 

**Obstet Gynecol 2003;102:1115-6 **

## Obstet Gynecol 2003;102:1115-6 

**Obstet Gynecol 2003;102:1115-6 **

## Slide 58

## The preparatory stage of labor

**The preparatory stage of labor**

## Preterm Labor

**Deficiency State**

**Common Terminal Pathway**

**Preterm Labor**