Premature Birth Update: Progress and Frustration

1
Premature Birth Update Progress and Frustration

• Karla Damus, RN MSPH PhD
• Dept of Ob/Gyn and Womens Health, AECOM, Bronx,
  NY
• Office of the Medical Director
• National March of Dimes, White Plains, NY
• kdamus_at_marchofdimes.com 914 997 4463

2
www.healthypeople.gov
3
Objectives

• Briefly review the epidemiology of preterm birth
  and differential impact on subgroups of the
  population
• Discuss the paradigm shift that most spontaneous
  preterm birth meets the criteria of other common
  complex disorders such as heart disease
• Describe some of the March of Dimes response to
  the increasing rates of preterm birth
• National Prematurity Campaign (2003-2010)
• Analysis of US cost data- infant hospitalizations
  and costs to employers
• Evaluation of evidence-based interventions (eg
  17P, 5As)
• PERI and PRI grants
• National research agenda for very preterm births
  (AJOG Sept 2005)
• International collaboration (eg PREBIC, PREGENIA)
• Review some key resources for perinatal providers

4
Why Preterm Birth?

• 1 obstetric challenge in the US
• Major cause of loss
• majority of all perinatal mortality
• leading cause of neonatal mortality (since 1999)
• leading cause of black infant mortality and
  second leading cause of all infant mortality in
  US
• Leading problem in pediatrics
• leading cause of neonatal morbidity
• half of all neurodevelopmental conditions
• Associated with higher rates of chronic illness
  in adults
• Serious, costly and common

5
Serious Leading Causes of Infant Mortality
United States, 1990 and 2002
Rate per 100,000 live births
Source National Center for Health
Statistics Prepared by March of Dimes Perinatal
Data Center, 2004
6
Infant MortalityUnited States, 1915-2002
Rate per 1,000 live births
Source National Center for Health Statistics,
final mortality data Prepared by March of Dimes
Perinatal Data Center, 2002
7
Leading Cause-specific IMR and ChangeUnited
States, 2001 and 2002
Rates are per 100,000 live births
8
Costly Distribution of Hospital Stays and
Hospital Charges, United States, 2003
All other infant stays 4,301,000
Hospital charges for all other infant stays 18.6
billion
Infant stays with any diagnosis of prematurity
413,000 8
12.9
Hospital charges for infant stays with any
diagnosis of prematurity 18.1 billion
Agency for Healthcare Research and Quality, 2003.
Nationwide Inpatient Sample. Prepared by March of
Dimes Perinatal Data Center, 2005.
9
Average Length of Stay for Selected Inpatient
Infant Hospitalizations, United States, 2003
24.2
13.6
2.0
Agency for Healthcare Research and Quality, 2003.
Nationwide Inpatient Sample. Prepared by March of
Dimes Perinatal Data Center, 2005.
10
Percent of Hospital Charges for Prematurity by
Expected Payer, US, 2002
Almost half of hospital charges for premature
infants or about 7.4 billion were billed to
employers and other private insurers.
Includes Medicare Source Agency for Healthcare
Research and Quality, 2002. Nationwide Inpatient
Sample Prepared by March of Dimes Perinatal Data
Center, 2005
11
Birth Weight and Coronary Heart Disease Barker
Hypothesis
Age Adjusted Relative Risk
Birthweight (lbs)
Rich-Edwards 1997
12
Birth Weight and Insulin Resistance Syndrome
Barker Hypothesis
Odds ratio adjusted for BMI
Barker 1993
Birthweight (lbs)
13
Common
Common ComplexDisorder
14
Preterm Birth RatesUnited States, 1983, 1993,
2003, 2004
Percent
gt 1 out of 8 births or 508,000 babies born
preterm in 2004
Percent
HP 2010 Objective
30 Increase
Preterm is less than 37 completed weeks
gestation. Source National Center for Health
Statistics, final natality data Prepared by March
of Dimes Perinatal Data Center, 2005 preliminary
15
Preterm Birth (lt37 wks) SC and US, 1993-2003
SC PTB increase 15.1 US PTB increase 11.8
16
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17
Preterm Birth as a Common Complex Disorder(like
other chronic conditions- heart disease, cancer)

• Complex
• Genetic contribution
• Familial aggregation
• Recurrence of preterm birth
• Racial disparity
• Environmental influences
• Gene-environment interactions
• Complex cubed (maternal, paternal, fetal)

18
Preterm Birth as a Common Complex Disorder

• Many of the risk factors are the same
• Communities know a lot about these risk factors
• Genomic approaches do not replace but can add to
• Community based interventions
• Patient / Consumer education
• Provider education
• Equity in health outcomes and health care

19
Definitions

• Preterm birth
• lt 37 completed weeks gestation
• Late preterm (or Near-Term)
• 34-36 completed weeks
• Very preterm
• lt32 completed weeks

20
Distribution of Live Births by Gestational
Age United States, 1990 and 2001
2001 Live Births n 3,986,102
1990 Live Births n 4,111,396
Not Preterm (88.4)
Not Preterm (89.4)
Very Preterm (1.9)
Moderately Preterm (8.7)
Moderately Preterm (10.0)
Very Preterm (1.9)
Total Preterm 10.6
Total Preterm 11.9
Note Live births with missing gestational age
data were excluded from the analysis.
Source National Center for Health Statistics,
final natality data Prepared by March of Dimes
Perinatal Data Center, 2003
21
Total (lt37 weeks), Very (lt32 weeks) and Late
Preterm Births (34-36 weeks) U.S., 1990- 2003
Percent
Late Preterm
22
Management of Preterm LaborACOG Practice
Bulletin, No 43, May 2003

• Level A (good and consistent scientific evidence)
• There are no clear first line tocolytic drugs
  to manage PTL. Clinical circumstances and
  physician preferences should dictate treatment
• Abs do not appear to prolong gestation and should
  be reserved for GBS prophylaxis in patients in
  whom delivery is imminent
• Neither maintenance treatment with tocolytic
  drugs nor repeated acute tocolysis improve
  perinatal outcome neither should be undertaken
  as a general practice
• Tocolytics may prolong pregnancy for 2-7 days,
  which may allow for administration of steroids
  (24-34 wks) to improve fetal lung maturity and
  the consideration of maternal transport to a
  tertiary care facility

23
Infant Mortality by Gestational AgeUnited
States, 1995 and 2002
Rate per 1,000 live births
Source National Center for Health
Statistics,1995 and 2002 period linked
birth/infant death data Data include infants born
between 23 and 44 weeks gestation and gt500
grams Prepared by March of Dimes Perinatal Data
Center, 2005
24
Distribution of Preterm Births by Gestational
Age, US, 2002
(lt32 Weeks)
Near term infants had significantly more medical
problems and increased hospital costs compared
with contemporaneous full term infants Near term
infants may represent an unrecognized at-risk
neonatal population. Wang, et al. Clinical
Outcomes of Near-Term Infants, Pediatrics (114)
372-6, 2004.
(36 Weeks)
(32 Weeks)
(33 Weeks)
60 of PTB 35 - 36 weeks
(34 Weeks)
(35 Weeks)
Source National Center for Health Statistics,
2002 natality file Prepared by the March of Dimes
Perinatal Data Center, 2004
25
Morbidities associated with Late PTB? Need to
separate causes and effects

• Increased immediate morbidities
• Respiratory distress
• Jaundice
• Feeding difficulties
• Hypoglycemia
• Temperature instability
• Sepsis
• Increased NICU use (and re-admissions)
• Increased cost
• Long term outcome - ?? - NO DATA!

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Seminars in Perinataology, Vol 1, Feb 2006
Optimizing Care and Outcomes for Late Preterm
(Near-Term) Infants Part 1 TONSE N. K. RAJU, MD
Guest Editor Introduction Tonse N. K. Raju
..................................................
.............................. 1 A Recommendation
for the Definition of Late Preterm (Near-Term)
and the Birth WeightGestational Age
Classification System William A. Engle
................... 2 Changes in the Gestational
Age Distribution among U.S. Singleton
Births Impact on Rates of Late Preterm Birth,
1992 to 2002 Michael J. Davidoff, et
al.......8 Preeclampsia As a Cause of Preterm and
Late Preterm (Near-Term) Births Baha M. Sibai
..................................................
.............................................
16 The Role of Stillbirth Prevention and Late
Preterm (Near-Term) Births Gary D.V. Hankins and
Monica Longo .....................................
.............................. 20 Cold Stress and
Hypoglycemia in the Late Preterm (Near-Term)
Infant Impact on Nursery of Admission Abbot
Laptook and Gregory L. Jackson ...................
....... 24 Short-Term Outcomes of Infants Born at
35 and 36 Weeks Gestation We Need to Ask More
Questions Gabriel J. Escobar, Reese H. Clark, and
John D. Greene . 28 Physiology of Fetal Lung
Fluid Clearance and the Effect of Labor Lucky
Jain et al.24 Place of Birth and Variations in
Management of Late Preterm (Near-Term) Infants
Marie C. McCormick, et al.........................
..................................................
.44 Drug Disposition in the Late Preterm
(Near-Term) Newborn Robert M. Ward .... 48
27
Gestational Age-Specific DistributionSingleton
Live Births, Spontaneous United States, 1992,
1997, 2002
28
Percent Change, Gestational Age-Specific
DistributionSingleton Live Births,
SpontaneousUnited States, 1992, 1997, 2002
Adjusted for maternal race/ethnicity and
maternal age. All rates significantly
different (p lt0.05) between 1992 and 2002, except
at 32-34 weeks.
29
Differences in Singleton Preterm Birth Rates by
Race/Ethnicity, 1992 and 2002
30
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31
Distribution of BirthsSC and US, 2001-2003 avg
SC
Nassau Co
US
US
Charleston 6.4 53.0 38.7
0.1 1.6
Race/Ethnicity
Maternal Age
32
MATERNAL AGEPreterm Births by Maternal AgeAmong
Singletons, US, 1990 and 2003
Percent
Source National Center for Health Statistics,
final natality data Prepared by March of Dimes
Perinatal Data Center, 2005
33
Preterm Birth Rates by State United States, 2003
U.S. Total 12.3
Percent of Live Births
Over 13.0
(16)
11
.6
to
13
.0
(18)
Note Value in ( ) number of states (includes
District of Columbia) Value ranges are
based on equal counts Source National Center for
Health Statistics, 2003 final natality
data Prepared by March of Dimes Perinatal Data
Center, 2005
Under 11.6
(17)
34
Risk Factors for Preterm Labor/Delivery

• The best predictors of having a preterm birth
  are
• current multifetal pregnancy
• a history of preterm labor/delivery or prior low
  birthweight
• mid trimester bleeding (repeat)
• some uterine, cervical and placental
  abnormalities
• Other risk factors

• low pre-pregnant weight
• obesity
• infections
• anemia
• major stress
• lack of social supports
• tobacco use
• illicit drug use
• alcohol abuse
• folic acid deficiency

• maternal age (lt17 and gt35 yrs)
• black race
• low SES
• unmarried
• previous fetal or neonatal death
• 3 spontaneous terminations
• uterine abnormalities
• incompetent cervix
• genetic predisposition

35
Folic Acid-Specific KnowledgeMarch of Dimes
Folic Acid Survey
Percentage of women ages 18-45
36
Factors that Contribute to Increasing Rates of
Preterm Birth

• Increasing rates of births to women 35 years of
  age
• Independent risk of advanced PATERNAL age
• Increasing rates of multiple births
• Indicated deliveries
• Induction
• Enhanced management of maternal and fetal
  conditions
• Patient preference/consumerism (section on
  demand)
• Substance abuse
• Tobacco
• Alcohol
• Illicit drugs
• Bacterial and viral infections
• Increased stress (catastrophic events, DV, racism)

37
Multiple Birth Ratios by RaceUnited States,
1980-2003
Ratio per 1,000 live births
Race of child from 1980-1988 Race of mother
from 1989-2003 Source National Center for
Health Statistics, final natality data Prepared
by March of Dimes Perinatal Data Center, 2005
38
Higher-Order Multiple Birth RatiosBy Maternal
Race, United States, 1980-2002
Ratio per 100,000 live births
Source NCHS, final natality data Prepared by
March of Dimes Perinatal Data Center, 2004
39
Multiple Birth Ratios SC and US, 1996-2003
by Maternal Age
All Multiple Births
40
PLURALITYPreterm and Low Birthweight Births By
Plurality, United States, 2002
Percent
14 decrease in 12.1 PTB rate if multiples
excluded
22 decrease in 7.9 LBW rate if multiples
excluded
Higher Order
Higher Order
Twins
Twins
Singleton
Singleton
Preterm is less than 37 weeks gestation Low
birthweight is less than 2500 grams or 5 1/2
pounds Source National Center for Health
Statistics, final natality data Prepared by March
of Dimes Perinatal Data Center, 2002
41
Singleton Preterm Birth (lt37 wks) SC and US,
1993-2003
42
TYPE of Preterm Birth
Spontaneous Preterm Labor
50
Spontaneous Premature Rupture of the Membranes
25-30
Preterm Birth
25-30
Iatrogenic (Medical Indication)
While this suggests distinct pathways, many of
the risk factors for all 3 are similar
43
Total and Primary Cesarean and VBAC United
States, 1993 - 2004
Preliminary
(1) Per 100 births(2) Per 100 births to women
with no previous cesarean(3) Per 100 births to
women with a previous cesarean Source NCHS,
final natality data, 1993-2003 and 2004
preliminary data Prepared by March of Dimes
Perinatal Data Center, 2005
44
Mode of Delivery SC and US, 1996-2002
VBACs
Cesarean Sections
45
Cesarean Section and Labor Induction Rates among
Singleton Live Births by Week of Gestation US,
1992 and 2002
46
State-of-the-Science Conference March 27-29, 2006

• to assess the available scientific evidence
  relevant to 4 questions
• What is the trend and incidence of cesarean
  delivery over time in the United States and other
  countries (when possible separate by intent)?
• What are the short-term (under one year) and
  long-term benefits and harms to mother and baby
  associated with cesarean by request versus
  attempted vaginal delivery?
• What factors influence benefits and harms?
• What future research directions need to be
  considered to get evidence for making appropriate
  decisions regarding cesarean on request or
  attempted vaginal delivery?
• cesarean delivery on maternal request (CDMR)
• http//videocast.nih.gov

47
Conclusions NICHD Conference CDMR 3-29-06

• The incidence of CD without medical/obstetrical
  indications is rising in the United States, and a
  component of this is due to CDMR. Given the tools
  available, the magnitude of the CDMR component is
  difficult to quantify.
• There is insufficient evidence to evaluate fully
  the benefits and risks of CDMR as compared to
  PVD, and more research is needed.
• Until quality evidence becomes available, any
  decision to perform a CDMR should be carefully
  individualized and consistent with ethical
  principles.
• Given that the risks of placenta previa and
  accreta rise with each CD, CDMR is not
  recommended for women desiring several children.

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Conclusions NICHD Conference CDMR 3-29-06

• CDMR should not be performed prior to 39 weeks or
  without verification of lung maturity, because of
  the significant danger of neonatal respiratory
  complications.
• Request for CDMR should not be motivated by
  unavailability of effective pain management.
  Efforts must be made to assure availability of
  pain management services for all women.
• NIH or another appropriate Federal agency should
  establish and maintain a web site to provide
  up-to-date information on the benefits and risks
  of all modes of delivery.

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Substance Abuse SC and US, 1999-2003
50
Smoking Cessation and Preterm Birth (Cochrane
Review)

• 64 trials (51 RCTs of 20,931 women) and 6
  cluster-randomised trials (over 7500 women)
  provided data on smoking cessation and/or
  perinatal outcomes
• Smoking cessation interventions reduced low
  birthweight (RR 0.81, 95 CI 0.70 to 0.94) and
  preterm birth (RR 0.84, 95 CI 0.72 to 0.98)
• One intervention strategy, rewards plus social
  support, resulted in a significantly greater
  smoking reduction than other strategies (RR 0.77,
  95 CI 0.72 to 0.82).
• Smoking cessation programs in pregnancy reduce
  the proportion of women who continue to smoke,
  and reduce low birthweight and preterm birth.

Lumley J, et al. Interventions for promoting
smoking cessation during pregnancy. The Cochrane
Database of Systematic Reviews 2004, Oct
18(4)CD001055.
51
Warning From the CDC

• A study showed that the number of heart
  attacks in Helena, MT, decreased substantially
  after the city banned indoor smoking, then rose
  quickly to its former level after the law was
  struck down in court.
• During the six-month period in 2002 when the ban
  was in effect, the number of heart attacks
  reported by Helena's heart hospital fell by 40 .
• Sargent RP, Shepard RM, Glantz SA. Reduced
  incidence of admissions for myocardial infarction
  associated with public smoking ban before and
  after study. BMJ328, 977-83, 2004. bmj.com
• Stay away from tobacco smoke if you are at risk
  for heart disease (common complex disorders)!
• "We don't make these kind of statements lightly. 
  What we are seeing in the data is a substantial
  biological change that occurs with even 30
  minutes of exposure to secondhand smoke."
• Terry Pechacek, Assoc Director of Science,
  CDC's Office on Smoking and Health

52
http//iml.dartmouth.edu
53
Sexually Transmitted Infections CategoriesSC and
US, 2003
54
The 3 Ps of Perinatal Depression Perinatal
Health, Provider Education and Public Awareness

• In 2004 Virginia Health Department received a
  250,000 grant from HRSA to train health
  providers and to give them tools to identify
  mothers with perinatal depression and to refer
  for treatment
• Web-Based Curriculum
• Module 1 Overview of Perinatal Depression
• (self-assessment, symptoms, risk factors, issues
  and barriers, providers role)
• Module 2 Perinatal Depression A Providers
  Guide to Screening and Dx
• (case studies, EPDS tutorial)
• Module 3 Your Role in Treating Perinatal
  Depression
• (case studies, role of family)
• Module 4 Resources Help for Providers,
  Patients, and Families
• (interview questions, helpful forms, resource
  database, coding guidelines for insurance)
• www.perinataldepression.org

55
Can Preterm Labor be Prevented?

• Primary prevention is the goal
• especially risk reduction in the preconceptional
  period and early in pregnancy
• Preterm prevention programs have focused on risk
  assessment or prediction of preterm labor
• risk assessment identifies only half of preterm
  births
• during pregnancy most biomarkers, even in
  combination with risk factors, do not have good
  positive predictive values
• Causation is the great unknown

56
March of Dimes National Prematurity Campaign
2003-2010
57
Major March of Dimes Funded Research

• Polio vaccines
• PKU, newborn screening
• Neonatal Intensive Care Unit (NICU)
• Fetal Alcohol Syndrome
• Surfactant therapy for RDS
• Nitric oxide therapy for PPHN
• PERI Grants
• PRI Grants

58
March of Dimes Investment in the Science and
Public Health of Preterm Delivery

• Toward Improving the Outcome of Pregnancy (TIOP
  I)- level designation, regionalization of
  perinatal care (1976)
• TIOP II - regionalization, continuum of
  reproductive health, elimination of health
  disparities (1992)

59
March of Dimes Birth Defects Foundation

• Mission
• To improve infant health by preventing infant
  mortality, birth defects and PTB/LBW
• The Continuum of Reproductive Health
• Improving health of infants requires focusing on
  the entire spectrum of reproductive health from
  prior to conception through the first year of an
  infants life and throughout the womans
  childbearing years
• Preconception health is the cornerstone of
  healthy infants, children, families and
  communities

60
Pre/Interconception Internatal Care

• Readiness for pregnancy (FP, prevent unintended
  pg, interval between pregnancies)
• Optimal management of medical conditions
  (diabetes, HBP, asthma, heart disease,
  addictions, depression)
• Infections and STIs
• Immunizations
• Family history, genetic counseling, carrier
  testing
• Substance abuse (smoking, alcohol, other drugs)
• Domestic violence (DV/IPV)
• Stress reduction
• Optimal weight and activity
• Good nutrition-- folic acid for men and women
• Avoid teratogens (work site, environment)
• Review all meds and home remedies with hcp

61
www.cdc.gov/mmwr
62
The Importance of Prenatal Care

• Early, comprehensive, culturally sensitive
  accessible, available prenatal care is always
  important.
• It has been shown to reduce fetal deaths, IMR and
  complications of pregnancy
• However studies have not shown that it reduces
  rates of PTB/LBW
• Early PNC may be too late to prevent some PTB

Preterm Births by Prenatal Care and
Race/Ethnicity, US, 2001
63
www.centeringpregnancy.org
64
Advisors and Collaborators

• Advisory Committees
• Scientific Advisory Committee (SAC)
• White Paper I (AJOG Sep, 2005)
• White Paper(s) II
• National Nurse Advisory Committee (NAC)
• Perinatal Data Center Advisory Committee (PAC)
• White Paper 2006
• National Professional Partners
• ACOG
• AAP
• AWHONN
• Alliance members

65
Campaign Goals

• 1. Increase public awareness of the problems of
  prematurity to at least 60 for women of
  childbearing age and 50 for the general public
  by 2010
• 2. Reduce the rate of preterm birth from 12.3
  in 2003 to the HP2010 objective of 7.6

66
March of Dimes Prematurity Campaign Aims

• 1. Generate concern and action around the
  problem of prematurity
• 2. Educate women of reproductive age about risk
  reduction and warning signs
• 3. Provide affected families with information,
  emotional support, and opportunities to help
  other families
• 4. Assist health practitioners to improve
  prematurity risk detection and address
  risk-associated factors
• 5. Invest more public and private research
  dollars to identify causes of preterm labor and
  prematurity, and to identify and test promising
  interventions
• 6. Expand access to health coverage in order to
  improve maternity care and infant health outcomes

67
www.marchofdimes.com
68
March of Dimes National Preterm Birth Initiatives

• Preconceptional Summit- June 2005
  (www.marchofdimes.com)
• MMWR Apr 21, 2006 Recommendations
• Late Preterm Conference- July 2005
• Seminars in Perinatology Supplement (Vol 1 and 2,
  2006)
• My 9 Months
• Institute of Medicine (IOM)
• October 2001 Environmental Toxicants and PTB
• 2005 Committee on Understanding Premature Birth
  and Assuring Healthy Outcomes
• Invitational Preterm Research Conference-
  November 2005
• PAD- Prematurity Awareness Day - Prematurity
  Summits
• JJPI-MOD national grand rounds program
• Family Medicine CQI PTB/LBW Initiative
• PREBIC (Preterm Birth International
  Collaborative)
• ?Demonstration Project to reduce spontaneous,
  singleton PTB

69
March of Dimes PERI and PRI Grants

• Perinatal Epidemiological Research Initiative
  (PERI 1998-2004)
• Six innovative research initiatives to define
  biomarkers and mechanisms
• Epidemiologic approaches to test biologically
  plausible hypotheses for the major determinants
  of preterm birth
• Examine the interactions of risk factors
  associated with prematurity and relevant biologic
  samples
• Prematurity Research Initiative- PRI (2005-?)

70
Major Pathways to Preterm Labor

• Inflammation/infection (ascending), 40
• cytokines
• Stress (maternal/fetal), 25
• CRH
• Bleeding (decidual hemorrhage, abruption), 25
• thrombin
• Stretching (uterine distention), 10

71
Pathological Uterine Distention
Inflammation
Activation of Maternal/Fetal HPA Axis
Decidual Hemorrhage Abruption
Infection - Chorion-Decidual - Systemic
Multifetal Preg Polyhydramnios Uterine
abnormalities

• Maternal-Fetal Stress
• Premature Onset of Physiologic Initiators

Prothrombin G20210A Factor V Leiden Proteins C,
S, Z Type 1 Plasminogen MTHFR
Interleukins IL-1, IL-5, IL-8 TNF-a Fas L
Gap jct IL-8
PGE2 Oxytocin recep
CRH E1-E3
Mechanical stretch
Chorion Decidua

CRH
CYP1A1 GSTT1
Susceptibility to Environmental toxins

MMPs
proteases
uterotonins
pPROM
Uterine Contractions
Cervical Change
PTB
Adapted from Lockwood CJ, Paediatr Perinat
Epidemiol 20011578 and Wang X, et al.
Paediatr Perinat Epidemiol 2001 15 63
72
Metabolic Genes and Cigarette Smoking

• Maternal smoking was associated with a mean birth
  weight reduction of 377 g
• CYP1A1 was associated with a 252 g reduction for
  the AA genotype group, and 520 g for the Aa/aa
  genotype
• GSTT1 was associated with a 285 g reduction and
  642 g for the present and absent genotypes
• If both were present, there was a 1285 g
  reduction in birth weight and a 5.5 wk reduction
  in gestational age
• Wang X (PERI grantee), Zuckerman B, Pearson
  C, et al. Maternal cigarette smoking, metabolic
  gene polymorphism, and infant birth weight.
  JAMA, 2002, 287(2) 195-202.

73
Candidate Gene Association Study

• Case-control study of 426 SNPs with PTD in 300
  mothers with PTD and 456 mothers with term births
  at Boston MC
• 25 candidate genes in the final haplotype
  analysis, a significant association was found for
  the F5 gene haplotype and PTD
• Ethnic specific analyses revealed
• consistent finding of the F5 gene
• IL1R2 in Blacks
• NOS2A in whites
• OPRM1 in Hispanics
• Results underscore the potentially important role
  of F5 gene variants in the pathogenesis of PTD
• Hao K, Wang X, Niu T, et al. A candidate
  gene association study on preterm delivery
  application of high throughput genotyping
  technology and advanced statistical methods.
  Human Molecular Genetics, 2004, 13(7) 683-91

74
Proteomics Help Identify Intra-amniotic
Inflammation

• Proteomic analysis of AF can promptly identify
  biomarkers characteristic of intrauterine
  inflammation
• Results can be available in 50 minutes, useful
  for clinical decision making
• Patients with PTL and evidence of intra-amniotic
  inflammation showed a distinctive proteomic
  profile involving neutrophils defensins -1 and -2
  and calgranulins A and C
• Scoring system developed which has a 92.9
  sensitivity and 91.8 specificity

Buhumschi, et al. Br J Obstet Gynaecol
112173-181, 2005.
75
Metabolomics in PTL A Novel Approach to Identify
Patients at Risk for PTD

• Researchers successfully profiled the amniotic
  fluid metabolome (the sum of all metabolic
  processes occurring in the AF), to identify which
  women who have experienced PTL are also at risk
  for PTB.
• Romero, et al studied the AF of 3 groups of
  patients with
• PTL who delivered at term
• intra-amniotic inflammation who had both PTL and
  PTD
• no sign of inflammation who still had PTL and PTD
• By using metabolomic profiling, 96 of the time
  patients belonging to the appropriate clinical
  group were correctly identified.
• Until now, we have never had a way to predict
  the course of preterm labor with such accuracy.
  Metabolomic profiling is providing that tool.

Romero, et al. SMFM, Reno, NV (Feb. 10, 2005)
76
PTB Risk Factors Revisited

• The strongest risk factors for PTB suggest a
  maternal or fetal genetic predisposition
• Women born preterm are more likely to deliver
  preterm
• 20 of women who deliver preterm have recurrence
  with the same partner
• changing partners reduces the risk by one third
• The heritability of PTB is estimated to be
  17-36
• 18 studies reviewed on genetic polymorphisms
  showed that polymorphisms in TNF alpha showed the
  most consistent increase in PTB
• Environmental factors such as infection, stress,
  and obesity suggest that environmental and
  genetic RF might operate and interact through
  related pathways.

Crider, et al. Genetic variation associated with
preterm birth a HuGE Review. Genetics in Med
7(9) 593-604, 2005.
77
(No Transcript)
78

• National Research Agenda for Preterm Birth
  (focus on lt32 weeks)
• Disparities
• Inflammation/infection
• Genetic, gene- environmental interactions
• Stress
• High risk interventions (multifetal, ART)
• Promising clinical interventions

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Green et al. AJOG 193626-35, Sept 2005.
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The 2005 PRI Grantees

• Genetic Analysis of Human Preterm Birth
• Identification of Loci Associated with
  Spontaneous Preterm Birth in Africian-Americans
  by Admixture Linkage Disequilibrium Mapping
• Molecular Mechanisms of Cervical Ripening
• Cellular Mechanisms in the Initiation of Labor
• Mechanisms Underlying Myometrial Smooth Muscle
  Relaxation During Pregnancy
• The Diagnosis of True Pre-Term Labor

81
The 2006 PRI Grantees

• A Comprehensive Study of Genetic Susceptibility
  to Preterm Delivery
• Pharmacological Investigation of Novel
  Anti-inflammatory Therapeutic Strategies for the
  Treatment and Prevention of Preterm Birth using
  Human Ex-Vivo Models
• Maternal and Infant Genetic Contributions to
  Preterm Birth the Inflammatory Response
• Abruption-induced Preterm Delivery Elicits
  Functional Endometrial Progesterone Receptors
• Progesterone Receptor Dysregularion and Preterm
  Birth
• Cytokines from Peridontal Disease Induce
  Premature Birth

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www.nature.com/omics
83
www.cdc.gov/genomics
84
www.marchofdimes.com/gyponline
85
PREBIC International MeetingsOdense, Denmark,
6/5-8/04Lake Arrowhead, California,
3/20-23/05 WHO, Geneva, Switzerland, 4/23-6/06
WHO, Geneva, Switzerland, 4/23-6/07
www.prebic.org
86

• Clinical
• Interventions
• Smoking Cessation
• 17 progesterone
• Infertility and multiple births

87
Conclusions

• Weekly injections of 17- ? Hydroxyprogesterone
  Caproate can provide significant and powerful
  protection against recurrent preterm birth and
  improve the neonatal outcome for pregnancies at
  risk

Meis P, et al. NEJM. 2003 3482379
88
Use of Progesterone to Reduce Preterm BirthACOG
Committee Opinion, No 291, November 2003

• Further studies are needed to evaluate
  progesterone use in patients with other
  high-risk obstetric factors
• multiple gestation, short cervical length,
  positive test results for cervicovaginal fFN)
• Unresolved issues, such as optimal delivery of
  the drug and its long-term safety, still remain
• Restrict use to only women with a documented
  history of a previous spontaneous preterm birth
  less than 37 weeks of gestation

• 2005 SMFM prior PTB must be lt34 weeks

89
Estimated Impact of 17P

• If all eligibles had received 17P therapy, nearly
  10,000 spontaneous PTB out of about 480,000 PTBs
  would have been prevented in 2002
• Nationally, the PTB rate would have been reduced
  by about 2 from 12.1 to 11.8 (plt0.001).

Petrini J, et al. Obstet Gynecol 105(2)267-272,
February 2005
90
Gestiva

• Adeza announced the submission of a New Drug
  Application (NDA) with the U.S. FDA for
  Gestiva(TM), the company's drug candidate to
  prevent preterm birth in women with a history of
  preterm delivery.
• Adeza has requested Priority Review and if
  granted would set a 6 month goal for review by
  the FDA.
• Adeza has also submitted an application
  requesting Orphan Drug designation.
• Gestiva is a long-acting, naturally occurring
  form of progesterone. If Gestiva is approved,
  Adeza will have the only commercially available,
  NIH-studied, ACOG-recommended and FDA-approved
  therapeutic for the prevention of recurrent
  preterm birth.

Adeza Press Release, Sunnyvalle, CA, May 4, 2006
91
Evidence-Based Protocols and Editorial Leaders

• Smoking
• U Pittsburgh affiliated programs UPMC St
  Margaret, Shadyside McKeesport
• Bacterial vaginosis
• Gene Bailey, SUNY
• Asymptomatic bacteriuria
• Tom Raff, Reading
• Depression
• Ian Bennett, U Penn
• Prolonging inter-pregnancy interval
• Wendy Barr, BI NYC and Josephine
  Fowler/Brian Jack, Boston U

92
Prevention of Preterm Labor, Preterm Delivery and
Prematurity

• Primary prevention
• identifying and managing risks
• risk reduction approach and strategies to
  reproductive health
• prevent PTL
• Secondary prevention
• prevent preterm delivery
• Tertiary prevention
• prevent/minimize complications of prematurity

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Prevent the Preventable

• Ø Unintended pregnancies
• Ø Folic acid deficiency
• Ø Alcohol
• Ø Tobacco
• Ø Illicit drugs
• Ø Infections (UTIs, STIs, periodontal disease)
• Ø Extremes of weight
• Ø Some medications (Rx, OTC, home remedies)
• Ø Environmental toxins
• Ø Known genetic/familial risks
• Ø Unnecessary interventions resulting in preterm
  birth
• Promote appropriate level designation and
  regionalization

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Take Home Messages

• Preterm birth is a common complex disorder
  meeting criteria for high public health priority
• Intervene throughout the continuum of
  reproductive health for women and men with
  culturally sensitive literacy appropriate risk
  reduction interventions
• All providers have a major role in the success of
  primary and secondary prevention
• All pregnant women are at risk for preterm labor
  and birth and should be taught the signs and
  symptoms beginning about 20 weeks of gestation
• A multidisciplinary approach is needed
• Everyone can make a difference

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Preterm Birth Legislation Introduced

• PREEMIE Act, authorizes expansion of research
  into the causes and prevention of prematurity and
  increases federal support of public and health
  professional education as well as support
  services related to prematurity.
• Prevent Prematurity and Improve Child Health Act
  of 2005, calls for improved access to health
  coverage for pregnant women, infants and
  children. It would provide states increased
  flexibility and federal resources to expand
  access to maternity care for income-eligible
  pregnant women and increased access to health
  coverage for infants and children with special
  health care needs.

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Thank you for your attention
this continuing education presentation is
sponsored by the March of Dimes - Johnson
Johnson Pediatric Institute Grand Rounds
Program as part of the
March of
Dimes National Prematurity Campaign
Additional Resources Pregnancy and Newborn Health
Education Center askus_at_marchofdimes.com
www.jjpi.com
www.marchofdimes.com