Research agenda for preterm birth: Recommendations
from the March of Dimes
Nancy S. Green, MD,a,b,* Karla Damus, RN, PhD,a,cJoe Leigh Simpson, MD,d
Jay Iams, MD,eE. Albert Reece, MD, PhD, MBA,fCalvin J. Hobel, MD,g
Irwin R. Merkatz, MD,cMichael F. Greene, MD,hRichard H. Schwarz, MD,i
and the March of Dimes Scientific Advisory Committee on Prematurity
March of Dimes, White Plains, NYa; Departments of Pediatrics and Cell Biology,band Department of Obstetrics &
Gynecology and Women’s Health,cAlbert Einstein College of Medicine, Bronx, NY; Department of Obstetrics and
Gynecology and Molecular and Human Genetics, Baylor College of Medicine, Houston, TXd; Department of
Obstetrics and Gynecology, Ohio State University, Columbus, OHe; Department of Obstetrics and Gynecology, Dean’s
Office, University of Arkansas for Medical Sciences, Little Rock, ARf; Departments of Obstetrics, Gynecology and
Pediatrics, Cedars-Sinai Medical Center, University of California Los Angeles School of Medicine, Los Angeles, CAg;
Department of Obstetrics and Gynecology and Reproductive Biology, Harvard Medical School, Boston, MAh;
Department of Obstetrics and Gynecology, Maimonides Medical Center, Brooklyn, NYi
Received for publication November 11, 2004; revised February 7, 2005; accepted February 18, 2005
Preterm birth (PTB) is a common, serious, and costly health problem affecting nearly 1 in 8 births
in the United States. Burdens from PTB are especially severe for the very preterm infant (!32
weeks’ gestation), comprising 2% of all US births. Successful prevention needs to include newly
focused and adequately funded research, incorporating new technologies and recognition that
genetic, environmental, social, and behavioral factors interact in complex pathogeneses and
multiple pathways leading to PTB. The March of Dimes Scientific Advisory Committee created
this prioritized research agenda, which is aimed at garnering serious attention and expanding
resources to make major inroads into the prevention of PTB, targeting six major, overlapping
categories: epidemiology, genetics, disparities, inflammation, biologic stress, and clinical trials.
Analogous to other common, complex disorders, progress in prevention will require incorpo-
rating multipronged risk reduction strategies that are based on sound scientific discovery, as well
as on effective translation into clinical care.
? 2005 Mosby, Inc. All rights reserved.
Preterm birth (PTB) is the major determinant of early
childhood mortality and morbidity and is the leading
cause of neonatal mortality (!28 days of life) and of
black infant mortality (!365 days of life) in the United
States.1As much as half of all pediatric neurodevelop-
mental problems can be ascribed to preterm birth.2
Moreover, the severity and incidence of adverse out-
comes inversely correlates with gestational age, espe-
cially birth before 32 completed weeks of gestation.
Beyond the enormous impact on affected families, the
* Reprint requests: Nancy Green, MD, Medical Director, March of
Dimes, 1275 Mamaroneck Ave, White Plains, NY 10605.
0002-9378/$ - see front matter ? 2005 Mosby, Inc. All rights reserved.
American Journal of Obstetrics and Gynecology (2005) 193, 626–35
economic costs are staggering. Although only 9% of all
infant hospitalizations in 2002 were related to prematu-
rity, the charges were $15.5 billion, representing nearly
half of all charges for infant hospitalization (unpub-
lished data from March of Dimes Perinatal Data Center.
Agency for Healthcare Research and Quality, National
Inpatient Sample, 2002.)
to an all time high of 12.1% in 2002, a 29% increase over
the previous 2 decades.3Most of this increase has been
reported in moderately preterm births (32-36 weeks of
gestation), as the rate for very preterm births (!32
use of infertility treatments,4with their significant en-
hancement of multiple birth rates.5,6Preterm births in
singleton pregnancies result most frequently from spon-
taneous preterm labor and preterm premature rupture of
membranes (PPROM).7-10In addition to spontaneous
PTB, 20% to 30% of preterm births are considered
medically indicated to avoid or minimize maternal and/
or fetal complications, such as intrauterine growth ab-
normalities. Advances in maternal, fetal, and neonatal
management have led to an increased willingness to
deliver high-risk pregnancies preterm.11,12Patient and
provider preferences may also be promoting clinical
interventions that are further increasing PTB rates at
later gestations, such as scheduled deliveries.13,14
Rates of PTB in the United States differ profoundly
among racial/ethnic groups, with the largest and most
persistent disparities occurring between non-Hispanic
white and non-Hispanic black births. In 2002, the rates
of preterm and very preterm births for Hispanics were
only modestly higher than for non-Hispanic white
infants, but respective rates for non-Hispanic black
infants were 60% and 250% higher (Table I, NCHS
data). Native Americans have intermediate rates,
whereas Asian PTB rates are the lowest of all these
groups. These disparities remain even after stratification
by plurality and adjusting for possible confounders such
as education and occupation, thus likely reflecting a
combination of genetic, environmental, and social
factors.15-20Racial/ethnic disparities in PTB are associ-
ated with persistent gaps in chronic health outcomes
Research has identified numerous risk factors for
spontaneous PTB, although accurate prediction and
prevention remain elusive.2,8-10,21-25A few of the major
risk factors have biologic plausibility, such as multifetal
gestation, a history of prior PTB or preterm labor and
certain cervical, uterine, and placental structural or
physiologic abnormalities. Much research has focused
on the roles of infection and the resultant cascade of
immunologic effects. However, environmental interac-
tionsdbroadly defined to include behavioral factors and
social underpinningdare also likely to play important
but less well understood roles. Other factors include
race/ethnicity, maternal age, socioeconomic status, in-
terconceptional interval, maternal medical conditions,
maternal weight, nutritional status, substance abuse,
paternal effects, stress, depression and other factors
(Table II). The precise mechanisms by which these risk
factors influence the preterm birth rate and the potential
impact of their successful modification on PTB are
Data collection variables for PTB
All prior pregnancy outcomes
Interval between pregnancies
Prenatal care (onset, timing/
number of visits)
Clinical course of pregnancy
Screening and diagnostic tests
Paternal ageSubstance use (alcohol, tobacco,
Stress (domestic violence,
catastrophic events, racism)
Induction /augmentation of
Mode of delivery and indication
Method(s) used to assess
All preexisting maternal medical
conditions (eg, infection,
depression, oral health)
Prepregnancy weight, body
mass index, and weight change
History of preterm labor/PTB
(spontaneous and iatrogenic)
Micronutrient and supplement use
Mode of conception
Incidence of PTB and very PTB in the United States, 2002, by race/ethnicity
PTB rate (!37 wks)
Very PTB rate (!32 wks)
All race categories exclude Hispanic births. Source: National Center for Health Statistics.
Green et al627
largely unknown. Unfortunately, most biomarkers as-
sessing risk of PTB have poor positive predictive value
for guiding clinical interventions.2,10,21-26
PTB is now best understood as the clinical endpoint
for a number of potential causes and pathogeneses
(Figure). In this context, at least 4 major pathophysio-
logic pathways have been described toward the shared
outcome of PTB: inflammation/infection with its asso-
ciated maternal and fetal cytokine response; maternal/
fetal stress with generation of placental and fetal mem-
brane-derived corticotrophin-releasing hormone, which
in turn, enhances placental estrogen and fetal adrenal
cortisol production; abruption or decidual hemorrhage
with thrombin-induced protease expression and distur-
bances in uterine tone; and mechanical stretch due to
multifetal pregnancy or polyhydramnios-induced abnor-
mal uterine and cervical distention.7These pathophysio-
logic pathways may occur independently but more
commonlyare present invarious degrees ofcombination.
PTB and successful clinical interventions.
In contemporary terms therefore, PTB is increasingly
conceptualized as a ‘‘common, complex disorder,’’27,28
posites of multiple gene-environment interactions.29-31
which arises from multiple inherited factors, including
smoking. The evidence supporting this conceptualization
of PTB includes findings of familial aggregation,32,33
nonmendelianheritability,34high rates of recurrence,24,35
and the existence of ethnic/racial disparities.15-17,36For
PTB, 2 corollaries thus follow: (1) that etiologic investi-
factors and mechanisms that need to be prioritized by
frequency and by level of impact; and (2) that successful
interventions will likely need to simultaneously and/or
sequentially target multiple risk factors and will require
tailoring for individuals and/or specific communities.
This work will be aided by use of the tools of genomics,
proteomics, and genetic epidemiology and by an im-
proved understanding of pathophysiology in preterm
birth. As a common, complex disorder, PTB also meets
priority and of major public health significance.29
Consistent with this conceptual framework, March of
Dimes initiated its Perinatal Research Initiative (PERI)
in 1998 to fund multidisciplinary research targeting
the interactions between epidemiologic and biologic
bases of prematurity.37,38Most recently, the Foundation
launched its National Prematurity Campaign in 2003 to
stimulate public concern for prematurity and to reduce
the nation’s rate of PTB,39,40with campaign partners of
the American College of Obstetricians and Gynecolo-
gists (ACOG), American Academy of Pediatrics (AAP),
and Association of Women’s Health, Obstetrics and
Neonatal Nursing (AWHONN). A principal aim of the
campaign is to foster research on PTB through increased
support from federal and other funding sources, includ-
ing the March of Dimes.
Development of a research agenda
A Scientific Advisory Committee (SAC) on Prematurity
was created to advise the National March of Dimes
has interdisciplinary representation of national experts
in PTB research and treatment, from fields of obstetrics-
gynecology, pediatrics, nursing and public health, with
representation from the 3 campaign partner organiza-
tions. It was charged to develop a national research
agenda that included prioritized recommendations. After
deliberation, the SAC concluded that research efforts
should focus primarily on cause and prevention of very
preterm birth (!32 weeks). The rationale was that the
study of the most severely affected would likely be more
Four subcommittees were formed to address the interre-
lated research categories of: basic science, clinical man-
agement, social and behavioral interactions, and racial/
ethnic disparities. Committee processes included formal
reviews of extant publications from relevant disciplines,
based on the members’ experience as investigators and
clinicians. External review of the resultant document was
then obtained from additional experts representing the
Prematurity Campaign partner organizations ACOG,
AAP, and AWHONN, as well as the National Institute
of Child Health and Human Development (NICHD),
ing to PTB. Depiction of combinations of etiologic pathways
and interacting factors leading to PTB. The elements shown
here are selectively chosen, unweighted, and not intended to
represent known quantifiable contributions or relationships.
Complex Interactions of factors and pathways lead-
628Green et al
Centers for Disease Control (CDC), and Society of
Maternal Fetal Medicine (SMFM).
The current report summarizes recommendations for
approaches needed to stimulate and implement the pri-
oritized prematurity research agenda. These recommen-
dations emphasize the most promising experimental
paradigms to elucidate the complex contributions of
genetic and environmental influences. Research on PTB
needs to: (1) better define the etiologic mechanisms
responsible for PTB; (2) identify biomarkers for PTB to
improve clinical risk assessment; (3) develop clinical
interventions that lead to reduction in rates of PTB; and
(4) eliminate disparities in PTB among racial/ethnic
groups in the United States. Genetics is a relatively new
aspect of prematurity research that brings an exciting
array of possibilities for new avenues of investigation
through new technologies. Ultimately, translating the find-
forindividualsandforcommunitieswill needto takeinto
account the effects of complex environmental influences.
By establishing a national emphasis on strategies that
have proven successful for other complex common
disorders, the Foundation hopes to attract investigators
to this important arena, including some not previously
vested in prematurity research. The March of Dimes thus
seeks to inspire novel innovative approaches to address
the challenges inherent in translating science into clinical
will be forthcoming to address broader research topics
within public, provider and health care delivery issues,
such as the impact of education, clinical management,
racial/ethnic disparities, stress, and behavioral modifica-
tions, particularly as they impact the large group of
moderately premature infants (32-36 weeks’ gestation).
Decreasing PTB will require enhanced efforts that
explore mechanisms of specific contributing genetic
and environmental factors and their interactions, as
well as a better understanding of uterine and placental
pathophysiology. These findings should lead to hypoth-
esis-driven, controlled clinical trials for prediction and
prevention of PTB, focussed on those births occurring
before 32 weeks’ gestation.
The SAC recommends 6 main targets for research
initiatives (Table III):
1. Contemporary epidemiologic studies of very preterm
births (%32 weeks’ gestation). The traditional epi-
demiology of PTB is rooted in decades-old clinical
data, much of which was acquired outside of the
United States9,41and does not focus as heavily on
early preterm births. Some of the latter were histor-
ically considered stillbirths, but now constitute the
source of the majority of perinatal and infant
morbidity and mortality. Robust epidemiologic
studies should be conducted on heterogeneous pop-
ulations for which data are collected on all relevant
biologic and environmental risk factors and clinical
management variables. These studies must be ade-
quately powered to establish sample sizes large
enough to accommodate appropriate stratification,
adjustment, and multivariate analytic techniques.
Although cross-sectional and case-control studies
are important, prospective cohort studies and cohort
studies of sequential pregnancies should also be
performed to generate positive and negative predic-
tive profiles of very preterm births.
a. Data collection variables. To provide uniformity,
comparability, and to conduct appropriate adjust-
ments and stratification that was based on prob-
able factors that afford risk or protection,
Six main research targets
1. Contemporary epidemiologic studies of very PTBs
(%32 weeks’ gestation)
Data collection variables
Adequate sample size
Biomarkers of PTB
Epidemiologic overlap between PTB and other adverse birth
2. Genes and gene-environment interactions
New analytic techniques and bio-information systems
3. Racial/ethnic disparities
Risk factor analysis
Health care delivery
4. Role of inflammatory responses in PTB
Effects of antibiotics
Role of the cervix
5. Stress responses and PTB
Biologic assessment of maternal and fetal stress
Effects of stress on racial/ethnic disparities
6. Clinical trials
Abruption and impaired uterine-placental blood flow
Assisted reproductive technologies
Risk reduction strategies
Green et al629
epidemiologic studies of preterm births should col-
lect at least the clinical variables listed in Table II.
b. Adequate sample size. Study designs should take
into account genetic and other heterogeneity, with
adequate case ascertainment and patient selection
that meet specific inclusion and exclusion criteria.
Sample sizes should be specified to ensure that
studies have adequate power to address the
hypotheses in question.
c. Biomarkers of PTB. Prediction of PTB should
include the identification of specific markers of
risk and their incorporation into epidemiologic
analyses. Such markers include genetic polymor-
phisms (see below), alterations in level of expres-
sion of specific genes and susceptibility to adverse
effects from smoking, genital tract infection, fetal
fibronectin, cervical length, and contour and other
d. Epidemiologic overlap between PTB and other
adverse birth outcomes. Other adverse perinatal
outcomes commonly occur with PTB, such as
birth defects42and intra-uterine growth restric-
tion.43,44The association between PTB with other
adverse birth outcomes need definition to delin-
eate overlapping mechanisms and to facilitate
predictions of treatment efficacy and outcomes.
2. Genes and gene-environment interactions. A search
for biologic regulatory substrates and circuits inte-
gral to preterm delivery is required. The qualitative
and quantitative roles of host susceptibility in infec-
tious and other environmental processes, the effects
of specific genes, genetic pathways, and epigenetic
regulation on host responses and on the biology and
molecular biology of parturition are all promising
areas for research.27,34,45,46Likely pathways of focus
include inflammation, which is mediated through
proinflammatory and anti-inflammatory pathways
involving cytokines such as tumor necrosis factor a
(TNF-a), interleukin-1b. Other pathways include
those regulating pro-apoptotic and anti-apoptotic
pathways, tissue maintenance, remodeling and stretch,
hemostasis and hemorrhage, cellular turnover and
degradation.45,47,48Promising strategies include:
a. High-risk phenotypes. Studies of individuals and
families with recurrent, idiopathic very PTB
should be given priority. Such cohorts provide
opportunities for identifying relevant genetic and
environmental factors and predictive biomarkers,
including some that may be amenable to inter-
vention or individualized risk assessment.
b. Newanalytic techniques
systems. New techniques for genetic, functional
genomic, and proteomic analysis should be de-
veloped and applied. Although candidate gene
approaches may be useful, microarray technolo-
gies permit comprehensive and pathway-based
genomic/proteomic analyses without presupposed
identification of target genes and proteins.45,46
Applications should be paired with collection
and storage of biologic specimens and bioinfor-
matics support. These tools should be applied in
conjunction with epidemiologic analyses, family
studies, cohorts of severely affected subjects,
community-based intervention trials, and relevant
c. Biobanking. Research studies on PTB should in-
clude collection and storage of biologic specimens
with the minimum of collection of maternal blood/
DNA samples. Sampling should include other
maternal samples (urine, vaginal secretions, pla-
centa, uterine tissue), paternal samples, and fetal
samples (amniotic fluid, cord blood). Samples
should be appropriately banked and made avail-
able to future investigators.
d. Animal models. Better use of animal models is
needed to elucidate the underlying mechanisms of
preterm labor and PPROM and to identify prom-
ising interventions. Rodent models are useful for
some areas of investigation, despite not being ideal
models of PTB. ‘‘Knock out’’ and ‘‘knock down’’
models of known and novel genes are needed.
Primates and other mammals are useful and re-
quire political as well as financial support.49,50
3. Racial/ethnic disparities. PTB is among the most
disparate health outcomes in the United States, espe-
cially for black Americans15-18,20,51(Table I). Re-
search on PTB should work toward attaining the
Healthy Peoples 2010 goal of eliminating health
disparities. Innovative research must address both
and inequities in systems of health care delivery so
that responsive, culturally sensitive interventions can
should combine biologic, sociologic, and epidemio-
logic paradigms, including prospective family and
community cohorts. These studies should encom-
pass quantifiable issues involving prior reproductive
outcomes, medical conditions, infection, immune
regulation, stress, and other biomarkers (described
previously), poverty, depression, racism, substance
and physical abuse, weight, and nutrition. Socio-
medical interventions, including those applied at the
community level should be studied. Similar ap-
proaches have had demonstrable success in preven-
tion and therapeutic intervention in other common
complex disorders such as cardiovascular disease.
Specific research priorities include:
a. Risk factor analysis. Develop improved measures
630Green et al
prevalence of specific risk factors among black
b. Genetic factors. Assessdifferentialethniceffectson
biologic responses of specific genetic factors, such
as polymorphisms in genes regulating immune
responses and steroid receptor polymorphisms38
and their interactions with various environmental
(including social and behavioral) factors.48
c. Behavioral factors. Determine the differential and
cumulative effects of behavioral risk factors such
as multiple partners, interval between pregnan-
cies, sexual activity during pregnancy, use of
barrier contraceptive methods that may prevent
ascending infections, douching, substance abuse
(tobacco, alcohol, and other drugs), nutrition,
preconception weight, and pregnancy weight gain
d. Health care delivery. Study how components of
ity of care, content, nontreatment, unequal treat-
ment, cost, and reimbursement impact on rates
4. Role of inflammatory responses in PTB. The micro-
bial environment and host response play pivotal roles
in both preterm labor and PPROM.18,46,53-55Infec-
as much as 70% for PTB less than 32 weeks,58as
documented by clinical signs, histologic chorioamni-
onitis, and microbial cultures of fetal membranes59,60
and amniotic fluid,61consistent with an ascending
pathway. Inflammation may play a primary or sec-
ondary role in PTB.46,53,55,62For example, treatment
of infections often does not ameliorate, andmay even
paradoxically increase the risk of PTB.63-65This
unexpected effect may reflect further stimulation by
endotoxin, and/or by-products of microbial demise
of inflammatory pathways already triggered by
infection, or may reflect a shared pathway between
susceptibility to infection and an underlying exagger-
ated inflammatory response.53,55These responses
to infection reflect an integration of genetic and
environmental influences that need elucidation, with
development of predictive biomarkers. Important
research areas are as follows:
a. Micro-organisms. Document the presence and
chronology of micro-organisms, including myco-
metrium and decidua that may contribute to PTB.
b. Infection. Elucidate the role of chronic endome-
tritis, ascent of vaginal flora and of inflammation
at distant sites, eg, periodontal disease on preterm
labor and birth.66-68
c. Effects of antibiotics. Investigate the results of
prenatal and preconception antibiotic treatment
on women with genitalinfection and/or prior PTB.
d. Role for the cervix. Study the mechanical and
immunologic role played by the uterine cervix.
e. Immune pathways. Identify pathways that regulate
maternal and fetal humoral and cell-mediated
immune responses to infection and noninfectious
f. Immune modulation. Study the effects of suppres-
sion or augmentation of inflammation on PTB.
Modulation may need to be general or targeted to
particular inflammatory mechanisms, possibly af-
fecting associated neurodevelopmental problems
such as cerebral palsy.
5. Stress responses and PTB. Pregnancy itself is a stress
on normal physiology and endocrinology of women,
with simultaneous yet competing demands to sustain
the fetus and to adapt to foreign antigens. Some
pregnancy states may be more susceptible to effects
from stress, such as in multifetal pregnancies, given
the extra physiologic demands placed on the mater-
psychosocial, nutritional, or other environmental
stress may increase risk of PTB via effects on several
pathways via maternal and/or fetal hypothalamic-
pituitary-adrenal (HPA) neuroendocrine axes (eg,
ACTH, cortisol) that result in premature triggering
of labor and/or a greater degree of activation of the
placental-fetal endocrine systems, including cortico-
trophin releasing hormone (CRH) and estrogens; (2)
immune mechanisms regulated by inflammatory re-
sponses, likely affecting susceptibility to maternal
infection such as bacterial vaginosis51; (3) intrauter-
ine/fetal inflammatory processes, thereby promoting
PTB through proinflammatory mechanisms; and (4)
maternal-placental-fetal vascular function, including
both uterine and umbilical blood flow.
Studies should be performed to delineate the role that
biologic and other types of acute and chronic stressors
play in PTB and in racial/ethnic disparities, functioning
within the context of the common complex disorder of
PTB. These studies should include:
a. Biologic assessment of stress, its timing and its
effects on maternal and fetal health. Focus on im-
proved biologic definition and quantification, and
identification of functional links between the bio-
logic, social, and environmental risk factors. This
should include validated quantitative biomarkers,
plasma and salivary cortisol, and other relevant
markers in the neuroendocrine stress and inflam-
matory pathways; mechanisms underpinning the
associations between stress, the HPA axis and the
autonomic nervous system, including the effects of
glucocorticoids and catecholamines; immunologic
changes such as type1/type 2 cytokine/cellular
Green et al631
responses; vascular effects in the placental circula-
tion, and related physiologic mechanisms.
b. Effects of stress on racial/ethnic disparities. Bio-
logically relevant and quantified markers of stress
should be examined regarding their role in dis-
parate outcomes among sub-populations, as de-
scribed in target area 4 (above).
6. Clinical Trials. In light of the overall paucity of prior
success with clinical trials and interventions in reduc-
ing the incidence of PTB, a change in expectation is
needed. The investigative approach should be broad-
ened so that the research is no longer organized to
reduce PTB by eliminating the effect of single risk
factors. Instead it should be guided by the overriding
concept of PTB as a common complex disorder, in
which interacting environmental and heritable fac-
tors must be addressed, concomitantly with the
clinical milieu. Moreover, progress may prove to be
incremental rather than monumental. Promising
interventions need to be tested in controlled trials of
sufficient sample size for stratification, enroll well-
defined populations, and include a clinical database
and anticipatory maternal and fetal/neonatal bio-
logic sampling. Studies should be primarily random-
ized trials with clearly established mechanistic
underpinnings and biologic analyses. Opportunities
to clarify areas of known disparities should receive
priority. Appropriate outcome measures for these
studies should include perinatal morbidity and mor-
tality, in addition to duration of prolongation of
pregnancy and gestational age at delivery.
A comprehensive agenda for clinical investigation re-
quires: (a) better timing and protocols for treatments
based on improved techniques for diagnosis of preterm
labor; (b) identification of high-risk women both before
(preconception) and during early pregnancy for risk
reduction and early intervention; and ultimately, (c)
reduction of risk among all women of reproductive
age through education, risk reduction programs, and
innovative community-based interventions with contem-
porary standards. These efforts should be population-
based, culturally sensitive, and appropriate for race,
ethnicity, parity, and educational level. Successful inter-
ventions will need to address multiple risk factors simul-
taneously or sequentially, and will require tailoring for
individuals and/or specific communities. They should
also be optimally timed during the preconception, prena-
tal, and interconception periods to attain the highest
impact on rates of PTB and neonatal morbidity and
Clinical investigations of women at increased risk of
PTB should integrate the areas described in the major
target areas 1 through 5 above, as well as:
a. Biomarkers. Determine effective biologic markers
with positive and negative predictive value for
risk of preterm labor and/or PPROM, as de-
b. Progesterone supplementation. Administered em-
pirically in the second trimester, progesterone
appears to reduce the risk of recurrent PTB for a
select group of women at very high risk for
PTB.72,73This recent clinical success should be
used to stimulate studies on the mechanisms of
action, optimal form, dose and route of adminis-
tration, identification of women who will, and just
as importantly, who will not benefit from proges-
terone prophylaxis use in stratified risk groups,
and clinical management and follow-up of off-
c. Infections. Screening and management of possible
bacterial and nonbacterial pathogens. These stud-
ies should examine effects from local, systemic
and distant infection such as bacterial vaginosis,
sexually transmitted diseases, urinary tract infec-
tions, or periodontal disease.66,68In addition to
novel strategies for antibiotic therapies, treatment
options may include manipulation of the maternal
and fetal cytokine milieu.
d. Abruption and impaired uterine-placental blood
flow. Screening and intervention for causes and
consequences of compromised placental blood
flow43,44and/or decidual hemorrhage abruption,
including acquired and inherited thrombophilias
and other coagulation abnormalities,74aberrant
response to protease-activated receptor (PAR)-
e. Multifetal pregnancies. Determine optimal man-
agement for spontaneous andartificially conceived
multifetal pregnancies, including the traditional
approaches, such as bed rest, tocolysis, cerclage,
and potential strategies to prevent PTB, such as
supplemental progesterone, anticoagulation, en-
hanced nutrition, and/or antioxidants.
f. Assisted reproductive technologies (ART). Eluci-
date the relationship between ART and PTB for
both multiple and singleton gestations, including
the attributable contribution of underlying mater-
nal and paternal pathology. Technical aspects
should be studied to optimize the yield of healthy
g. Risk reduction strategies. Studies should evaluate
the impact on rates of PTB of comprehensive
individual risk assessment and, where possible,
intervention with both genetic and environmen-
tal variables (Table II). Interventions include
eliminating or minimizing environmental factors
such as smoking78and exposure to other toxic
agents and stressors,
medical disorders, and optimizing preconcep-
tional and prenatal maternal medical and mental
632Green et al
Productive research on PTB requires several essential
elements included in this report: promising paradigms to
frame investigative approaches; innovative methodolo-
gies to address the problem; well-delineated genotypes
clinical animal models and in vitro materials; adequate
funding; and trainee support. As for other common,
complex disorders, research on PTB must consider the
contributions of genetic, psychosocial, cultural, racial/
ethnic, nutritional, behavioral, and environmental fac-
tors. Research programs already aimed at prevention of
prematurity and that are consistent with this report’s
recommendations include the March of Dimes PERI
research portfolio and the newly created Prematurity
Research Initiative (PRI), which specifically focuses on
the causes of PTB,79existing federally funded research
programs on approaches such as the use of progesterone,
studies on racial/ethnic disparities, community-based
programs, and a new NICHD program, ‘‘Genomic and
Proteomic Network for Premature Birth Research,’’80as
well as being incorporated in the National Children’s
Study championed by NICHD. Sufficient funding must
bemadeavailabletosupportandsustainthese efforts. To
expand the ranks of scientists focused on PTB, new
investigators in PTB need to be recruited through
sustained efforts to attract and retain culturally compe-
tent, junior and multidisciplinary investigators.
Design and testing of promising methods to prevent
PTB are best served by enhanced understanding of basic
biologic mechanisms that inform well-focused, robust,
controlled, clinical trials and innovative community-
based, participatory research. Ideally, basic, clinical,
and community research programs are designed to
reciprocally inform all responsible research on PTB.
However, identification of effective interventions to pre-
vent PTB based on sound epidemiologic approaches may
be possible, despite limits in the understanding of specific
biologic mechanisms. Two recent, notable examples of
successful perinatal interventions are the periconcep-
tional intake of folic acid to prevent serious neural tube
defects81and the supine positioning and safe sleep
environment to prevent Sudden Infant Death Syn-
drome.82,83Promising treatments such as supplemental
need to expeditiously test the most promising interven-
tions based on epidemiologic, laboratory, and clinical
research. The urgent problem of PTB, with its profound
impact on health throughout life and on health dispar-
ities, mandates intense, priority research attention
through a multipronged ‘‘full court press.’’ The March
of Dimes and its SAC are hopeful that approaching PTB
as a common complex disorder will catalyze research,
improvements in clinical care, and the education of
communities to increasingly respond to this serious birth
We acknowledge the thoughtful input from the leader-
ship of ACOG, AAP, and AWHONN, SMFM, as well
as Dr Catherine Spong at NICHD. We also thank
several March of Dimes staff members for their valuable
contributions: Drs Jennifer Howse, Michael Katz,
Joann Petrini, Siobhan Dolan; and Motoko Oinuma,
Ann Umemoto, Lorraine Gore.
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Members of the March of Dimes Scientific Advisory
Committee on Prematurity:
Frederick C. Battaglia, MD, Lillian R. Blackmon, MD,
Coleen Boyle, PhD, Harvey J. Cohen, MD, PhD,
Margaret C. Freda, EdD, RN, Fredric Frigoletto,
MD, Ronald S. Gibbs, MD, Michael F. Greene, MD,
Calvin J. Hobel, MD, Vijaya Hogan, DrPH, MPH, Jay
D. Iams, MD, Richard B. Johnston, Jr, MD, Mark A.
Klebanoff, MD, MPH, Eve M. Lackritz, MD, Charles
J. Lockwood, MD, Irwin R. Merkatz, MD, Mary Lou
Moore, PhD, RNC, E. Albert Reece, MD, PhD, MBA,
Richard H. Schwarz, MD, Joe Leigh Simpson, MD.
Research subgroup chairs: Dr Simpson–Basic science;
Dr Hobel–Multidisciplinary and behavioral approaches.
Green et al635