HEALTH DISPARITY IN PRETERM BIRTH:  THE ROLE OF INFECTIOUS AND 
INFLAMMATORY PROCESSES

Release Date:  December 14, 2000

RFA:  HD-01-005

National Institute of Child Health and Human Development
 (http://www.nichd.nih.gov)

Letter of Intent Receipt Date:  January 29, 2001
Application Receipt Date:       March 12, 2001

THIS RFA USES THE “MODULAR GRANT” AND “JUST-IN-TIME” CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The purpose of this Request for Applications (RFA) is to determine the role 
of infectious and inflammatory processes leading to preterm birth and adverse 
neonatal outcomes in different ethnic populations. The research proposed in 
response to this solicitation should involve multidisciplinary investigations 
to clarify the potential role of infectious diseases and the associated 
immune response as a cause of early preterm birth and fetal and neonatal 
morbidity.  

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas.  This Request for 
Applications (RFA) is related to one or more of the priority areas.  
Potential applicants may obtain "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) Research Project 
Grant (R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant. This 
RFA is a one-time solicitation.  Future unsolicited competing continuation 
R01 applications will compete with all investigator-initiated applications 
and be reviewed according to the customary peer review procedures.  The 
anticipated award date is December 1, 2001.

Specific application instructions have been modified to reflect “MODULAR 
GRANT” and “JUST-IN-TIME” streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.  

FUNDS AVAILABLE 

The NICHD intends to commit approximately $1.5 million in total costs [Direct 
plus Facilities and Administrative (F&A) costs] in FY 2001 to fund four to 
seven new grants in response to this RFA.  An applicant may request a project 
period of up to five years and a budget for direct costs of up to $200,000 
per year.  Because the nature and scope of the research proposed may vary, it 
is anticipated that the size of each award will also vary.  Although the 
financial plans of the NICHD provide support for this program, awards 
pursuant to this RFA are contingent upon the availability of funds and the 
receipt of a sufficient number of meritorious applications. 

RESEARCH OBJECTIVES

Background

Health disparities are major contributors to the morbidity and mortality 
associated with many disease conditions in the United States.  Among the most 
striking of U.S. health disparities is the rate of preterm births among 
African American women.  Preterm delivery accounts for 70 percent of 
perinatal mortality and nearly half of the long-term neurologic morbidity of 
newborns.  Despite years of intense effort to reduce preterm delivery rates, 
approximately ten percent of all births in the United States are still 
preterm and the incidence of very early preterm births has been rising in 
recent years.  Preterm births are twice as high among African American women 
as among any other group of women in the United States, with an even greater 
discrepancy in the rate of very early preterm birth.   

Our understanding of the underlying mechanisms of preterm birth is limited; 
less than half of all preterm births have an identifiable risk factor.  
Recent information suggests that infection/inflammation has an important, 
complex role in early preterm delivery and its sequelae.  Up to 80 percent of 
early preterm births are associated with intrauterine infection that precedes 
the rupture of membranes; however, trials of antibiotic therapy in women with 
preterm labor and women with genital tract infections such as bacterial 
vaginosis have not been effective in preventing preterm delivery.  A number 
of markers for delivery before 32 weeks, e.g., fetal fibronectin, cervical 
length, and bacterial vaginosis, also suggest a role for infection in preterm 
delivery.  Intriguing preliminary information suggests that fetuses who are 
exposed to inflammation have an increased risk for arrested lung development 
and bronchopulmonary dysplasia, necrotizing enterocolitis, and cerebral 
palsy.  
 
The differences in distribution of preterm birth across U.S. population are 
unexplained; however, more African American women have bacterial vaginosis, 
histologic and clinical chorioamnionitis and postpartum endometritis, and 
genital tract infection.  Some African American women also may have a low-
grade chronic intrauterine infection before or between pregnancies that may 
be the cause of repeated spontaneous preterm births.  These infections appear 
to be unrelated to age of onset of sexual activity or number of sexual 
partners.  A history of a previous spontaneous preterm birth, especially in 
the second trimester, represents another important risk factor for preterm 
delivery

The objectives of this RFA are to determine the role of infectious and 
inflammatory processes that result in preterm birth and adverse neonatal 
outcomes in different ethnic populations.  The approach should involve 
multidisciplinary investigations to clarify the potential role of infectious 
diseases and the associated immune response as a cause of early preterm birth 
and fetal and neonatal morbidity.  Because a large portion of the difference 
in infant mortality rates between African American and non-African American 
populations appears related to infection-induced preterm birth, this RFA is 
designed as a step in reducing one of the major disparities in health 
outcomes, one of the NIH Areas of Emphasis and incorporated in the FY 2001-
2006 Department of Health and Human Services Strategic Plan.  This RFA is 
intended to stimulate investigators interested in preterm birth/prematurity 
to focus on ethnic disparities and to create a body of data upon which future 
clinical trials may be developed.

Research Scope

To address these research needs, this RFA seeks research projects focused on 
one or more of the following goals:

(a)  To identify the determinants of the discrepancy among races in early 
preterm delivery associated with infectious/inflammatory disease, including 
infectious, immunologic, and genetic factors.

(b) To examine mechanisms and timing of intrauterine infection/inflammation 
among racial/ethnic groups. 

Research topics that are responsive to the intent of this RFA include, but 
are not limited to, the following: 

o  Potential mechanisms and timing of intrauterine infection/inflammation 
among racial/ethnic groups; 

o  Potential mechanisms by which the mother and fetus respond to bacterial 
infection and the relative contributions of the maternal and fetal 
compartment to the overall inflammatory response, specifically evaluating the 
biology of the host response stratified along health disparities;  

o  Identification of more discriminate markers for the diagnosis of 
subclinical maternal, fetoplacental, and neonatal infection and preterm 
delivery, including chronic uterine infection;

o  Research on the genetic component of very early preterm delivery 
associated with intrauterine infection/inflammation among different 
racial/ethnic groups;

o  Identification of susceptibility genes that may increase the risk of 
premature labor due to infectious/inflammatory stimuli; 

o  Elucidation of the mechanism(s) by which inflammatory mediators 
(cytokines, chemokines, etc.) induce premature labor;

o  Identification of population-based differences in the local immune 
response to pathogens that result in uterine infection and/or inflammatory 
response;

o  Identification of mechanisms that result in a hyper-immune response to 
uterine or fetal infection/inflammation.  

Applications proposing solely epidemiologic and/or descriptive studies, or 
clinical trials on infection/inflammation as related to the racial 
disparities of preterm delivery, will not be considered responsive to this 
RFA. 

SPECIAL REQUIREMENTS

Applicants are encouraged to consider the complexity of issues surrounding 
the meaning and assessment of race and ethnicity, and should consider 
collaborating with scientists in other disciplines when developing concepts 
and measures related to race and ethnicity.  As appropriate for their 
particular proposals, applicants should consider the following:  lack of 
congruence of biologic and social definitions of race and ethnicity; fluidity 
in racial and ethnic self-identification; and new Office of Management and 
Budget (OMB) directives on classifying race and ethnicity.  In addition, 
community involvement in implementation of the proposed projects is strongly 
encouraged.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of 
the research.  This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines is available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.  The 
revisions relate to NIH-defined Phase III clinical trials and require:  a) 
all applications or proposals and/or protocols to provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) all investigators to report accrual, and to conduct and report 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects’ research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
“NIH Policy and Guidelines on Inclusion of Children as Participants in 
Research Involving Human Subjects,” published in the NIH Guide for Grants and 
Contracts, March 6, 1998, and available at: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html. 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of this RFA.  
Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows NICHD staff to estimate the potential review workload and 
plan the review.

The letter of intent is to be sent to Dr. Catherine Spong at the address 
listed under INQUIRIES, below, by January 29, 2001.

APPLICATION PROCEDURES


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research, on the Internet at 
http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the 
Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-
7910, telephone 301-435-0714, E-mail:  grantsinfo@nih.gov. 

Application Instructions 

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award.  It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers, and NIH 
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.

For this RFA, Modular Grant applications will request direct costs in $25,000 
modules, up to a total direct cost request of $200,000 per year. The total 
direct costs must be requested in accordance with the program guidelines and 
the modifications made to the standard PHS 398 application instructions 
described below:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $200,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative (F&A) costs] for the initial 
budget period.  Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD:  Do not complete Form Page 
4 of the PHS 398.  It is not required and will not be accepted with the 
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT:  Do not complete the 
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION:  Prepare a Modular Grant Budget Narrative 
page.  (See http://grants.nih.gov/grants/funding/modular/modular.htm for 
sample pages.)  At the top of the page, enter the Total Direct Costs 
requested for each year.  This is not a Form Page.

Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project.  No individual salary information should 
be provided.  However, the applicant should use the NIH appropriation 
language salary cap and the NIH policy for graduate student compensation in 
developing the budget request.

For Consortium/Contractual costs, provide an estimate of Total Costs (Direct 
plus F & A) for each year, each rounded to the nearest $1,000.  List the 
individuals/organizations with whom consortium or contractual arrangements 
have been made, the percent effort of all personnel, and the role on the 
project.  Indicate whether the collaborating institution is foreign or 
domestic.  The total cost for a consortium/contractual arrangement is 
included in the overall requested modular direct cost amount.  Include the 
Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH:  The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three 
pages may be used for each person.  A sample biographical sketch may be 
viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the Form Page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST:  This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate the 
type of agreement and the date.  All appropriate exclusions must be applied 
in the calculation of the F&A costs for the initial budget period and all 
future budget years.

o  The applicant should provide the name and telephone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.

Submission Instructions

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
stapled to the bottom of the face page of the application and must display 
the RFA number HD-01-005.  A sample RFA label is available at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.  Please note this 
is in the pdf format.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application should be 
sent to:

L. R. Stanford, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03, MSC 7510
Bethesda MD 20892-7510
Rockville MD 20852 (for express/courier service)

Applications must be received by March 12, 2001.  If an application is 
received after that date, it will be returned to the applicant without 
review.  

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness to this RFA by NICHD.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further consideration.  
Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by NICHD in accordance with the review criteria stated below.  As 
part of the initial merit review, all applications will receive a written 
critique and may undergo a process in which only those applications deemed to 
have the highest scientific merit will be discussed, assigned a priority 
score, and receive a second level review by the National Advisory Child 
Health and Human Development Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the Principal Investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support?

In addition, applications will be evaluated with respect to:

o  Justification of the definitions of race and ethnicity used in the 
proposal.

o  Discussion of the impact of the proposed definitions of race and ethnicity 
on the ability to interpret the findings and generalizability of the 
findings.

o  If appropriate, the applicability of animal models to the human model of 
infection-related preterm delivery.

o  The adequacy of the proposed plan to share data, if appropriate.

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

Schedule

Letter of Intent Receipt Date:    January 29, 2001
Application Receipt Date:         March 12, 2001
Peer Review Date:                 July 2001
Council Review:                   September 2001
Earliest Anticipated Start Date:  December 1, 2001

AWARD CRITERIA

Criteria that will be used to make award decisions include:

o  scientific and technical merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Catherine Y. Spong, M.D. 
Pregnancy and Perinatology Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B03, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5577
FAX:  (301) 496-3790
E-mail:  spongc@exchange.nih.gov

Or

Linda Wright, M.D.
Pregnancy and Perinatology Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B03, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5577
FAX:  (301) 496-3790
E-mail:  wrightl@mail.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17E, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1303
E-mail:  shawverd@exchange.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.865.  Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.


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