RESEARCH INTO MECHANISMS OF FETAL GROWTH RESTRICTION RELEASE DATE: April 7, 2003 RFA: HD-03-018 National Institute of Child Health and Human Development (NICHD) ( CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.865 LETTER OF INTENT RECEIPT DATE: June 23, 2003 APPLICATION RECEIPT DATE: July 23, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Child Health and Human Development (NICHD) invites research grant applications to investigate the mechanisms of fetal growth restriction. The aim of this initiative is to stimulate research into the mechanisms of fetal growth restriction and to gain a better understanding of the factors that regulate fetal growth during pregnancy. RESEARCH OBJECTIVES Background Fetal growth restriction (FGR) results in significant perinatal complications, including fetal death, prematurity, neonatal death, fetal compromise in labor, neonatal morbidity, induction of labor, and cesarean delivery. Studies have shown that nearly half of non-malformed stillborn fetuses were growth restricted. Neonates with FGR who survive are at increased risk for neonatal morbidity and mortality. The incidence of fetal growth restriction is estimated to be approximately five percent in the general obstetric population. However, the incidence varies depending on the population under examination (including racial and geographic location). In assessing perinatal outcome by weight, infants who weigh less than 2,500 grams (five pounds, eight ounces) at term have a perinatal mortality rate that is five to 30 times greater than that of infants whose birth weights are at the 50th percentile. The mortality rate is 70 to 100 times higher in infants who weigh less than 1,500 grams (three pounds, five ounces). Perinatal asphyxia involving multiple organ systems is one of the most significant problems in growth-restricted infants. Despite expert neonatal care, a significant proportion of these children suffer impairments (often neurological) in childhood. In addition, there is evidence to suggest that chronic diseases (such as hypertension, ischaemic heart disease, and diabetes) of later adult life are more common in individuals born suffering from fetal growth restriction. Inadequate fetal growth may occur in the absence of recognized causal factors such as maternal hypertension, smoking or inadequate nutrition. It may be associated with intrauterine fetal demise or immediate neonatal and long-term consequences for the infant. In most cases, the reasons for poor fetal growth are not known. Known associations with fetal growth restriction include fetal chromosomal, Mendelian or congenital structural abnormalities; placental factors such as placental mosaicism and abnormal placentation; and maternal factors including hypertension/preeclampsia, antiphospholipid antibody syndrome (APS), and inherited thrombophilia. In addition, extrinsic factors such as altitude, infectious agents, nutritional deficits, and toxins (cigarette smoking, alcohol, illicit drugs) may result in fetal growth restriction. Currently, the management of under-grown fetuses is empirical, aimed primarily at selection of safest time for delivery. There are no effective treatments to prevent or reverse fetal growth restriction. Further research into the mechanisms that control normal fetal growth will lead to our understanding of and prevention of situations of abnormal fetal growth. Providing the best possible environment for the fetus would not only ensure adequate fetal growth and health in the newborn period, but also protect against the development of diseases in adult life. Scientific Knowledge to be Achieved Through Research Supported by the RFA The aim of this initiative is to stimulate research into the mechanisms of fetal growth restriction and to gain a better understanding of the factors that regulate fetal growth during pregnancy. Objectives of this Research Program The major objectives of this RFA are the identification and characterization of the mechanisms of fetal growth; to clarify how these mechanisms are altered in fetal growth restriction; and to develop noninvasive methods to detect the abnormalities. The following are some examples of research topics that are responsive to this RFA, but they are not to be viewed as exclusive or restrictive: o Identification of the cellular and molecular mechanisms that result in fetal growth restriction such as studies dealing with apoptosis, oxidative stress, abnormal cytokine milieu, etc. o Elucidation of the mechanisms by which confined placental mosaicism (CPM) and uniparental disomy (UPD) result in abnormal fetal growth. Examples include studies on the role of imprinted genes, gene dosage, and cis and trans regulatory factors responsible for mediating the effects of CPM and UDP on fetal growth. o Identification and characterization of novel genes and DNA polymorphisms involved in fetal growth. o Characterization of normal and abnormal placentation resulting in normal and growth restricted fetuses. o Characterization of the placenta, its blood flow, and its attachment to the uterus during pregnancy that result in fetal growth restriction. o Identification and characterization of marker molecule(s) such as growth factors or cytokines that are associated with fetal growth restriction. o Comparative study of animal and human tissues to determine applicability of information obtained in the animal to human in terms of a mechanism, molecule or process identified. o Evaluation of the role of the fetus and its potential self-regulation of fetal growth. o Identification of the mechanisms underlying known maternal factors including chronic diseases (e.g., hypertension, diabetes), environmental factors such as toxins of abuse (smoking, alcohol), and environmental exposures. o Investigation of the differential effects of abnormal fetal growth on specific organ maturation and development. In addition to the above, potential applicants are encouraged to utilize characterized mutant mice with phenotypes of abnormal fetal growth that are being produced at NIH-funded mutagenesis facilities such as the mouse mutagenesis and phenotyping facilities at Baylor College of Medicine, at Jackson Laboratories or the Tennessee Mouse Genome Consortium. This RFA will provide an excellent opportunity for researchers to exploit these rich genomic and genetic resources. MECHANISM OF SUPPORT This RFA will use the NIH Program Project Grant (P01) and Research Project Grant (R01) award mechanisms. The complex and multivariate nature of this research goal necessitates the use of both individual-investigator research studies (R01) and integrated, multidisciplinary, and multi-site approaches involving expertise in a number of disciplines (PO1). NICHD Program Project Guidelines may be obtained at: As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is April 01, 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. FUNDS AVAILABLE The NICHD intends to commit approximately $2.5 million total costs [Direct plus Facilities and Administrative (F and A) costs] in FY 2004 to support three to five new and/or competing continuation grants in response to this RFA. An applicant for an R01 may request a project period of up to five years and a budget for DIRECT costs of up to $350,000 per year. An applicant for a P01 may request a project period of up to five years and a budget for TOTAL costs of up to $750,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration 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. ELIGIBLE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign Foreign institutions are only eligible to apply for RO1 grants. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Principal Investigators from projects funded through this RFA will be expected to attend an annual NICHD meeting to share findings, research approaches, and core instrumentation. Application budget requests should include funds to support travel to the Washington DC area for a two-day meeting in each year of the grant. In addition, following the award of grants resulting from this RFA, the funded investigators and NICHD will develop an informal communication collaboration to provide ongoing information and advice relevant to critical issues and trends in the field at large to supplement the aforementioned formal annual meetings. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: John Ilekis, Ph.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 4B03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5575 FAX: (301) 496-3790 Email: o Direct your questions about peer review issues to: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1485 FAX: (301) 402-4104 Email: o Direct your questions about financial or grants management matters to: Kathy Hancock Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5482 FAX: (301) 402-0915 Email: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o 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 by the date listed at the beginning of this document. The letter of intent should be sent to: John Ilekis, Ph.D. Pregnancy and Perinatology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 4B03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5575 FAX: (301) 496-3790 Email: SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SUPPLEMENTAL INSTRUCTIONS: Applications for the Program Project Grant (P01) should be prepared in a manner consistent with the information presented in the NICHD Program Project Guidelines, available from the contact listed under WHERE TO SEND INQUIRIES, above, and at USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The RFA label is also available at: SENDING AN APPLICATION TO THE NIH: 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 must be sent to: Robert Stretch, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5B01, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the 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: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Advisory Child Health and Human Development Council. REVIEW CRITERIA REVIEW CRITERIA FOR P01 APPLICATIONS: The scientific and technical merit peer review of Program Project (P01) applications focuses on three areas: (1) review of the component research subprojects; (2) review of the core units; and (3) review of the overall program as an integrated effort. P01 applications submitted in response to this RFA will be evaluated according to the review criteria described in the NICHD P01 Guidelines, available at: REVIEW CRITERIA FOR R01 APPLICATIONS: 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: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. 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. 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? 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? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 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)? 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? ADDITIONAL CRITERIA/CONSIDERATIONS APPLYING TO P01 AND R01 APPLICATIONS ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below.) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below.) CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: June 23, 2003 Application Receipt Date: July 23, 2003 Peer Review Date: October/November 2003 Council Review: January 2004 Earliest Anticipated Start Date: April 01, 2004 AWARD CRITERIA Criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling justification is 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 clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 ( -02-001.html); a complete copy of the updated Guidelines is available at The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 the inclusion of children as participants in research involving human subjects that is available at REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website ( provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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