oppRFA-DD-18-001-cfda93.073-cidRFA-DD-18-001-instructions.pdf

Centers for Disease Control

National Center on Birth Defects and Developmental Disabilities Extramural Research Program

Office

Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) II

RFA-DD-18-001

Application Due Date: 02/20/2018

Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) II

RFA-DD-18-001

TABLE OF CONTENTS

Part 1. Overview Information Key Dates Required Application Instructions Executive Summary

Part 2. Full Text Section I. Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII. Other Information

Part 1. Overview Information Participating Organization(s) Centers for Disease Control Components of Participating Organizations National Center on Birth Defects and Developmental Disabilities Extramural Research Program Office (NCBDDD ERPO) National Center on Birth Defects and Developmental Disabilities (NCBDDD) Notice of Funding Opportunity (NOFO) Title Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS) II Activity Code U01

Notice of Funding Opportunity Type New Agency Notice of Funding Opportunity Number

RFA-DD-18-001

Catalog of Federal Domestic Assistance (CFDA) Number(s) 93.073 Category of Funding Activity:

Health NOFO Purpose The purpose of this NOFO is to identify causes of certain major, structural birth defects and stillbirths using epidemiologic and genetic research methods and to provide information that could be translated into public health prevention messages.

Component A. BD-STEPS II Core. To support the epidemiological and genetic research capabilities of the Centers for Birth Defects Research and Prevention (CBDRP) through the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS). BD-STEPS is a case-control study of genetic and environmental risk factors for birth defects that focuses on the key areas of: (1) maternal chronic diseases and their treatments; (2) infectious disease in pregnancy;

and (3) medications.

Component B. BD-STEPS stillbirth. To support the exploration of modifiable risk factors for stillbirths. Component B applicants must also apply for Component A.

Key Dates Publication Date: To receive notification of any changes to RFA-DD-18-001, return to the synopsis page of this announcement at www.grants.gov and click on the "Send Me Change Notification Emails" link. An email address is needed for this service.

Letter of Intent Due Date: 01/16/2018 https://www.grants.gov

Application Due Date: 02/20/2018

On-time submission requires that electronic applications be error-free and made available to CDC for processing from eRA Commons on or before the deadline date. Applications must be submitted to and validated successfully by Grants.gov/eRA Commons no later than 5:00 PM U.S. Eastern Time. Note: HHS/CDC grant submission procedures do not provide a period of time beyond the application due date to correct any error or warning notices of noncompliance with application instructions that are identified by Grants.gov or eRA systems (i.e., error correction window).

Scientific Merit Review: 04/05/2018

Secondary Review: 05/03/2018

Estimated Start Date: 09/01/2018

Expiration Date: 02/21/2018 Due Dates for E.O. 12372: Executive Order 12372 does not apply to this program.

Required Application Instructions It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise in this NOFO. Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Note: The Research Strategy component of the Research Plan is limited to 25 pages.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Telecommunications for the Hearing Impaired: TTY 1-888-232-6348

Executive Summary Purpose. CDC has previously implemented population based case control studies of birth defects known as the National Birth Defects Prevention Study (NBDPS) for births from 1997- 2011 and the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS I) which started with births in 2014 and is ongoing. The purpose of BD-STEPS II is to identify causes of birth defects and stillbirths using epidemiologic and genetic research methods and provide information that could be translated into public health prevention messages.

The activities under this NOFO will be supported by two separate but related funding components:

1. Component A. BD-STEPS II Core. To support the epidemiological and genetic research capability of the Centers for Birth Defects Research and Prevention (CBDRP) through http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf

BD-STEPS. The intent of BD-STEPS II is to carry out the same basic BD-STEPS study design with a focus on the key areas of: (1) maternal chronic diseases and their treatments; (2) infectious disease in pregnancy; and (3) medications. In BD-STEPS II, we will add the focus area of infectious causes of birth defects, and pilots will be conducted to determine feasibility of medication use validation. Both new sites and current BD-STEPS sites are encouraged to apply for this component. Maintaining the same basic study design and overall protocol integrity will allow for data pooling across NBDPS, BD-STEPS I, and BD-STEPS II.

2. Component B. BD-STEPS stillbirth. To support the exploration of modifiable risk factors for stillbirths. The intent of this component is to conduct a case-control study of stillbirth risk factors using the BD-STEPS II Core interview and a follow-up interview with mothers affected by stillbirths and mothers of livebirths. To be funded for Component B, applicants must have a responsive application for Component A and receive Component A funding. Both new sites and current BD-STEPS sites are encouraged to apply for this component.

Applicants should clearly indicate the Component(s) for which they are applying and should include at the beginning of the title, the Component(s) under which the application should be considered (i.e., Component A or Component B). Separate applications are required for each Component.

Mechanism of Support. Cooperative Agreement Funds Available and Anticipated Number of Awards. We anticipate 5 – 7 awards being made for Component A under this NOFO, with 2 recipients also receiving funding for Component B. The estimated total level of funding for Components A and B (direct and indirect for entire project period) is $28,500,000. Awards issued under this NOFO are contingent upon availability of funds and a sufficient number of meritorious applications. Because the nature and scope of the proposed research will vary from application to application, it is also anticipated that the size and duration of each award may also vary. The total amount awarded and the number of awards will depend upon the number, quality, duration and cost of the applications received.

o Budget and Project Period.

1. Component A. BD-STEPS II Core: The estimated total funding (direct and indirect) for the first budget period, 9/1/2018-8/31/2019, is $5,300,000. The estimated total funding (direct and indirect) for the entire project period, 9/1/2018-8/31/2023, is $26,500,000. Estimated Number of Awards: up to 7.

Average annual amount of each award is $800,000-$900,000.

2. Component B. BD-STEPS Stillbirth: The estimated total funding (direct and indirect) for the first budget period, 9/1/2018-8/31/2019, is $400,000. The estimated total funding (direct and indirect) for the entire project period, 9/1/2018-8/31/2023, is $2,000,000. Estimated Number of Awards: up to 2.

Average annual amount of each award is $200,000.

Application Research Strategy Length: Page limits for the Research Strategy are clearly specified in Section IV. Application and Submission Information of this announcement.

http://www.cdc.gov/od/pgo/funding/grants/additional_req.shtm#SectionIV

Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A.

are eligible to apply.

Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. NOTE:

CDC does not make awards to individuals directly. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply.

Number of PDs/PIs. Applications may include more than one PI; however, the first PI listed on the application will be the “contact PI” for all correspondence. Any additional PIs are permitted, but would be referred to as Co-PIs.

Number of Applications. Eligible applicant institutions may submit more than one application for each component, provided that each application is scientifically distinct.

Application Type. New Special Date(s). Not Applicable.

Application Materials. See Section IV.1 for application materials. Please note that Form

D is to be used when downloading the application package. http://grants.nih.gov/grants /how-to-apply-application-guide/forms-d/general-forms-d.pdf%20 o Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY: 1-888-232-6348.

Part 2. Full Text Section I. Funding Opportunity Description

Statutory Authority This program is authorized under Sections 301 and 317C of the Public Health Service Act [42 U.S.C. 241, and 247b-4 as amended].

1. Background and Purpose The National Center on Birth Defects and Developmental Disabilities (NCBDDD), Division of Congenital and Developmental Disorders (DCDD), seeks to fund a collaborative project for a multi-site case control study of selected major birth defects and stillbirths.

Birth defects affect about three percent of all births in the United States and are a leading cause of infant mortality, morbidity, and healthcare costs. Birth defects account for one in five infant deaths and contribute substantially to long-term disability. Although several human teratogens and genetic factors have been identified, the causes of two-thirds of birth defects remain unknown. It is important to study specific birth defects individually, because the etiology of specific birth defects may differ substantially. Because individual types of birth defects are relatively rare, it has been difficult in the past to conduct a study large enough to provide the necessary power to assess risk factors for specific defects(1).

Overview of Funding History In 1996, Congress appropriated funds to initiate some of the activities described in the Birth Defects Prevention Act of 1998, including the funding of the Centers for Birth Defects Research http://era.nih.gov/commons/index.cfm#SectionIII1A http://grants.nih.gov/grants/ElectronicReceipt/submit_app.htm#SectionIV1 http://grants.nih.gov/grants/how-to-apply-application-guide/forms-d/general-forms-d.pdf%20 http://grants.nih.gov/grants/how-to-apply-application-guide/forms-d/general-forms-d.pdf%20 and Prevention (CBDRP). Since FY 1996, cooperative agreements have been awarded to 9 different states(2). The two major collaborative activities of this project have been multi-site case-control studies called the National Birth Defects Prevention Study (NBDPS) and the Birth Defects Study to Evaluate Pregnancy exposureS (BD-STEPS). Both rely on data from the existing birth defects surveillance systems.

CBDRP Study Designs (NBDPS and BD-STEPS) Data collection for the NBDPS began for births on or after October 1, 1997 and ended with births on December 31, 2011, the last interview was conducted in March 2013(3, 4). Up to 9 sites were funded during the study period and CDC was included as an additional study site.

Pregnancies affected by one of more than 30 major structural birth defects and those unaffected by a major structural birth defect were ascertained using birth hospital medical records and vital records, respectively. Clinicians used standard definitions to review cases for eligibility(5, 6). If the birth defect was known or strongly suspected to be caused by a syndrome or other known genetic or teratogenic factor, the case was excluded. Computer-assisted telephone interviews were conducted with more than 40,000 women, who were asked about exposures from 1 month before through the end of pregnancy. At the end of the maternal interview, mothers were sent buccal (cheek) cell collection kits to collect cells from themselves, the biological father, and the infant (if living)(7).

In September 2013, NCBDDD funded 6 study sites (with CDC serving as the 7th site) to conduct BD-STEPS I, which extended and focused the data collection efforts of the NBDPS. A subset of 17 NBDPS birth defects were included, those which are most reliably ascertained and likely to have the greatest public health importance. In this NOFO, we will refer to the currently funded BD-STEPS as BD-STEPS I and the plans for BD-STEPS as described in this NOFO will be referred to as BD-STEPS II. In BD-STEPS I, the maternal interview was modified to limit the exposure period to the month before and the first 3 months of pregnancy and to better capture certain exposures; however, many of the questions from the NBDPS interview are included in the BD-STEPS I interview, and due to the similarity in study methods, data will be able to be combined across studies. BD-STEPS I incorporates online questionnaires to obtain more detailed information about exposures women report during the phone interview. The first online questionnaire focuses on occupational exposures. In order to be able to assess genetic risk factors for birth defects, access to residual newborn bloodspots to use in genetic research is being requested from mothers in most BD-STEPS sites.

In addition, two of the BD-STEPS I study sites include stillbirths without birth defects as a separate case group to allow research of this understudied birth outcome. Women with pregnancies affected by a stillbirth (pregnancy loss at 20 or more weeks of gestation) and women with pregnancies unaffected by a stillbirth or birth defect are asked to complete a follow-up interview after the BD-STEPS Core interview to collect information on exposures later in pregnancy and exposures most relevant to elucidating causes of stillbirths.

The CBDRP has been a collaborative effort between CDC’s NCBDDD and the funded recipients. For the past 20 years, the CBDRP case-control studies have provided a unique and unprecedented opportunity to assess a variety of exposures for their potential association with specific birth defects.

The research experience from the CBDRP collaboration demonstrated several areas in which public health birth defects research could benefit from further study. As an example, although the association between diabetes, obesity and specific birth defects was observed in the analyses from the collaborative projects, it is not clear whether changes in body fat distribution or increasing physical activity might mitigate some of the negative impact of obesity and diabetes on birth defects. Evaluating this relationship is an important next step if targeted and appropriate public health recommendations for maximum public health impact need to be made.

For studies assessing medications, experience from this collaborative research demonstrates the importance of documenting the indication for which the medication was taken (e.g. fever vs.

pain for acetaminophen) and the dose that was consumed (e.g. 25 to 200 mg/day for sertraline).

These data were not available from the NBDPS but are available in BD-STEPS I.

This notice of funding opportunity will continue to support the infrastructure of CBDRP’s Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS II). Component A will be an open competition to identify study sites with the capability to conduct the epidemiological and genetic research of BD-STEPS I with a focus on the key areas of (1) maternal chronic diseases and their treatments; (2) infectious disease in pregnancy; and (3) medications. By including multiple study sites, BD-STEPS II will aim for a study population that is representative of the US population with regards to the racial/ethnic composition of the study regions. Implementing BD-STEPS II will increase the total pooled sample size especially for some rarer exposures and less common birth defects. The addition of some birth defects and the ascertainment of infection status from the state health department will allow a new focus on infectious causes of birth defects and, with the focus on medications, BD-STEPS II will provide the opportunity to look at newly released medications and provide current prevalence of prescription and over-the-counter medication use during pregnancy.

Component B provides an opportunity for up to 2 successful Component A applicants to explore modifiable risk factors for stillbirths.

Healthy People 2020 and other National Strategic Priorities This program addresses the “Healthy People 2020” objective to reduce the rate of infant mortality related to birth defects and due to congenital heart defects (MICH-1.6 and MICH-1.7) and the objective to reduce the prevalence of spina bifida (MICH-28.2).

Measurable outcomes of the program will be in alignment with the first performance goal for the National Center on Birth Defects and Developmental Disabilities: Prevent major birth defects attributable to maternal risk factors.

Public Health Impact Birth defects account for one in five infant deaths and contribute substantially to childhood morbidity and long-term disability. Currently, the causes of two-thirds of birth defects are unknown. This NOFO supports the continuation of BD-STEPS I data collection, which will increase the sample sizes of individual birth defects for investigation of high priority hypotheses, thereby enhancing the potential of BD-STEPS to successfully investigate birth defect risk factors. BD-STEPS II will also allow for the ascertainment of newly released medications, as new drugs get released every year. This is especially important since pregnant women are usually not included in clinical trials. The recent Zika outbreak has highlighted the devastating effect external factors can have on the developing fetus. In BD-STEPS II, we will explore the feasibility of looking at maternal infectious diseases as a cause of birth defects.

Each year, more than 26,000 pregnancies in the U.S. end in a stillbirth (pregnancy loss at 20 or more weeks of gestation). Stillbirths are an under-evaluated and under-reported public health issue. There is little information on the causes of stillbirths. This NOFO supports investigations of risk factors for stillbirths by asking women affected by stillbirths and those unaffected by stillbirths to complete a follow-up interview after the BD-STEPS Core interview that includes questions designed to elucidate risk factors of stillbirth. This represents a unique opportunity in a currently underexplored area.

Relevant Work The CBDRP has been a collaborative effort between CDC’s NCBDDD and the funded recipients. For the past 20 years, the CBDRP case-control studies have provided a unique and unprecedented opportunity to assess a variety of exposures for their potential association with specific birth defects. Over 250 publications in peer-reviewed journals have reported data from the collaboration, and results from analyses have also been disseminated through conference proceedings and coverage by the popular press. A few highlights of these findings are described here: (1) The relationships between obesity and diabetes and specific birth defects have been elucidated by using data from the collaborative projects; (2) Results from the analysis assessing selective serotonin reuptake inhibitors (SSRIs) and specific birth defects contributed important information for decision-making when treating pregnant women with depression; (3) Data from the collaborative projects have also been used to confirm previous observations of an association between the use of opioid analgesics and spina bifida and heart defects, as well as the association between maternal smoking and orofacial clefts; and (4) Gastroschisis, a defect with increasing prevalence that is strongly associated with young maternal age, was found to be associated with report of genito-urinary infections early in pregnancy.

2. Approach To meet the goals of the NOFO, this opportunity includes 2 separate funding components:

1. Component A. BD-STEPS II Core will support the epidemiological and genetic research capability of the Centers for Birth Defects Research and Prevention (CBDRP) through the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS I). This new opportunity will allow for increased sample size for some of the rarer exposures, and will add a new focus on infectious causes of birth defects.

2. Component B. BD-STEPS stillbirth will support the exploration of modifiable risk factors for stillbirths. To be funded for Component B, applicants must have a responsive application for Component A and receive Component A funding.

Applicants should clearly indicate the Component(s) for which they are applying and should include at the beginning of the title, the Component(s) under which the application should be considered (i.e., Component A or Component B). Separate applications are required for each Component.

Objectives/Outcomes

Component A: BD-STEPS II Core

a. To collect information on early pregnancy exposure to modifiable risk factors via a maternal telephone interview with a specific focus on:

1. Maternal chronic diseases and their treatments: Certain chronic conditions are increasingly common among women of childbearing age, and therefore also among pregnant women. In BD-STEPS I, we introduced innovative questions to the maternal interview on asthma, autoimmune disease, diabetes, obesity and thyroid disease. As the medical field is advancing, women survive severe illness and become pregnant after surviving cancer or transplants. BD-STEPS explores these exposures and the medications that women take for these conditions. Regarding obesity, it is not clear whether body fat distribution or increasing physical activity might impact the association of obesity and birth defects. The BD-STEPS interview allows collection of information on these factors, and builds on the existing data from the NBDPS to provide more power than any previous study to assess the interrelation of these factors, an important next step if we want to develop effective public health interventions.

Mental health conditions including depression, anxiety, stress, and insomnia have the potential to impact pregnancy through manifestations of the condition, the exposures potentially increased as a consequence of the condition (e.g. smoking or alcohol use), and medications taken to control the condition. The BD-STEPS maternal interview captures this information and will allow better characterization of the birth defects risk associated with these conditions and any modifying factors that might reduce the risk.

2. Infectious disease in pregnancy: The outbreak of Zika virus has shown that novel causes of birth defects can be identified at any time. During the emergency response it became clear that this mosquito-borne and sexually transmitted flavivirus is associated with devastating birth defects when infection occurs during pregnancy. To allow for further investigation of infectious causes of birth defects new questions about possible exposure to infectious disease will be added to the questionnaire in BD-STEPS II and additional defects suspected to be associated with prenatal infectious disease will be added (i.e. microcephaly, eye defects, and arthrogryposis). It is expected that grantees working on BD-STEPS II will ascertain reportable disease records for consenting participants in their state health departments to ascertain diseases such as Zika, sexually transmitted diseases, and Lyme disease.

3. Medications: Approximately 50% of pregnant women take at least one prescription medication during the first trimester, and even more report the use of over-the-counter medications. Medications have the potential to act as strong teratogens, as evidenced by thalidomide and isotretinoin. New medication products are constantly being introduced to the market, but the randomized-controlled trials that test drug safety and efficacy typically exclude pregnant women. In addition, some medications are used for an expanded list of indications over time which can increase the likelihood of exposure, such as the use of some antiepileptic medications for migraines, a much more common condition in reproductive aged women.

Increases in chronic disease among pregnant women translate to increases in long term exposure to maintenance medications to control their conditions, and data are needed to inform the public of the risk/benefit assessment of continuing to take a medication during pregnancy.

The BD-STEPS interview collects information on the condition for which the medication was taken (e.g. whether topiramate, an antiepileptic, is being used to control seizures, manage migraines, or assist with weight loss), and the dose that was consumed (e.g. for clomiphene citrate whether it was 50, 100, or 150 mg).

b. To identify genetic or epigenetic risk factors or to validate environmental exposures through analysis of bloodspots. Mothers of all liveborn infants in BD-STEPS will be asked to consent for use of residual newborn bloodspots, if blood spots are retained in the state. The combination of genetic and interview data can allow for for gene-environment interaction studies if the study population is large enough.

c. To collaborate with all recipients and CDC to compile data repositories and to conduct epidemiological analyses to assess risk factors for birth defects.

d. To train the future generation of birth defects researchers. Recipients will be expected to establish a training plan and employ junior researchers for training and mentoring such as Masters- and PhD-level students, post-doctoral fellows, medical students and residents, and other junior public health professionals. The training plan should address how junior researchers will gain skills in dysmorphology, birth defects epidemiology, and other study-related activities through this mentoring.

e. To validate maternal self-reported medication use during pregnancy. Recipients will be required to conduct a pilot project that focuses on specific prescription medications, such as SSRIs, antihypertensives, or thyroid medications. Potential sources for validation data include, but are not limited to, electronic medical records, insurance records, or pharmacy records. The pilot project should encompass a full year of births and include an evaluation component.

Results from the pilot studies will be used to inform validation projects to be implemented by all Centers across BD-STEPS.

Project management Recipients are expected to develop a management and staffing implementation plan for the proposed program. This plan will include the provision of evidence of legal authority to access data needed to accomplish the activities required by this NOFO and the recipient’s application, including HIPAA and IRB requirements. The recipient should also provide evidence of legal authority to share identifiable, individual-level contact information with CDC and its contractors and individual-level data without names and addresses with other recipients of this cooperative agreement to create a pooled analytic database. The updated Common Rule requires single IRB approval of cooperative (i.e., multi institutional) research conducted in the United States (https://www.gpo.gov/fdsys/pkg/FR-2017-01-19/pdf/2017-01058.pdf). The central IRB model is expected to be more efficient and require less personnel time and fewer resources than the previous model requiring review and approval from each institution’s IRB.

Compliance with this requirement starts January 20, 2020, which is within the timeframe of the current NOFO. The intent behind the delay is to provide time for development of institutional policies and procedures necessary for implementation. Thus, recipient’s local IRBs will be expected to defer to the CDC IRB unless 1) the CDC determines and documents that use of a single IRB is not appropriate, or 2) the recipient is an institution that requires more than single IRB review by law (including tribal law). This policy does not relieve local study sites of their obligations to protect human subjects.

For joint academic/state applications, the recipient will include documentation of a planned meaningful collaboration between the state health department and the academic center. If a https://www.gpo.gov/fdsys/pkg/FR-2017-01-19/pdf/2017-01058.pdf center cannot defer to a central IRB, uniform study protocols and materials will need to be submitted to the local IRB without modification. If modifications are required by the local IRB, documentation needs to be provided to CDC, to consider implementation study wide.

Data and specimen collection The recipients are expected to use data from existing, state-funded, population-based, birth defects surveillance systems to identify all cases (either live born, stillborn, or induced abortions) diagnosed with any of the proposed eligible birth defects (Table 1) in the first year of life. Additional information needed to determine case eligibility or classification will be abstracted from hospital records or vital records by the recipient. The recipients will select a random sample of live births without major birth defects from the same source population as the cases to serve as the comparison group. These random samples are expected to include approximately 75-100 births for each study year at each study site. Recipients will describe the existing birth defects surveillance system, its attributes, its funding, and the geographical area the source population will encompass. Funds from this NOFO cannot be used to support the core birth defects surveillance system, but can be used to enhance the system (e.g., inclusion of prenatally diagnosed cases, improved timeliness). The recipient should be able to send 80% of the cases to the central interviewing contractor within 10 months after birth. The identified source population for the study should include between 30,000-75,000 births per year, and all cases identified in the source population with the defects listed in Table 1 should be considered eligible.

The recipients are expected to work with their State Health Department to obtain available information from the National Electronic Disease Surveillance (NEDS) System to ascertain any of the following tentative list of reportable conditions (Chickungunya, Chlamydia, Dengue fever, Gonorrhea, Hepatitis A B or C, Lyme disease, Malaria, Novel Influenza A virus, West Nile virus, Zika virus) that affected the participants in the two years before or during pregnancy.

Participants will be asked for consent to link this information. The recipients will include requests to retrieve residual newborn bloodspots with the interview thank you letters, if they are able to retrieve and store bloodspots linked to the study participant.

Recipients are expected to conduct a pilot project to validate maternal self-reported medication use during pregnancy. These pilot projects should focus on specific prescription medications, such as SSRIs, antihypertensives, or thyroid medications. Potential sources for validation data include, but are not limited to, electronic medical records, insurance records, or pharmacy records. The pilot project should encompass a full year of births and include an evaluation component. Results from the pilot studies will be used to inform validation projects to be implemented by all Centers across BD-STEPS A copy of the draft protocol is available upon request see Section VII. Agency Contacts, Scientific / Research Contact(s) Marcella Law to obtain a copy. The protocol will be finalized by CDC in consultation with the recipients after the awards are made.

Table 1

Birth Defects included in BD-STEPS II Core

Spina bifida without anencephaly

Microcephaly if combined with brain anomaly

Holoprosencephaly

Anophthalmia/microphthalmia

Cataracts, glaucoma

Posterior eye defects

Anotia/microtia

Transposition of the great arteries (TGA)

Tetralogy of Fallot

Truncus arteriosus

Pulmonary atresia

Tricuspid atresia

Coarctation of aorta

Hypoplastic left heart syndrome

Anomalous pulmonary venous return

Cleft lip +/- cleft palate

Cleft palate

Esophageal atresia

Arthrogryposis in 2 or more joints

Transverse limb deficiency

Diaphragmatic hernia

Gastroschisis

Data reporting Recipients are expected to collect, store, and transmit data in a standardized and secure manner with common elements mutually agreed upon by CDC and recipients. On a weekly basis, recipients will transfer contact information to the central interviewer using the CDC-provided Secure Access Management Service. Recipients should be able to utilize .SQL and ACCESS databases in conjunction with their existing birth defects surveillance infrastructure.

Recipients will be responsible for compiling mailings to be sent to parents (e.g. introductory packets, thank you letters, various reminders, etc.); these mailings will include incentives as determined by the protocol. Recipients will not conduct the telephone interviews with the participants. The final thank you for all participants will notify them that they might be contacted at a later time for additional study components. Any information on the reportable diseases will be transferred to a central database at CDC. Any collected bloodspots will be stored by the recipients at a local facility.

Additional study components currently include an online questionnaire for a subset of participants with selected occupations, but further online components may be developed after discussion with the recipients.

Objectives/Outcomes (continued) Component B. BD-STEPS stillbirth To improve understanding of the causes of stillbirths that will inform public health prevention efforts, up to 2 study sites will focus on conducting research focused on stillbirths. There is little information on the causes of stillbirths and what impact having a stillbirth will have on future pregnancies. Significant racial disparities exist in the occurrence of stillbirths, with non- Hispanic Black women at much higher risk of having a stillbirth than non-Hispanic White women. Mothers over the age of 35 are also at greater risk for stillbirths. Working with CDC, two BD-STEPS I study sites have developed a supplementary phone interview with questions aimed specifically at elucidating causes of stillbirth.

a. To ascertain, review and classify pregnancies that end in a stillbirth within the geographical region determined for BD-STEPS II.

b. To collect information on exposures throughout pregnancy to modifiable risk factors via a maternal telephone interview.

Women who experienced a stillbirth and women who had babies born without birth defects (controls) will be invited to participate in the BD-STEPS II core interview and after completion, they will be invited to participate in a stillbirth interview to allow for the exploration of modifiable risk factors, such as sleeping position and maternal disease and medication use throughout pregnancy.

Project management Recipients are expected to develop a management and staffing implementation plan for the proposed program. This plan should include the provision of evidence of legal authority to access data needed to accomplish the activities required by this NOFO and the recipient’s application, including HIPAA and IRB requirements. The recipient will also provide evidence of legal authority to share identifiable, individual-level contact information with CDC and its contractors and individual-level data without names and addresses with other recipients of this cooperative agreement.

Data and specimen collection The recipients are expected to identify pregnancies that end in a stillbirth without a birth defect from fetal death records, or delivery records and conduct clinical review for case confirmation.

The recipients are expected to use the same region that is being covered for BD-STEPS II Core.

The controls selected for BD-STEPS II Core will also be invited to participate in the stillbirth-specific interview.

Data reporting Recipients are expected to collect, store, and transmit data in a standardized and secure manner with common elements mutually agreed upon by CDC and recipients. On a weekly basis, recipients will transfer contact information to the central interviewer using the CDC-provided Secure Access Management Service. Recipients will be responsible for compiling mailings to be sent to parents (e.g. introductory packets, thank you letters, various reminders, etc.); these mailings will include incentives as determined by the protocol. Recipients will not conduct the telephone interviews with the participants. The final thank you for all participants will notify them that they might be contacted at a later time for additional study components.

A copy of the draft protocol is available upon request see Section VII. Agency Contacts, Scientific / Research Contact(s) Marcella Law to obtain a copy. The protocol will be finalized by CDC in consultation with the recipients after the awards are made.

Timeline Component A. BD-STEPS II Core & Component B. BD-STEPS Stillbirth The anticipated general timeline for the project will consist of 3 phases over 5 years. The aim for Phase I is to initiate data collection as soon as possible.

Phase 1: Development (Months 1-6)

Obtain IRB approval Develop the case and control ascertainment protocols Develop data sharing and publication agreements Develop and test database linkage to central tracking database Develop protocol to validate maternal self-reported medication use

Phase 2: Data collection and analyses (Months 7-54)

Active case and control ascertainment Mailings to eligible cases and controls Case review and classification Conduct maternal interviews and collection of biologic samples Implement data validation pilot project (to include 1 year of births) Analyze pilot data and select method(s) to implement studywide Implement data validation procedures for self-reported medication use Data analyses, publications, and presentations

Phase 3: Complete study, ongoing publications and dissemination (Months 54-60)

Complete ascertainment of cases and controls Complete mailings to eligible cases and controls Complete case review and classification Complete participant mailings and collection of biologic samples

Conduct analyses, write manuscripts, prepare presentations

OMB will apply, the current OMB (#0920-0010) will expire on 2/29/2020.

References:

1. Dolk H. Preventing birth defects: The value of the NBDPS case-control approach. Birth Defects Res A Clin Mol Teratol. 2015.

2. Moore CA, Yoon PW, Edmonds LD, Erickson JD. Editorial perspectives from the founding CDC leadership of the National Birth Defects Prevention study. Birth Defects Res A Clin Mol Teratol. 2015.

3. Reefhuis J, Gilboa SM, Anderka M, Browne ML, Feldkamp ML, Hobbs CA, et al. The national birth defects prevention study: A review of the methods. Birth Defects Res A Clin Mol Teratol. 2015.

4. Yoon PW, Rasmussen SA, Lynberg MC, Moore CA, Anderka M, Carmichael SL, et al.

The National Birth Defects Prevention Study. Public Health Reports. 2001;116 Suppl 1:32-40.

5. Botto LD, Lin AE, Riehle-Colarusso T, Malik S, Correa A, National Birth Defects Prevention S. Seeking causes: Classifying and evaluating congenital heart defects in etiologic studies. Birth Defects Research. 2007;79(10):714-27.

6. Rasmussen SA, Olney RS, Holmes LB, Lin AE, Keppler-Noreuil KM, Moore CA, et al.

Guidelines for case classification for the National Birth Defects Prevention Study. Birth Defects Research. 2003;67(3):193-201.

7. Rasmussen SA, Lammer EJ, Shaw GM, Finnell RH, McGehee RE, Jr., Gallagher M, et

al. Integration of DNA sample collection into a multi-site birth defects case-control study. Teratology. 2002;66(4):177-84

Target Population BD-STEPS II Core: The target population is women of childbearing potential, families contemplating pregnancy, public health care professionals, pregnant women, families of pregnancies affected by selected major birth defects, and families of children without selected major birth defects.

BD-STEPS stillbirth: The target population is women of childbearing potential, families contemplating pregnancy, public health care professionals, pregnant women, and families affected by stillbirths with and without selected major birth defects.

Collaboration/Partnerships Recipients are expected to establish collaborations between state health departments, educational institutions, other recipients under this NOFO, and with the CDC. Ideally, research centers should be a meaningful collaboration between state health departments and academic centers. When appropriate, centers should collaborate and coordinate across state agencies and clinical settings for data collection not only for the ascertainment of birth defects, but also for the ascertainment of reportable infectious diseases. Recipients should work with CDC and other recipients to develop and implement standardized processes, methods, data collection, and other project activities. Recipients will provide members for key study committees (e.g., coordinating council, data sharing committee, clinicians committee, and a biologics committee). These committees have representatives from each site including the Georgia study site at CDC and will be charged to provide guidance and oversight over all aspects of BD-

STEPS.

Evaluation/Performance Measurement BD-STEPS II Core: The recipients will be expected to provide an annual progress report 90 days after the end of each budget period containing information on the following topics: 1) the timeliness of case identification and transfer to the central database measured from date of birth to date the introduction packet was sent out; 2) the quality of the provided address information measured as rate of initial contact success; 3) the speed with which additional data (case notes, contact information) requests are addressed; 4) the number and title of manuscripts prepared with BD-STEPS or NBDPS data; 5) the number and title of presentations given on BD-STEPS or NBDPS data; and 6) the number of junior researchers that were mentored each year and a description of activities undertaken.

BD-STEPS stillbirths: The recipients will be expected to provide an annual progress report 90 days after the end of each budget period containing information on the following topics: 1) the timeliness of case identification and transfer to the central database measured from date of delivery to date the introduction packet was sent out; 2) the number and titles of manuscripts on stillbirth specific research; and 3) the number and title of presentations given on stillbirth specific research.

Translation Plan Recipients will be expected to analyze data and publish findings from BD-STEPS, as well as analyzing data previously collected for the NBDPS. All recipients will be provided access to the NBDPS pooled data upon local IRB approval and for use within the context of data sharing policies. This can include genetic analyses performed at local or external laboratories and funded through alternative funding sources. The main mode of dissemination of information to the public is expected to be through the production and publication of peer-reviewed scientific manuscripts. Each recipient will be expected to publish multiple manuscripts per year with a minimum of 10 published peer-reviewed manuscripts at the end of the 5 year project period.

The coordinating council will establish public health priorities each year, and the centers will be expected to prioritize their research accordingly. A confidential abstract draft should be provided to CDC for each manuscript developed that was supported in part or whole by this cooperative agreement; the draft should be submitted to CDC at the time the manuscript is accepted for publication. Study results will be presented at national scientific conferences and published in the peer-reviewed literature for dissemination to key stakeholders in order to facilitate translation into prevention messages.

Section II. Award Information Funding Instrument Type: Cooperative Agreement A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed:

New - An application that is submitted for funding for the first time. Includes multiple submission attempts within the same round.

Estimated Total Funding: $28,500,000 Component A: BD-STEPS II Core estimated total funding per year is $5,300,000 with the average annual amount of each award of $800,000 - $900,000. Award Floor amount is $700,000 and Award Ceiling amount is $1,000,000.

Component B: BD-STEPS Stillbirth estimated total funding per year is $400,000 with the average annual amount of each award of $200,000. Award Floor amount is $150,000 and Award Ceiling amount is $250,000.

Anticipated Number of Awards: 6 We anticipate 5-7 total awards for Component A: BD-STEPS II Core. Of these funded awards, we are also anticipating 2 awards for Component B: BD-STEPS Stillbirth.

Awards issued under this NOFO are contingent on the availability of funds and submission of a sufficient number of meritorious applications.

Award Ceiling: $1,100,000 Per Budget Period Award Floor: $700,000 Per Budget Period Total Period of Performance Length: 5 year(s)

Throughout the Period of Performance, CDC's commitment to continuation of awards will depend on the availability of funds, evidence of satisfactory progress by the recipient (as documented in required reports), and CDC’s determination that continued funding is in the best interest of the Federal government.

HHS/CDC grants policies as described in the HHS Grants Policy Statement (https://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf) will apply to the applications submitted and awards made in response to this NOFO.

Section III. Eligibility Information

1. Eligible Applicants Eligibility Category: Unrestricted (i.e., open to any type of https://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf entity above), subject to any clarification in text field entitled "Additional Information on Eligibility"

Additional Eligibility Category:

2. Foreign Organizations Foreign Organizations are not eligible to apply.

Foreign components of U.S. Organizations are not eligible to apply.

For this announcement, applicants may not include collaborators or consultants from foreign institutions. All applicable federal laws and policies apply.

3. Special Eligibility Requirements For an application to be considered, it must be responsive to the following special eligibility requirements:

Component A. BD-STEPS II CORE recipient:

1. Access to a pre-existing population-based birth defects surveillance system that can provide data on all birth defects listed in Table 1 and access to necessary data sources to ascertain liveborn control infants (i.e. vital records or birth hospital records) as evidenced by a letter from the State health department or other State or private organization.

2. Description of the selected birth population and geographic area which has to include 30,000 – 75,000 births annually as evidenced by a table listing the counties in the covered area, number of births in 2015, and race/ethnic distribution.

3. Evidence of legal access to the birth defects surveillance system is required. If the applicant is not a State health department, inclusion of a letter or memorandum of understanding from the State health department confirming the applicant has access to the necessary data sources in order to ascertain case and control subjects.

4. Access to the state’s National Electronic Disease Surveillance (NEDS) system for ascertainment of reportable infections as evidenced by a letter of support from the State's NEDS program.

Component B. BD-STEPS Stillbirth recipient:

1. Access to necessary data sources to ascertain stillborn infants (i.e. fetal death records or birth hospital records) as evidenced by a letter from the State health department or other State or private organization.

2. Description of the selected birth population and geographic area that includes 30,000 – 75,000 births annually as evidenced by a table listing the counties in the covered area, number of births in 2015, and race/ethnic distribution. This area has to be the same geographical area as described for Component A.

4. Justification for Less than Maximum Competition Not Applicable.

5. Responsiveness Evidence for these criteria must be presented in Appendix A of the application and may include:

Component A. BD-STEPS II Core

Demonstrated access to a pre-existing population-based birth defects surveillance system that can provide data on all birth defects listed in Table 1 and ensuring access to data sources necessary to ascertain liveborn control infants (i.e. vital records or birth hospital records).