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SECTION V
RESEARCH AND POLICY



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Preterm Birth: Causes, Consequences, and Prevention SECTION V RESEARCH AND POLICY

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Preterm Birth: Causes, Consequences, and Prevention 13 Barriers to Clinical Research on Preterm Birth and Outcomes for Preterm Infants ABSTRACT The complex of interrelated biological, psychological, and social factors involved in preterm birth necessitate a multidisciplinary approach to research directed at understanding its etiologies, patho-physiology, diagnosis, and treatment. This research must be conducted over a sustained period of time and requires stable funding. In addition to the scientific and clinical challenges of preterm birth, other important barriers must also be addressed. Although some of these barriers are common to all clinical disciplines, others are unique to physician scientists trained in obstetrics and gynecology. Of primary importance are the recruitment and participation of scientists in the type of investigation that must be pursued to address prematurity. Other barriers include issues related to career choices and training; the difficulties of conducting clinical investigations, particularly drug studies, during pregnancy; the relatively low levels of research funding, given the size of the problem; ethical and liability issues; and the need for coordinated scientific leadership in the field. The barriers to conducting research faced by physician scientists trained in obstetrics and gynecology were the subject of a workshop hosted by the Institute of Medicine (IOM) Committee on Understanding Premature Birth

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Preterm Birth: Causes, Consequences, and Prevention and Assuring Healthy Outcomes on August 10, 2005. Although some of these barriers are common to all clinical disciplines, others are unique to obstetricians and gynecologists. Workshop speakers addressed issues related to the workforce available to conduct research, career development, funding available for research, ethical and liability issues in reproductive research, training required for conducting reproductive research, and academic leadership challenges (see Appendix A for the agenda and participants). This chapter presents a summary of presentations on these topics. CAREER DEVELOPMENT In general, there has been a significant shortfall over time in the resources needed to train clinical investigators and to support clinical research. Numerous reports produced over the past decade have focused on the need to (1) increase the number of physician scientists (IOM 1992; IOM, 1994; Nathan and Wilson, 2003; NIH, 1997), (2) increase interdisciplinary efforts among the clinical and basic sciences (Nathan, 2002; NRC, 2004), (3) promote multidisciplinary and translational research as a means of solving complex health problems (Nathan, 2002), and (4) foster the independence of young investigators (NRC, 1994, 2000, 2005). All of these issues are relevant to fostering careers and promoting research in preterm birth. Thus, as clinical research needs are addressed more broadly, research on preterm birth—which is inherently interdisciplinary, multidisciplinary, and translational—will benefit. This section focuses on issues specific to promoting careers in clinical research on preterm birth. Training Scientists for Future Reproductive Research A major roadblock to advancing research on preterm birth and its consequences is the lack of experienced clinician scientists to conduct research and serve as mentors in obstetrics and gynecology departments as well as in pediatrics departments. Experienced mentors are needed to help research trainees plan their careers and support their development. Particularly needed are investigators who are successful with receiving funding from the federal research funding system. However, it is not clear that a significant pool of R011 grant-funded investigators is available to take on the task of mentorship in research on preterm birth. 1 R01 grants provide support for health-related research and development based on the mission of the NIH.

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Preterm Birth: Causes, Consequences, and Prevention Resources for Training Despite the continuing shortage of clinical scientists, the National Institutes of Health (NIH) has made substantial investments in the training of biomedical scientists, particularly physician scientists. Some programs have been specific to reproductive health; for example, the Reproductive Scientist Development Program. This is an obstetrics and gynecology-focused research training program for those who have completed a residency. It has had excellent success in preparing investigators who have gone on to obtain individual, extramural support, primarily from NIH. In addition, NIH’s Women’s Reproductive Health Research program and the Building Interdisciplinary Research Careers in Women’s Health program are contributing to increasing the pool of physician scientists working in areas relevant to women’s health. NIH has also instituted a program of K02 (career development) grants. Those who have achieved an R01 grant can apply for these K02 grants to gain extra protected time to pursue research. K23 awards are available for more advanced clinical research, as are the smaller research grants, R03 and R21 grants. These grants cover the complete cost of training individuals for careers in biomedical science, both doctoral scientists and physician scientists (see below). In the private sector, the American Association of Gynecology and Obstetrics Foundation (AAOGF) has partnered with the Society for Maternal-Fetal Medicine to provide 3 years of research support designed to supplement the standard 3-year clinical fellowships in maternal- fetal medicine. Each organization contributes $150,000 annually so that each fellow receives $100,000 per year for 3 years. Many, but not all, fellows study prematurity-related topics. AAOGF also has a similar partnership with the American Board of Obstetrics and Gynecology to provide research support for beginning investigators in obstetrics and gynecology. In the area of pediatrics, a 3- to 4-year postresidency physician scientist program has been established and funded by the Association of Pediatric Department Chairs, the National Institute of Child Health and Human Development, and various foundations. Despite these efforts, a shortage of clinical researchers in the areas of perinatology, neonatology, developmental disabilities, and health services remains. Knowledge in all these areas is critical to achieving a better understanding of preterm birth and its consequences for individuals who survive after they are born preterm. Importantly, few opportunities exist for pediatricians and for obstetricians and gynecologists to train and work together in active association with investigators in epidemiology and the biological, behavioral, and social sciences.

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Preterm Birth: Causes, Consequences, and Prevention Costs Cost is a significant barrier to the training of clinical scientists. The cost of training a doctoral student is about $200,000 over the course of 4 years of medical school, including a stipend and tuition.2 Graduate medical education funds for a residency position total at least $200,000, and then a 3-year fellowship in maternal-fetal medicine or neonatology costs another $200,000. A postdoctoral fellowship of 3 to 4 years to train a biomedical scientist costs another $300,000 to 400,000. Start-up expenses for a new faculty member are about $750,000.3 The Burroughs-Wellcome Fund has generated excellent data on the start-up packages that individuals receive when they take on their first independent academic position as an investigator (see below). In general, these funds do not come from NIH but, rather, are provided by research institutions. In total, it costs more than $1 million to train a physician scientist. Length of Training The research careers of both M.D. and Ph.D. investigators progress slowly. The median age at the time of the first independent appointment to a faculty position was 38 years, and progressively declining numbers of investigators under the age of 35 years are receiving research grants (data from the Association of American Medical Colleges [AAMC] faculty roster as of March 31, 2004 [NRC, 2005]). The median age at which a person receives his or her first R01 grant award is 42 years, and some investigators never receive a second R01 award (NRC, 2005). This has several implications. First, somewhere between the postdoctoral training period and the time of receipt of the first award, individuals are often unable to obtain independently the funds that they need to establish a laboratory and conduct research. In the interim, Ph.D. researchers and their departments must find alternative means of financial support. Second, for M.D. researchers, participation in clinical practice generates income and provides important clinical correlations that inform their research. However, a commitment to clinical practice that takes up more than 10 to 15 percent of their time quickly creates demands that disrupt their focus on research. Moreover, because liability insurance costs for obstetricians are high and are not related to practice volume, physician scientists conducting research related to preterm birth must pay the same malpractice insurance premiums as those 2 Data presented by Jerome Strauss, University of Pennsylvania Medical Center, at the August 2005 IOM workshop. 3 Data presented by Enriqueta Bond, Burroughs-Wellcome Fund, at the August 2005 IOM workshop.

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Preterm Birth: Causes, Consequences, and Prevention paid by an obstetrician in full-time practice. This confluence of stresses increasingly forces academic obstetrics and gynecology departments to depend on clinical revenues to pay the costs of academic programs. All of these factors discourage younger trainees who may want to pursue a career in science. Major structural changes are needed to address this issue. Without such changes, fewer individuals, particularly those in undergraduate medical education, will be willing to consider a research career. This dilemma has been the subject of a previous report of the National Academies, Bridges to Independence: Fostering the Independence of New Investigators in the Life Sciences (NRC, 2005). Need for Change The committee discussed various options for addressing this complex set of challenges to developing a critical mass of scientists from various disciplines focused on research on preterm birth. The committee determined that a systematic evaluation of the entire process of medical education as a continuum is needed. Ways to streamline postgraduate medical education for those obstetricians and gynecologists who are clearly tracking into an academic path should include some combination of residency, clinical fellowship, and research training that decreases the total postdoctoral education period—a strategy that the disciplines of internal medicine and pediatrics have used successfully—as the time that it takes to prepare a physician with no research experience for a competitive career in investigation has been underestimated. The American Board of Pediatrics, for example, has instituted several special pathways to board certification for those committed to careers as physician scientists. Special pathways should also be considered in obstetrics and gynecology. In addition, chairs in obstetrics and gynecology departments should encourage and facilitate research activities, provide appropriate start-up funding and laboratory space, and create opportunities for clinicians to conduct research on a part-time basis. Mentors—and young mentors in particular—should be recognized and compensated for their time. Despite the challenges to establishing research careers, the excitement and rewards of research should be showcased for medical students, perhaps by highlighting the success stories of some physician investigators. Finally, the changing gender demography of academicians must be addressed. Structural issues that impede the progress of women in the academic ranks need to be addressed. Family-friendly policies can facilitate the process of appointments and promotions without compromising the quality and quantity of scholarship. Furthermore, mentorship support that is gender specific and that provides guidance on how female physician scientists can manage career, family, and time should be provided. Having suc-

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Preterm Birth: Causes, Consequences, and Prevention cessful role models is also essential. These research training and faculty issues are not specific to obstetrics and gynecology, neonatology, or maternal-fetal medicine. Who Is Selecting Obstetrics and Gynecology as a Career Path? A review of those who participate in NIH’s Medical Scientist Training Program reveals that few of the talented people who are committing themselves to careers in biomedical research have selected obstetrics and gynecology as their career choice. In addition, Gariti et al. (2005) found that students considering obstetrics and gynecology as a specialty are dissuaded by lifestyle concerns (i.e., a lack of control in scheduling) and liability issues (see Box 13-1). The available data show that obstetrics and gynecology is often at the bottom of the list of the specialty choices of new physicians. Specific to research needs, too few doctors in training consider women’s health and the health of mothers as key research areas in which to pursue their scholarly work. The demographics of those entering obstetrics and gynecology are changing as well, and it is important to be sensitive to these changing demographics in terms of how individuals are prepared to pursue careers in biomedical science and clinical research. There has been a progressive increase in the number of female graduate students in the biomedical sciences and medicine. However, the record for advancement opportunities for women in obstetrics and gynecology is discouraging, even though 70 to 80 percent of those in the residency pool are women. The percentage of female full professors did not change between 1999 and 2003: it remained at 14 percent. This does not compare well with the proportions of female full professors in other areas of medicine or law (see the further discussion below).4 Career Development for Women In the 1970s, women began to see more opportunities and were prepared with the science backgrounds needed to attend medical school. At the time, more than 20 new medical schools opened in a very short period. Approximately 7 years after this increase in the numbers of female students in the early 1970s, the percentage of women faculty started to increase. During the 1970s, the percentage of men who chose the obstetrics and gynecology specialty also began to decrease. About 20 years ago, approximately 11 percent of both men and women in every medical school class 4 These data were presented by AAMC at the August 2005 IOM workshop.

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Preterm Birth: Causes, Consequences, and Prevention BOX 13-1 Obstetrics and Gynecology Workforce Data The American College of Obstetricians and Gynecologists (ACOG) has slightly more than 49,000 members, of whom more than 31,000 are practicing in the United States (personal communication, R. Hale, 2005). Of that number, 44 percent are women. An additional 1,500 osteopathic obstetricians and gynecologists practice obstetrics. Urban and suburban areas tend to have the highest concentrations of obstetricians and gynecologists; it is rare for areas with populations of less than 10,000 to have an obstetrician-gynecologist. In those areas family physicians tend to be the obstetricians, although their numbers are dropping rapidly because of the cost of liability Insurance. Approximately 1,100 residents in obstetrics and gynecology complete their training each year. Of this number slightly more than 10 percent go into subspecialty training. Of those who pursue subspecialty training, approximately 30 percent choose maternalfetal medicine, 25 percent select oncology, 30 percent enter reproductive medicine, and 20 percent select urology-gynecology. The actual numbers vary from year to year, depending on position availability (personal communication, R. Hale, 2005). As of September 2005, there were 1,165 fourth-year residents in obstetrics and gynecology. Seventy-six percent of these fourth-year residents were female (personal communication, A. Strunk, January 10 and January 12, 2006). Data from ACOG professional liability surveys indicate that in 2003, 22 percent of ACOG members decreased the amount of high-risk obstetric care that they offer, 9.2 percent decreased the number of deliveries, and 14 percent stopped practicing obstetrics altogether because of liability claims or litigation. This compares to respective proportions of 18.7, 6.3, and 8.9 percent of physicians providing affirmative responses to these questions in 1996. Because of the reduced affordability and the lack of availability of liability insurance, in 2003 25.2 percent of ACOG members reported that they decreased the amount of high-risk obstetric care that they provided, 12.2 percent reported that they decreased the number of deliveries, and 9.2 percent reported that they stopped practicing obstetrics altogether. The national response rates for the survey were 44 percent in 1996 and 45.45 percent in 2003 (personal communication, A. Strunk, January 10 and January 12, 2006). selected obstetrics and gynecology. The numbers have decreased some for women but have decreased more dramatically for men. In 2004, 8.5 percent of women and 2.1 percent of men in medical school selected obstetrics and gynecology (AAMC, 2005a). Data from the faculty roster at AAMC on individuals who pursue ca-

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Preterm Birth: Causes, Consequences, and Prevention reers in obstetrics and gynecology show that in 2004, 74.7 percent of residents in obstetrics and gynecology were women. (In 2004, 98,000 residents and fellows were training in medical schools and teaching hospitals in the United States, of whom 40,000 were women.) About 3,500 women obstetricians and gynecologists (of a total of 4,681 available positions) were in training in the United States in 2004 (AAMC, 2005a). Today in the United States women represent 51 percent of all applicants to medical school, and that figure is not increasing. In 2004, women represented 50 percent of all first-year medical students, 48 percent of all medical students, 46 percent of all graduates of medical schools, 41 percent of all residents, 30 percent of all faculty, 26 percent of all associate professors, 14 percent of full professors, and 10 percent of all department chairs. In 2004, 10 percent of all medical school deans were women. This proportion represents a doubling of the number of women deans over the last 5 years (AAMC, 2005a). Faculty Vitality As mentioned above, fewer medical students are choosing obstetrics and gynecology as their specialty, and research indicates that medical students who had inspiring teachers or a great clerkship experience are more likely to enter a specialty. A snapshot of the 2004 data that are derived annually from the Women in Medicine section of the Office for Faculty Development and Leadership of AAMC provides a framework for a discussion of what is called faculty vitality. Faculty vitality is the result of the mutual contribution of institutions and individuals to the achievement of shared goals and is a concept that can help provide a context for ways in which the career development of reproductive scientists might be considered. Faculty vitality can be thought of in terms of what needs to be offered to boost professional development and provide support. It is organized around the concepts of responsibility, capability, and community for institutions and individuals. From an institutional perspective, the policies for advancement and tenure common in the 19th century were designed to support the academic freedom of those who joined faculties at a young age, but the world has changed significantly since then and the policies have changed little. Employment policies are needed that keep faculty on track for the duration of their careers. An academic institution enhances its faculty by providing coaching, mentoring, and the other resources needed to facilitate learning. The clinical research community builds its expertise in a variety of conference settings and with funding that extends social and professional networking outside of the laboratory and that develops largely through peer-to-peer

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Preterm Birth: Causes, Consequences, and Prevention problem solving. Clinical researchers also build their professional networks through attendance at meetings. Thus, vitality for clinical researchers could be supported by considering the joint products of clinical care and research, linking collaborative research to career development. Some programs, some of which are described below, accomplish this; but not all young faculty members are aware of them. Although for both clinician scientists and Ph.D. scientists, the research is the heart of the effort on an individual level, the institution expects a contribution as well. For clinicians, that means clinical practice and grant support for research; for Ph.D. scientists it means grant support. There are several ways to help scientists in these efforts, including the documentation of activities that move researchers forward and the development of management skills related to the researcher’s career, office, and laboratory. In addition, leadership by example is needed, as is the ability to share a passion for professional activities. The following are some of the activities and programs offered nationally through AAMC that may help scientists stay engaged in academic life: The Early Career Women in Medicine Program focuses on the issues of orientation to faculty life, including determining the focus of research and how to identify the mentors, grant opportunities, and professional networks necessary to sustain a career. The Mid-Career Women in Medicine Program is for associate professors and early full professors, with a focus on how women professors may extend their professional networks and mentor others as a form of leadership. The Women Liaison Officers updates are for the women liaison officers at every medical school in the country. Faculty Vitae is a new online resource for professional development. Its features include news, resources, and lessons in leadership and management to support U.S. medical schools and teaching hospitals. The 80-hour work week was implemented to improve balance between personal and professional lives for all residents. RESEARCH FOR DRUG DEVELOPMENT The development of drugs to preterm labor encounters the same challenges encountered during the development of all drugs, as well as the additional challenges of careful adherence to human subject research guidelines when they involve pregnant women and infants. Relevant and tractable targets must be identified, followed by the development of compounds with appropriate affinities, specificities, pharmacokinetic characteristics, cytochrome P450 characteristics, safety profiles, and efficacies. Thus, the char-

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Preterm Birth: Causes, Consequences, and Prevention acteristics of the drug related to absorption, elimination, and metabolism must be evaluated. Typically, early drug development studies are conducted as Phase I trials with adult men. In the testing of drugs for the prevention of preterm labor, safety studies must be conducted early and before Phase I studies are conducted with pregnant women. In addition, studies must be able to determine the potential effect on the fetus. This slows the development of new drugs. The typical practice in the development of drugs for the prevention of preterm labor is to conduct Phase I studies with healthy nonpregnant volunteers, assess the pharmacokinetics of the drug, and then extrapolate the findings to the target population. However, pregnant women have unique physiological characteristics, including changes in the glomerular filtration rate and the up-regulation of cytochrome P450 and PGP. This means that data from Phase I studies cannot be extrapolated perfectly into this patient population, which creates more uncertainty when the drug enters Phase II studies and requires more pharmacokinetic analyses in studies with the target population. Studies of the safety of the drug are also important and must be based on sufficient studies with animals and other preclinical research. Another challenge in drug development is evaluation of the benefit of a drug. Will a delay in delivery benefit the fetus? Will chronic tocolysis be beneficial? Some preliminary evidence shows that a newborn infant who was born preterm may have a shortened stay in the neonatal intensive care unit (NICU) if the pregnancy can be prolonged. Although the shortened NICU stay might have an economic benefit, it does not necessarily translate into an overall improved clinical outcome (see Chapter 9 subsection on Information Informing Decisions Surrounding Perinatal Interventions for discussion). A delay of preterm labor at later times in gestation (for fetuses at greater than 32 weeks of gestation) may not demonstrate a significant health benefit for the infant, and the benefits of delaying preterm labor are greater at earlier gestational ages, but fewer of these pregnancies are available for study. In addition, it is ethically problematic to use a placebo control group in studies with pregnant women. Studies of new drugs are further complicated by the fact that the standard for the use of tocolytic agents varies within and among countries. No tocolytic agent has been approved for use by the Food and Drug Administration, although many agents for tocolysis are used off label (that is, for an indication other than that for which they have been approved); for example, magnesium, β2-antagonists, indomethacin, and nifedipine. Robust data for efficacy, defined as neonatal benefit, are not available for any of these therapies, however (see Chapter 9). Atosiban has been approved for use in Europe as a means of delaying delivery, but it is not approved for use in the

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Preterm Birth: Causes, Consequences, and Prevention United States because the sponsor was unable to show a significant benefit to the fetus. The lack of data on these agents makes it difficult to design ethical studies. A particularly troublesome concern is whether a reduction in mortality will result in increased morbidity, such as ventricular hemorrhage and respiratory distress. Longer-term follow-up must be performed to evaluate the effects of new drugs on certain end points, such as quality of life, quality of function, or degree of disability. Biomarkers of preterm labor are also needed to assist with determination of threatened versus actual preterm labor. The identification of biomarkers of preterm labor could refine and reduce the population to be studied and allow treatment only of those patients who are more likely to benefit. For example, one drug being pursued by pharmaceutical developers involves the oxytocin receptor. Data from in vitro and in vivo studies suggest that blockade of the oxytocin receptor is effective in delaying preterm labor. The compound being studied, 221149, is a small nonpeptide molecule that is a selective oxytocin antagonist. Any such molecule, however, must have specificity for the oxytocin receptor to avoid effects on, for example, the hemodynamics of fetal tolerance to physiological stress. The effects of the agent must also be reversible or capable of being slowed. The pharmaceutical industry is working on drugs in several areas of potential application to preterm labor and relies on teams of investigators to translate the findings from early laboratory studies—that is, Phase I and Phase IIa studies, which test the proof of concept—to clinical use. Other physician scientists are responsible for studying the drug in the later phases. Most of these studies rely heavily on the skills acquired by investigators through such programs as the Medical Scientist Training Program. To succeed in developing drugs for the prevention of preterm labor, the industry must actively recruit people who understand both the basic science and clinical medicine. In collaborating with academic scientists, industry frequently finds the policies of academic institutions regarding intellectual property and conflicts of interest to be complex obstacles, though sometimes necessary safeguards, in research. Developing drugs to prevent preterm labor is an important research area, for which many barriers exist. Study design for trials of agents is a critical problem for the pharmaceutical industry. A mechanism to facilitate product development would be to establish optimal designs through partnerships between industry, academic researchers, and the FDA. In addition, moving drug development to prevent preterm birth under the protection of public health drug law might encourage industry interest. Unfortunately, this has been proposed for other “public health” drugs such as contraceptives, but there has been little traction. As noted, family planning and access to contraception could have a significant impact on reducing prematurity. Omnibus legislation that would encourage drug develop-

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Preterm Birth: Causes, Consequences, and Prevention ment to improve all aspects of reproductive health would be a welcome advance. FUNDING FOR RESEARCH ON PRETERM BIRTH The primary sources of funding for research on premature birth and individuals who survived preterm birth are NIH, the Centers for Disease Control and Prevention (CDC), and nonprofit voluntary health or philanthropic organizations, such as the March of Dimes and the Burroughs-Wellcome Fund. These agencies and organizations support research related to the basic science of the events that lead to preterm labor, interventions that can be taken to prevent preterm labor, treatments for infants who are born preterm, and assessment of the developmental and cognitive outcomes of children who were born preterm. Detailed descriptions of the programs and funding as they were described to the committee at the workshop are provided in Appendix E. Because of the many scientific perspectives involved in understanding preterm birth, it is difficult to ascertain the total amount of funding available for research on preterm birth specifically. In particular, pinpointing the amount of funding that NIH spends on research on preterm birth is difficult because the funding is codified under a broad general category called prenatal birth-preterm low birth weight, which encompasses all research on low birth weight infants, including but not limited to those born preterm, as well as all research concerned with normal and preterm labor and fetal physiology, nutrition, and status. The separation of funding for preterm birth in particular from funding for the general category of prenatal birth-preterm low birth weight is not possible with the information on NIH funding currently available. Although NIH and CDC provide much of the federal support for research on preterm birth, other federal agencies also contribute to this effort. In addition to the information presented at the IOM committee’s workshop, additional information regarding research pertaining to preterm birth has been made available. In 2004, the Interagency Coordinating Council on Low Birth Weight and Preterm Birth of the U.S. Department of Health and Human Services (DHHS) prepared the report Inventory of Research and Databases Pertaining to Low Birth Weight, Preterm Birth, and Sudden Infant Death Syndrome (DHHS, 2004). The council compiled the inventory as a first step in stimulating multidisciplinary research, policy initiatives, and collaborations among DHHS agencies to achieve the goal of reducing infant mortality. Secretary Tommy Thompson had requested a department-wide research agenda on low birth weight and preterm birth, which, as discussed in this report, are major contributors to infant mortality. Agencies with research activities related to preterm birth prevention

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Preterm Birth: Causes, Consequences, and Prevention and infants born preterm or with low birth weights and their sequelae include the following: Administration for Children and Families Agency for Healthcare Research and Quality Centers for Disease Control and Prevention National Center for Birth Defects and Developmental Disabilities National Center for Chronic Disease Prevention and Health Promotion National Center for Health Statistics Centers for Medicare and Medicaid Services Food and Drug Administration Health Resources and Services Administration Bureau of Primary Health Care Maternal and Child Health Bureau Indian Health Service National Institutes of Health National Center for Complementary and Alternative Medicine National Center on Minority Health and Health Disparities National Heart, Lung, and Blood Institute National Institute on Alcohol Abuse and Alcoholism National Institute of Allergy and Infectious Disease National Institute of Child Health and Human Development National Institute on Deafness and Other Communication Disorders National Institute of Dental and Craniofacial Research National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Drug Abuse National Institute of Environmental Health Sciences National Institute of Mental Health National Institute of Nursing Research Substance Abuse and Mental Health Services Administration ETHICAL AND LIABILITY ISSUES IN REPRODUCTION RESEARCH Many ethical issues involved in reproduction research are being discussed and debated at this time, and some may be obstacles to this research. One issue involves whether there is a benefit to the mother and her fetus of inclusion in reproduction research and whether those who are enrolled in research are better off than those who are not. Another challenge involves the documented prevalence of off-label medication use and the professional obligation to study off-label medication use. For neonates, there has been a

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Preterm Birth: Causes, Consequences, and Prevention discussion of the need for alternative approaches to obtaining informed consent, such as a process that would facilitate research during various clinical emergencies when informed consent cannot be obtained. Other challenges include the requirement expressed in 45 CFR 46, Subpart B,5 that sufficient data from preclinical studies and clinical studies of nonpregnant women and adults are needed to assess the potential risk of an agent or treatment to pregnant women and fetuses before research can proceed; conflicts of interest of clinical investigators regarding the termination of pregnancy and the determination of viability; innovative practices, such as maternal-fetal surgery; and obtaining informed consent when the research offers only the prospect of a direct benefit to the fetus. A statement by the Committee on Ethics of the American College of Obstetricians and Gynecologists notes a concern that the recognition of distinct paternal rights before the birth of a child might undercut the mother’s autonomy. Therefore, if the research would be of direct benefit to the woman and the fetus, only the mother’s informed consent is required. Regulations for Protecting Human Subjects of Research Two issues that deserve focus because of the applicability of 45 CFR 46, Subpart B, are research at the threshold of viability and the ability of adolescent pregnant women to consent to research. In the 2001 revision to Subpart B, the term neonate was used as applied to research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates. Subpart B defines a viable neonate as one that, given the benefit of medical therapy, is able to survive after delivery to the point of independently maintaining a heartbeat and respiration. The National Human Research Protections Advisory Committee of the DHHS Office for Human Research Protections expressed concern about this definition, pointing out that, in fact, many neonatal patients are of uncertain viability and are kept alive for days, weeks, and perhaps months and that depending on how this definition is applied, some infants would now be considered premature under this definition (see Box 13-2 for a further discussion.) Institutional review boards (IRBs) are struggling with how to apply the concept discussed in Box 13-2, particularly the differences between minimal risk and no added risk. 5 Note that 45 CFR 46, Subpart B, applies only to research that is funded or supported by DHHS.

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Preterm Birth: Causes, Consequences, and Prevention In reviewing the clinical causes of prematurity, the adolescent pregnant woman is an important subpopulation of interest. There are two basic approaches to obtaining informed consent from an adolescent woman, particularly if the parent is not involved. The first are the so-called mature minor state statutes, and the second is emancipation. A mature minor is someone who is thought to be able to make decisions about clinical care, including sexually transmitted diseases and family planning, without parental involvement. An emancipated individual is one who qualifies as a legal adult, even though he or she is under the usual age for attaining legal adulthood. It is unclear whether the pertinent legal statutes and principles apply to research. State law often does not address research. Therefore, researchers must rely on the interpretation of legal counsel at a particular institution about the applicability of state law, which leads to a wide degree of variability (Campbell, 2004). When the FDA adopted the informed consent regulations that apply to the pediatric population, the agency specifically chose not to adopt the section of the DHHS research regulations that covers waivers of informed consent. Although some IRBs have allowed adolescents to provide informed consent for research in situations in which the adolescents were thought to be mature enough to make their own decisions about treatment, drug research with this population requires parental permission. Although there is no question that protecting human subjects is important and that oversight in this area is needed, it is also clear that there is a point at which the protection processes involved may impede the ability to do meaningful and important research if the IRB bureaucratic requirements become overwhelming. Inappropriate delays can deprive patients of beneficial research advances and increase the costs to the institution, NIH, and the individual researchers. This problem is especially relevant to research on preterm births and infants born preterm. To address these issues, some institutions have formed a specific IRB subcommittee related to pregnancy and neonatology that comprises experts in pregnancy and neonatology who review research protocols only in those areas of study. This recent innovation has streamlined the process, but it is not known how common this practice is at universities that perform obstetric and neonatal research with many participants. However, concerns remain that the regulatory demands that have been imposed on clinical researchers over the last 5 to 10 years are making it extremely difficult to conduct large-scale, multi-institutional clinical care-related research on the problems of preterm birth and those encountered by infants born preterm.

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Preterm Birth: Causes, Consequences, and Prevention BOX 13-2 Research Involving Pregnant Women and Neonates Pregnant women or fetuses may be involved in research if all of the conditions that are listed in the federal regulations at 45 CFR 46.204 are met. There should be sufficient preclinical and clinical data to assess potential risks to pregnant women and fetuses. Absent the prospect of direct benefit for either the pregnant woman or the fetus, the risk to the fetus must be minimal and the knowledge to be obtained must be important and unobtainable by any other means. The definition of minimal risk is defined in 45 CFR 46 as follows: “Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” If the research holds out the prospect of direct benefit solely to the fetus, then the consent of the pregnant woman and the consent of the father are obtained in accord with the informed consent provisions of 45 CFR 46, Subpart A, except that the father’s consent need not be obtained if he is unable to consent because of “unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest.” Otherwise, the consent of the pregnant woman is sufficient. For children who are pregnant, assent and permission must be obtained in accord with the provisions of Subpart D of 45 CFR 46. In addition, there must be an independent assessment of the viability of the neonate. Neonates of uncertain viability and nonviable neo- Liability Issues Obstetricians and gynecologists are charged significantly higher premiums for liability insurance than physicians in other specialties (MacLennan et al., 2005). When clinical departments must pay $150,000 or $165,000 a year for a faculty member’s malpractice insurance, as they are in Pennsylvania and Alabama, respectively, it absorbs resources that might otherwise be available to support research. The AAMC Report on Medical School Faculty Salaries, 2003–2004 (AAMC, 2005b) shows that the mean compensation for an assistant professor of maternal-fetal medicine breaks down by region as follows: $205,000 for the Northeast, $220,000 for the South, $234,000 for the Midwest, and $196,000 for the West. The addition of the annual compensation and the annual liability insurance premium in New Jersey and Florida, for example, gives total costs of $308,235 and $411,700, respectively, illustrating just how expensive it is to provide protected time

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Preterm Birth: Causes, Consequences, and Prevention nates may be involved in research if the following conditions are met: neonates of uncertain viability may not be involved in research unless the research holds out the prospect of enhancing the probability of survival of the neonate to the point of viability and any risk is the least possible for achieving that objective, or the purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means and there will be no added risk to the neonate resulting from the research. If neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent’s legally authorized representative can be obtained. After delivery a nonviable neonate may not be involved in research unless all of the following additional conditions are met: (1) the vital functions of the neonate will not be artificially maintained; (2) the research will not terminate the heartbeat or respiration of the neonate; (3) there will be no added risk to the neonate resulting from the research; (4) the purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means; and (5) the legally effective informed consent of both parents of the neonate is obtained (unless either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, or the consent of the father need not be obtained if the pregnancy resulted from rape or incest). The consent of a legally authorized representative of either or both of the parents of a nonviable neonate will not suffice. SOURCE: G. R. Baer and R. M. Nelson, A Review of Ethical Issues Involved in Premature Birth (Appendix C of this report). for research (Gibbons, 2005). Decreased reimbursement from government and third part payers also contributes to the decreased ability of clinical departments to support investigators. NIH research grants pay a relatively small percentage of the expense of the research enterprise. The remainder primarily comes from funds generated from patient care, and if those funds are being used for liability insurance, little is left to support the academic department’s research infrastructure. The individual obstetrician and gynecologist trying to conduct research must earn enough income to pay for malpractice insurance. This requires 4 or 5 days of patient care services each week, which leaves virtually no time for clinical research (Chauchan et al., 2005). Support mechanisms by which insurance issues can be minimized should be considered. Aside from federal or state action to limit medical liability awards, other solutions could come in the form of increased grant support

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Preterm Birth: Causes, Consequences, and Prevention or through changes in insurance company liability policies. For example, grant supports could share part of the liability insurance costs for the time investigators spend in clinical research. Two changes in insurance company liability policies that would be helpful are known as “split positions” and “split assignments.” A split position involves two doctors each working half time and each paying half of a premium instead of a full one. A split assignment occurs when one doctor spends 50 percent of her or his time in clinical research and the other 50 percent of her or his time taking care of patients. In such a case it would be helpful if that doctor could pay half the full-time premium or if the premium could be significantly reduced. All of these obstacles to research in this area contribute to the mood of the faculty and the culture of the institution, which are much more negative than they have been in the past. It is not surprising that students and residents who listen to clinical researchers in obstetrics and gynecology talk about liability issues, the difficulties involved in working with IRBs, and increased regulations become unenthusiastic about doing clinical research in obstetrics and gynecology. LEADERSHIP CHALLENGES AND NEEDS Preterm delivery is a complex problem, with genetic, immunologic, infectious disease, environmental, social, and psychological dimensions. It produces a syndrome that is hidden until its manifestation as preterm labor; however, the events responsible for preterm labor might have occurred at any time before its initiation, even as far back as the development of the mother as a fetus. Because of its complexity, few inroads into the prevention and treatment of preterm birth have been made. However, there have been successes in gaining a better understanding of some of the mechanisms implicated in preterm birth. These could lead the way to more treatment trials. Such trials, however, must be more specific and focused on smaller and more well-defined cohorts. Despite the efforts of the research community to develop new strategies to prevent and treat preterm labor, they have been insufficient. At the federal level, the Advisory Committee on Infant Mortality, established to advise the DHHS secretary on the department’s programs to reduce infant mortality and improve the health of pregnant women and infants, called attention to the problem of preterm delivery and recommended the establishment of an interagency working group on low birth weight and preterm birth to stimulate multidisciplinary research, scientific exchange, and collaboration among DHHS agencies (ACIM, 2001). NIH-sponsored individual research grants are an important component in progress, but more concerted and concentrated efforts must be made to build multidisciplinary investigative teams and develop new investigators

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Preterm Birth: Causes, Consequences, and Prevention mentored and led by more experienced investigators in specialized centers that focus on the problems related to preterm birth. This will require a higher level of funding than is currently available and funding sustained over a period of time that allows a research infrastructure to be created and sustained so that new knowledge can be developed. Medical schools and academic medical centers should facilitate and encourage research programs in their obstetrics departments. In addition, obtaining R01 grants are seen as critical for judging junior faculty for appointments and promotions. Given the importance of multidisciplinary approaches in research and availability of other funding sources such as U grants, K grants, and other contracts, these should also be viewed as important in the promotion process. A few universities have built active research programs by reallocating research dollars obtained from clinical revenues. This approach allows the creation of an infrastructure that can focus on obtaining future funds through grants. This is essential to identifying and recruiting basic scientists and physician scientists with expertise in statistics, epidemiology, nutrition, immunology, muscle physiology, molecular biology, microbiology, and other relevant disciplines. Building such a program requires a sustained commitment on the part of the department chair. Once the program is established, clinical data sets must be created and maintained. These data sets can then be used for the preparation of grant applications. The collection of baseline data provides resources for analysis by young investigators, which facilitates the development of new ideas. This may involve relationships with large clinical care providers to provide access to more data. A few programs have advanced from a retrospective database or chart review approach to include analysis of existing biological samples, prospective cohort studies, randomized trials, and multidisciplinary, multicenter studies. Trainees are more likely to be drawn to such centers because of the strength and vitality of the clinical research program. Challenges in Building a Sustainable Research Enterprise Research progress on preterm birth and infants born preterm will require scientists from many disciplines working in concert. Physician scientists from obstetrics and gynecology are an important component of such teams. What is needed is a paradigm shift in the field of obstetrics and gynecology to provide clinical investigators who can translate the research findings that come from basic science laboratories or pharmaceutical companies into new clinical diagnostic and treatment knowledge. The research training of such individuals is a high priority. It is estimated that only 50 physicians in departments of obstetrics and gynecology received NIH training or career development support between 1980 and 1990. During that same time period, 112 obstetricians and gynecologists were funded with

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Preterm Birth: Causes, Consequences, and Prevention R01 grants, an average of 12 a year. The track record has been worse for training grants. However, there has been some progress. In 2004, 31 departments of obstetrics and gynecology had more than five NIH awards. There needs to be increased recognition of the importance of research in obstetrics, whether it is done in a basic science department or a clinical department in the context of an academic medical center. In addition to neonatology, pediatrics, and obstetrics and gynecology departments, other departments need to include investigations of preterm birth in their research programs. Importantly, deans of medical schools should expect their obstetric and gynecology departments to develop research programs that address preterm birth and should support them in those efforts. Medical schools and research institutions need to create opportunities for physician scientists to conduct research on preterm birth by providing protected time, funds, and appropriate ethical guidance and oversight. Obstetrics research is difficult for obstetricians and gynecologists because they must spend large amounts of time in practice. Therefore, an infrastructure like those that exist in research-intensive departments is also needed to assist with manuscript preparation, grant applications, and administrative activities that support clinical practice and research. Appropriate leadership, administrative structures, and organizations will facilitate the changes that are needed to make more progress on reducing the rates of preterm birth. This may require the creation of a center of excellence that is outside of departments of obstetrics and gynecology but that is associated with them and that has an administrative structure different from that of departments of clinical medicine. Although NIH has helped to build faculties in obstetrics and gynecology in schools of medicine, NIH cannot provide complete support for faculty members. Serious research programs must be prepared to share the costs for the faculty time and the resources needed to attract and train talented investigators who are committed to careers in biomedical research on preterm birth and its consequences. Finding 13-1: There is need for a major focus on the problem of preterm birth. This will require the efforts of individuals from a broad spectrum of clinical, basic, and social science disciplines; the recruitment of more investigators; and increased funding. There are special barriers to the recruitment and participation of physician scientists who are trained in obstetrics and gynecology, such as a paucity of departments of intensive research in obstetrics and gynecology, the length of time required for combined clinical and research training, and the cost of liability insurance that is not proportional to clinical activity.