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industry for compensation or any other form of remuneration3 (see Table). This includes senior staff in the office of the director; directors and deputy, clinical, and scientific directors at the institutes and centers; and members of the extramural staff. Some scientists which ones and how many have not been determined would be allowed to engage in outside consulting. They would be subject to a stricter internal approval process and new limits, such as a proposed maximum of 400 hours of outside consulting per year and a proposed compensation cap of 25 percent of their base salary. Zerhouni also intends to prohibit the holding of stock in individual biotechnology and pharmaceutical companies as is done at the Food and Drug Administration. He will increase the number of senior managers who must publicly disclose their compensated activities and the amounts received.3 The number of employees who would be subject to these rules has not been determined. Some are urging tougher standards that would ban or nearly ban drug-industry payments to all NIH employees. In a report issued in July, Marilyn Glynn, the acting director of the Office of Government Ethics, discussed a permissive culture that has existed at the NIH and noted that expanded disclosure is not a substitute for appropriate substantive standards of ethical conduct. Without broader restrictions than those currently contemplated, the institutes could give the appearance that some level of misuse of office is tolerable.

Conflicts of Interest at the NIH Resolving the Problem

There are ongoing investigations by the Office of Inspector General of the Department of Health and Human Services and the Government Accountability Office, and there may be more congressional hearings after Labor Day. The NIH seeks to eliminate the possibility that the activities of its employees could harm its public health mission because of real or perceived conflicts of interest. The biggest challenge for all of us is the uncertainty, Kington said. We are in the midst of drafting the final proposed regulations. We are in the midst of completing some of the investigations that are under way. I am optimistic that once we finalize what the rules will be, this will be behind us. For the moment, however, it is still unclear how restrictive the new rules will be and how many employees will be affected. The NIH has made progress, but its conflict-of-interest problem has yet to be resolved.
1. Willman D. Stealth merger: drug companies and government medical research. Los Angeles Times. December 7, 2003:A1. 2. Steinbrook R. Financial conflicts of interest and the NIH. N Engl J Med 2004;350:327-30. 3. Zerhouni EA. Testimony before the House Energy and Commerce Oversight Investigations Subcommittee, June 22, 2004. (Accessed August 13, 2004, at http://olpa.od.nih.gov/hearings/ 108/session2/testimonies/conflictc.asp.) 4. Report of the National Institutes of Health Blue Ribbon Panel on Conflict of Interest Policies: a working group of the Advisory Committee to the Director National Institutes of Health, June 22, 2004. (Accessed August 13, 2004, at http://www.nih.gov/about/ ethics_COI_panelreport.pdf.) 5. Willman D. NIH is pressured to bar drug industry stipends. Los Angeles Times. August 6, 2004:A1.

SIDS A Syndrome in Search of a Cause

Michael H. Malloy, M.D.
Related article, page 978

The sudden infant death syndrome (SIDS) was initially defined in 1969 with the goal of identifying infants who had similar characteristics before sudden death so that a common underlying mechanism of death might be discovered. The original definition was quite broad, and its development was driven in part by parents of infants whose deaths were unexplained. Since then, the definition has been refined, first by an expert group convened by the National Institute of Child Health and Human Development (NICHD) and more recently by an expert panel of forensic pathologists whose defini-

tion includes several categories of SIDS. This most recent approach defines SIDS generally as the sudden unexpected death of an infant less than 1 year of age, with the onset of the fatal episode apparently occurring during sleep, that remains unexplained after a thorough investigation including performance of a complete autopsy and review of the circumstances of death and the clinical history.1 Despite attempts to define SIDS, the classification of deaths of infants and the tracking of trends in SIDS in the United States remain inexact. The classification of a death as caused by SIDS depends

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SIDS A Syndrome in Search of a Cause

Figure. Rates of Sudden, Unexplained Infant Death and Death Due to SIDS. The specific diagnosis of SIDS was not used for reporting sudden, unexplained infant deaths in the United States until after 1978. The number of sudden, unexplained infant deaths the majority of which were attributed to SIDS peaked in 1979; it began to decrease sharply after 1992.

on a death certifiers compliance with the current definition of the syndrome and the version of the International Classification of Diseases (ICD) coding for the underlying cause of death that is currently in use by the National Center for Health Statistics. After SIDS was defined in 1969, the number of sudden, unexplained deaths of infants reported in the United States began to increase dramatically (see Figure). In 1979, the rates of death due to SIDS began to be published in the Vital Statistics of the United States (Vol. II, Mortality, Part A) as a separate category of death; SIDS accounted for the vast majority of sudden, unexplained infant deaths. In 2001, the deaths of 2234 infants in the United States were attributed to SIDS.2 A number of casecontrol studies conducted between 1970 and 1990 in Europe, Australia, and New Zealand reported an association between the prone positioning of infants for sleep and the occurrence of SIDS. Although no specific mechanism had been identified, hypotheses to explain the risk associated with prone positioning included oropharyngeal obstruction, rebreathing with associated hypoxia and hypercarbia, and overheating. On the basis of these observations, several investigators began advocating positioning infants on their backs for sleep recommendations that were highly publicized in the lay press. Subsequently,

preliminary reports from New Zealand and the United Kingdom showed decreases in the incidence of SIDS. In the United States, the Task Force on Infant Positioning and SIDS of the American Academy of Pediatrics (AAP) published a document in 1992 recommending that infants be placed on their backs for sleep in order to prevent SIDS.3 The NICHD then joined forces with the AAP and several SIDS Alliance groups to begin a national Back to Sleep campaign in 1994.4 Thanks to this effort, the proportion of infants in the United States who were placed in the prone position for sleep was reduced from approximately 70 percent in 1992 to 20 percent in 1998, and the number of deaths classified as caused by SIDS decreased by more than 50 percent between 1992 and 2001. Although much of this decrease is probably attributable to the avoidance of the prone position, it is possible that some of the reduction may be explained by alternative classifications of these deaths. In this regard, it is notable that the rate of SIDS continued to decrease from 1999 to 2001, while the overall postneonatal mortality rate stabilized.2 Given the difficulty of identifying the features of a sudden infant death that make it classifiable as SIDS, it is perhaps understandable that little progress has been made in identifying a particular cause or causes of this syndrome. Whereas a classic epidemiologic investigation involves definite clinical and pathological findings that can be used to identify a disease state, a diagnosis of SIDS essentially indicates the absence of a known explanation for the death. Demographic characteristics of the mother that are associated with SIDS thus reflect the characteristics of populations at risk for other causes of infant death namely, youth, a low level of education, and disenfranchisement. Other risk factors for SIDS such as preterm birth and maternal smoking have not been shown to be causally related to SIDS by any specific mechanism and are known to be associated with other causes of infant death. Bed sharing has been associated with SIDS, primarily in association with mothers who smoke or abuse alcohol or drugs. Rates of recurrence within families remain uncertain, and when SIDS occurs in two or more siblings, concern may be aroused about possible infanticide. The hypothesis that SIDS occurs in biologically vulnerable infants who are exposed to an environmental risk factor implies that these infants should be identifiable before the event. Recordings of neo-

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natal cardiorespiratory activity in large populations, however, have not been useful for prospective identification of such infants. In this issue of the Journal, Smith et al. (pages 978986) report a positive association between second-trimester levels of maternal serum alphafetoprotein and the subsequent risk of SIDS. They conclude that the association may be mediated in part through impaired fetal growth. Alpha-fetoprotein, however, is a nonspecific marker of placental and fetal dysfunction that may be associated with a number of causes of fetal and infant death. The clinical importance, relative to other demographic and behavioral risk factors, of the observed doubling of the risk of SIDS that is associated with a second-trimester alpha-fetoprotein level in the fourth or fifth quintile as compared with the lowest quintile remains uncertain. The cause of SIDS is not all that remains unknown about this syndrome. A clearer, more iden-

SIDS A Syndrome in Search of a Cause

tifiable presentation and a more precise definition would also be helpful. In the meantime, one hopes that as death-scene investigations and autopsy procedures become more thorough and widespread, the number of infant deaths that are sudden and unexplained will continue to diminish.
From the Department of Pediatrics, University of Texas Medical Branch, Galveston.
1. Krous HF, Beckwith JB, Byard RW, et al. Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach. Pediatrics 2004;114:234-8. 2. CDC Wonder. Compressed mortality file: underlying cause of death: mortality for 1979-1998 with ICD 9 codes: mortality for 1999-2001 with ICD 10 codes. (Accessed August 13, 2004, at http:// wonder.cdc.gov/mortSQL.html.) 3. AAP Task Force on Infant Positioning and SIDS. Positioning and SIDS. Pediatrics 1992;89:1120-6. [Erratum, Pediatrics 1992; 90:264.] 4. Willinger M, Hoffman HJ, Hartford RB. Infant sleep position and risk for sudden infant death syndrome: report of meeting held January 13 and 14, 1994, National Institutes of Health, Bethesda, MD. Pediatrics 1994;93:814-9.

Body Fat, Leptin, and Hypothalamic Amenorrhea

Rexford S. Ahima, M.D., Ph.D.
Related article, page 987

Hypothalamic amenorrhea can be defined as the cessation of menstruation due to a dysfunction of hypothalamic signals to the pituitary gland, resulting in a failure of ovulation. Typically, young women who are affected by the condition have no obvious structural abnormalities of the hypothalamus or the rest of the brain, pituitary gland, or ovaries. The common type of hypothalamic amenorrhea (also called functional amenorrhea) is a diagnosis of exclusion. Hyperprolactinemia, primary deficiency of gonadotropin-releasing hormone, and other hormonal abnormalities must be ruled out. Affected women are reportedly more likely to be underweight, athletic, engaged in intellectual professions, or exposed to social stress than women without the disorder. Hypothalamic amenorrhea may be preceded by a history of irregular menses and may last several months to years. When it occurs in association with weight loss or intense exercise, hypothalamic amenorrhea is considered to result from energy deficiency. Deficits in nutrients, hormonal perturbations, or both may signal to the brain, lead-

ing to the disruption of the pulsatile secretion of gonadotropin-releasing hormone and luteinizing hormone as well as of the menstrual cycle. On the other hand, hypothalamic amenorrhea has also been described in nonathletic women of normal weight a variant that may be associated with psychogenic factors such as stressful life events or adverse childhood experiences. Moreover, psychogenic amenorrhea, like exercise-related amenorrhea, has been associated with subtle deficits in calorie and macronutrient intake, as well as with neuroendocrine abnormalities. Thus, a central signal related to energy deficit may be the common factor underlying the two forms of hypothalamic amenorrhea (see Table). Hormonal evaluation in women with functional amenorrhea often reveals a reduction in the mean and pulsatile gonadotropin secretion and a diminished estradiol concentration during the early follicular phase of the menstrual cycle. Other hormonal abnormalities may include a slight increase in the cortisol level and a suppression of thyrotropin and thyroid hormone. Osteopenia may be present,

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