USE OF ESTROGEN DOES NOT REDUCE RISK OF DEMENTIA IN OLDER WOMEN

Contrary to findings in several previous studies, estrogen therapy does not decrease, but rather may increase, the risk for dementia in older, postmenopausal women, according to a study in the June 23 JAMA. Sally A. Shumaker, PhD, of Wake Forest University School of Medicine in Winston-Salem, with investigators from the Women’s Health Initiative Memory Study (WHIMS) sought to determine whether conjugated equine estrogens alone decreased an older woman’s risk for dementia or mild cognitive impairment. The WHIMS previously found an increased risk for dementia and no effect on mild cognitive impairment in women treated with estrogen plus medroxyprogesterone acetate.

The WHIMS—an ancillary study to the Women’s Health Initiative—consisted of randomized, double-blind, placebo-controlled clinical trials of estrogen or estrogen plus progestin in community-dwelling women ages 65 to 79. The studies were conducted from June 1995 to July 8, 2002 (estrogen plus progestin; n = 4,532), or to February 29, 2004 (estrogen-alone; n = 2,947). Participants in the estrogen-alone trial received either one daily tablet containing 0.625 mg of estrogen or matching placebo; in the estrogen plus progestin trial, they received either one daily tablet containing estrogen (0.625 mg) plus progestin (2.5 mg) or matching placebo.

In the estrogen-alone trial, 47 participants were diagnosed with probable dementia, of whom 28 had been assigned to receive estrogen and 19 to receive placebo. During follow-up, the incidence of probable dementia was 49% higher among women assigned to receive estrogen compared with those receiving placebo, but this difference was not significant, the investigators reported.

Incidence rates for probable dementia in the estrogen-alone trial were statistically similar to those in the estrogen plus progestin trial. When data from the two trials were pooled, the overall risk for probable dementia was significantly increased by 76%. After excluding participants with certain baseline scores at or below the cut point, suggesting early cognitive decline, risk for probable dementia increased a nonsignificant 77% in the estrogen-alone trial and a significant 2.19 times in the pooled trials.

The risk of being diagnosed with mild cognitive impairment in the estrogen group was increased a nonsignificant 34% compared with the placebo group. In the combined trials, the risk was similar. The women assigned to estrogen had a significant 38% increased risk of having either mild cognitive impairment or probable dementia at some time during the trial, compared to the women assigned to placebo. “Use of hormone therapy to prevent dementia or mild cognitive impairment in women 65 years of age or older is not recommended,” the authors concluded.

In an accompanying editorial, Lon S. Schneider, MD, from the University of Southern California, Los Angeles, noted that some important questions regarding estrogen therapy remain. “Most important is whether short-term use of estrogen over several years in early postmenopause is effective in reducing dementia two or three decades later. This is the crux of the observational data, suggesting that previous hormone therapy during a critical period is protective while recent or current use is not. By initiating hormone therapy at an approximate mean age of 71 years and following up patients to four to five years, WHIMS is intervening fairly late in life while seeking to identify relatively infrequent earlier-onset Alzheimer’s disease cases around age 75 years.”

Dr. Schneider added that “the WHIMS results do not prove that estrogen therapy has no effect on Alzheimer’s disease or dementia, but they do clearly indicate that women older than 65 should not be treated with estrogen with or without progestin to prevent dementia or enhance cognition.”

Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291:2947-2958.
Schneider LS. Estrogen and dementia: insights from the Women's Health Initiative Memory Study. JAMA. 2004; 291:3005-3007.

ANTIBIOTICS MAY PREVENT MENINGITIS OUTBREAKS

The risk of meningococcal disease in household contacts of a patient can be reduced by an estimated 89% if they take antibiotics known to eradicate meningococcal carriage, according to a report in the June 5 BMJ. Bernadette Purcell, of the Communicable Disease Surveillance Centre in Gloucester, UK, and colleagues recommended chemoprophylaxis for the index patient and for all household contacts.

The researchers analyzed the evidence for antibiotics preventing further cases of meningococcal disease through chemoprophylaxis given to the index patient, household contacts, and children in day care settings after a single case. They reviewed studies that included at least 10 cases in which outcomes were compared between treated and untreated groups. The main outcome measure was subsequent cases of meningococcal disease one to 30 days after onset of disease in the index patient. Ultimately, four observational studies and one small trial met the inclusion criteria.

Meta-analysis of the studies on chemoprophylaxis given to household contacts showed a significant reduction in risk, according to the researchers. The number needed to treat to prevent a case was estimated as 218. Primary outcome data were not available in studies of chemoprophylaxis given to the index patient. When prophylaxis had not been given, the rate of carriage after discharge from the hospital was estimated as 3%, probably an underestimate of the true rate, noted Ms. Purcell’s group. No studies of chemoprophylaxis in day care settings were identified that met the inclusion criteria.

“We found that if household contacts of a patient with meningococcal disease are given prophylaxis with antibiotics that eradicate meningococcal carriage there are fewer subsequent cases,” Ms. Purcell and colleagues reported. “The reduction in risk is considerable.”

The main difficulty, however, in interpreting the findings is that they were obtained from retrospective observational studies, the investigators pointed out. “Risk factors for meningococcal disease, such as young age, male sex, passive smoking, and lower socioeconomic status, are all potential confounding factors. None of the studies took account of these factors in their analysis. There is evidence that people of lower socioeconomic status are less likely to receive preventive interventions. If this were the case for meningococcal disease, these observational studies would overestimate the true benefit of treatment. On the other hand, adults have a lower baseline risk of disease and if children were more likely to get prophylaxis than adults this would underestimate the true effect.”

Purcell B, Samuelsson S, Hahné SJM, et al. Effectiveness of antibiotics in preventing meningococcal disease after a case: systematic review. BMJ. 2004;328:1339-1342.

PERINATAL FACTORS IN AUTISM

Autism is unlikely to be caused by a single obstetric factor, according to a report in the June Archives of General Psychiatry. Emma J. Glasson, PhD, and colleagues in the School of Population Health at the University of Western Australia, Crawley, asserted that “the increased prevalence of obstetric complications among autism cases is most likely due to the underlying genetic factors or an interaction of these factors with the environment.”

The investigators arrived at their conclusion by examining 465 cases of children born in Western Australia between 1980 and 1995 and diagnosed with an autism spectrum disorder per DSM criteria (314 autism, 67 Asperger syndrome, 84 pervasive developmental disorder not otherwise specified). The cases were compared to their siblings (481) and a random population-based control group (1,313) for the following variables:

• Parental characteristics, including maternal and paternal age at the time of the infant’s birth.
• Pregnancy characteristics, including such complications as threatened abortion prior to 20 weeks’ gestation, urinary tract infection, preeclampsia, antepartum hemorrhage, premature membrane rupture.
• Labor and delivery characteristics, including type of anesthesia, labor onset, labor complications, hours of labor, type of delivery, and birth presentation.
• Infant characteristics, including birth order, gestational age, head circumference, length, weight, Apgar scores at 1 and 5 minutes, time to spontaneous respiration, and time spent in special care.

Dr. Glasson reported that case parents were significantly older than control subject parents (28.62 versus 27.01 for case mothers and control mothers, respectively, and 31.74 versus 30.13 years for case fathers, respectively). Among case mothers, 37.6% had at least one pregnancy complication, compared with 32.4% of control mothers. Threatened abortion before 20 weeks’ gestation, use of anesthesia, no labor, induced labor, or labor duration less than one hour were all more common in case mothers than control mothers. Case mothers also had a greater frequency of labor complications (62.4% versus 51.8%) including postpartum hemorrhage, and were more likely to have either an elective or emergency cesarean delivery, she noted.

Regarding the infants themselves, the investigators reported that case infants were more likely than their siblings or control infants to have experienced fetal distress (odds ratio, 1.64), and were more likely to have taken more than one minute before the onset of spontaneous respiration. There were no differences between cases and their siblings or controls for gestational age, premature birth, weight for gestational age, head circumference, or length, they said.

“The findings indicate that individuals diagnosed within the autism spectrum are more likely to have experienced obstetric difficulties during pregnancy, labor, delivery, and the neonatal period compared with people without an autism diagnosis,” Dr. Glasson wrote. This is in agreement with previous studies, she remarked. “The strongest findings were increased maternal age and a threatened abortion during pregnancy”; however, “it is unlikely that single factors or events cause autistic disorders, although it is possible that early nongenetic influences may act on the causal pathway for some cases. The observed complications are generally nonspecific and cannot predict autism development,” she noted.

NR

Glasson EJ, Bower C, Petterson B, et al. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry. 2004;61:618-627.

—C. Justin Romano and Colby Stong

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