Clinical consequences of MRI activity in treated multiple sclerosis.

BACKGROUND: Inflammation on brain MRI is the most sensitive marker of disease activity in multiple sclerosis (MS) but its clinical consequences remain controversial. OBJECTIVE: Here we investigated the clinical consequences of MRI activity in MS subjects treated with two different first line disease modifying agents. METHODS: Seventy-five treatment-naïve subjects with relapsing-remitting MS (N = 61) or clinically isolated syndromes at risk of MS (N = 14) from the BECOME study that had been randomized to interferon beta-1b (N = 39) or glatiramer acetate (N = 36) and followed for up to two years by monthly brain MRI optimized to detect inflammatory activity were studied for the clinical consequences of lack of MRI remission. RESULTS: MRI remission occurred in 46.4% of participants transiently and in 23.2% completely while it was never achieved in 30.4%. There was no difference by treatment in MRI remission, progression of physical disability, or cognitive function. The percentage of relapse-free subjects was 87.5% for the group in complete MRI remission, 47.6% in the group never in remission and 59.4% in the group in transient remission (p = 0.017). Similar differences were observed for six-month-confirmed worsening of ambulatory function as measured by the timed 25 foot walk (p = 0.026) and by Expanded Disability Status Scale (EDSS) (p = 0.10). Cognitive function was lowest at baseline for the group that never reached MRI remission on treatment; this group improved the least upon repeated cognitive testing during the two years of treatment (p < 0.001). CONCLUSIONS: Lack of MRI remission during treatment with interferon beta-1b or glatiramer acetate is associated with higher relapse rate and worsening of physical and cognitive function.

Linear derivatives of Saccharomyces cerevisiae chromosome III can be maintained in the absence of autonomously replicating sequence elements.

Replication origins in Saccharomyces cerevisiae are spaced at intervals of approximately 40 kb. However, both measurements of replication fork rate and studies of hypomorphic alleles of genes encoding replication initiation proteins suggest the question of whether replication origins are more closely spaced than should be required. We approached this question by systematically deleting replicators from chromosome III. The first significant increase in loss rate detected for the 315-kb full-length chromosome occurred only after all five efficient chromosomal replicators in the left two-thirds of the chromosome (ARS305, ARS306, ARS307, ARS309, and ARS310) had been deleted. The removal of the inefficient replicator ARS308 from this originless region caused little or no additional increase in loss rate. Chromosome fragmentations that removed the normally inactive replicators on the left end of the chromosome or the replicators distal to ARS310 on the right arm showed that both groups of replicators contribute significantly to the maintenance of the originless chromosome. Surprisingly, a 142-kb derivative of chromosome III, lacking all sequences that function as autonomously replicating sequence elements in plasmids, replicated and segregated properly 97% of the time. Both the replication initiation protein ORC and telomeres or a linear topology were required for the maintenance of chromosome fragments lacking replicators.

Serum levels of CXCL13 are elevated in active multiple sclerosis.

There is increasing recognition of the important role that B cells play in the pathogenesis of multiple sclerosis (MS). Recently it was reported that the B cell chemokine CXCL13 is elevated in MS serum and cerebrospinal fluid. Here we study whether serum levels of CXCL13 are associated with active MS. We measured serum levels of CXCL13 by enzyme-linked immunosorbent assay in 74 patients with relapsing MS randomized to interferon beta 1b or glatiramer acetate and examined with monthly 3 T brain MRI scans optimized for detection of gadolinium-enhancement for up to 2 years. The median (range) serum levels of CXCL13 pre-treatment were 40 (3-171) pg/ml. Serum levels of CXCL13 were significantly higher at times of active brain MRI scans (p < 0.01). Furthermore, serum levels were higher in patients who never reached MRI remission compared with those in complete (p < 0.01) or partial (p = 0.01) remission. There was a significant positive correlation between the pattern of serum levels of CXCL13 and MRI activity during the first (r = 0.33, p < 0.05) and the full 2 years (r = 0.35, p < 0.01) of the study. Treatment with interferon beta 1b or glatiramer acetate did not affect serum CXCL13. We conclude that the serum levels of the B cell chemokine CXCL13 are associated with active MS.

Association of pathologic diagnoses with clinical findings in chronic endometritis.

OBJECTIVE: To investigate the association of chronic endometritis (CE) with abnormal uterine bleeding, chronic pelvic pain, human immunodeficiency virus (HIV) infection, genital tract infection and salpingitis. STUDY DESIGN: In this retrospective study, specimens obtained from endometrial biopsy, dilatation and curettage or hysterectomy were identified. A total of 123 patients with CE and 177 without CE who were used as controls were included in the study. RESULTS: The patients with CE were younger than controls (p = 0.0001) and were more likely to be premenopausal (p = 0.0004). There was no association of CE with body mass index (p = 0.82), pelvic pain (p = 0.88) or abnormal uterine bleeding (p = 0.80). None of the specimens with CE had atrophic endometrium (p = 0.0018). CE was significantly associated with history of genital tract infection (p = 0.0032), HIV infection (p = 0.0018) and salpingitis (p = 0.0007). CONCLUSION: There was significant association of CE with historical factors, but not with symptomatology.

Duration of lactation is associated with lower prevalence of the metabolic syndrome in midlife--SWAN, the study of women's health across the nation.

OBJECTIVE: The objective of the study was to evaluate whether lactation duration is associated with lower prevalence of metabolic syndrome (MetSyn) in midlife, parous women. STUDY DESIGN: This was a cross-sectional cohort analysis of 2516 parous, midlife women using multivariable logistic regression to determine the independent association of lactation and lactation duration on prevalence of MetSyn. RESULTS: One thousand six hundred twenty women (64.4%) reported a history of breast-feeding, with average lifetime duration of lactation of 1.16 (+/- 1.04) years. MetSyn was present in 536 women (21.3%). Adjusting for age, smoking history, parity, ethnicity, socioeconomic status, study site, physical activity, caloric intake, and high school body mass index, women with prior lactation had significantly lower odds of MetSyn (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.63 to 0.99). Furthermore, increasing duration of lactation was similarly associated with lower odds of MetSyn (OR 0.88, 95% CI 0.77 to 0.99). CONCLUSION: Duration of lactation is associated with lower prevalence of MetSyn in a dose-response manner in midlife, parous women.

Does the presence of vaginitis on a Pap smear correlate with clinical symptoms in the patient?

OBJECTIVE: To investigate the association of the finding of trichomoniasis, candidiasis or bacterial vaginosis (BV) on Pap smear with possible symptoms, findings on the clinical examination or treatment that the patient received shortly before or shortly after the results of the Pap smear. STUDY DESIGN: Cases were selected from the Department of Pathology, UMDNJ-University Hospital, Newark. Retrospective chart review of patients who had a diagnosis of Trichomonas or Candida infection or bacterial vaginosis on Pap smear was performed. Controls were patients with none of these organisms on Pap smear. RESULTS: We reviewed 761 charts. Of the patients represented, 78 were menopausal, 258 were pregnant and 425 were neither menopausal nor pregnant; 533 (70%) of the patients had an organism associated with vaginitis on their Pap smear. There was a significant association (p <0.001) between a positive Pap smear finding and signs, symptoms or treatment for vaginitis overall. By individual organism, there was a significant association between a positive Pap smear and clinical indicators of Candida and Trichomonas, but not of BV. CONCLUSION: Finding Candida or Trichomonas organisms on a Pap smear is a reliable indicator of vaginitis associated with these organisms. Finding organisms consistent with a shift in vaginal flora (BV) on Pap smear did not correlate with clinical indicators of vaginitis.

Do stillborns with no identifiable pathology have leaner cords than liveborns?

OBJECTIVE: To evaluate whether stillbirths with no explanation found at autopsy have thinner cords than live, gestational-age-matched controls. STUDY DESIGN: Stillbirth autopsies performed at University Hospital, Newark, New Jersey, from January 1995 to October 2002 were reviewed. Cases with no explanation for the death at autopsy had their umbilical cord diameters compared to those in 3 groups of age-matched controls: stillbirths with an identifiable cause of death, liveborns with placentas submitted for pathology evaluation and liveborns from which the placentas were not submitted to pathology. Age-adjusted ANOVAs were performed for comparisons. RESULTS: Of 181 autopsies performed during the review period, 21 cases (11.6%) provided no information at autopsy that would explain or contribute to an understanding of the death. There was no significant difference in cord diameters between either group ofstillbirths or the pathology-submitted controls. Third-trimester placentas from liveborns without placental submission to pathology had significantly greater cord diameters (p = 0.001). CONCLUSION: This study does not support the theory that a cord accident or decreased umbilical blood flow resulting from a leaner umbilical cord can explain a significant number of stillbirths with no other findings at autopsy. However, it supports the literature in that leaner cords appear to be associated with a wide variety of adverse perinatal conditions.

Does histologic chorioamnionitis correspond to clinical chorioamnionitis?

OBJECTIVE: To evaluate the degree to which histologic chorioamnionitis, a frequent finding in placentas submitted for histopathologic evaluation, correlates with clinical indicators of infection in the mother. STUDY DESIGN: A retrospective review was performed on 52 cases with a histologic diagnosis of acute chorioamnionitis from 2,051 deliveries at University Hospital, Newark, from January 2003 to July 2003. Third-trimester placentas without histologic chorioamnionitis (n = 52) served as controls. Cases and controls were selected sequentially. Maternal medical records were reviewed for indicators of maternal infection. RESULTS: Histologic chorioamnionitis was significantly associated with the usage of antibiotics (p = 0.0095) and a higher mean white blood cell count (p = 0.018). The presence of 1 or more clinical indicators was significantly associated with the presence of histologic chorioamnionitis (p = 0.019). CONCLUSION: Histologic chorioamnionitis is a reliable indicator of infection whether or not it is clinically apparent.

Six-year incidence of visual loss in african americans with type 1 diabetes mellitus: the New Jersey 725.

OBJECTIVE: To report the 6-year incidence of visual loss and associated risk factors in African Americans with type 1 diabetes mellitus. METHODS: African Americans with type 1 diabetes (n=483) who participated in the New Jersey 725 study were reexamined as part of a 6-year follow-up. Best-corrected visual acuity, a structured clinical interview, fundus photographs, and blood pressure measurements were obtained. The biological evaluation included blood and urine assays. Any visual loss was defined as a visual acuity of 20/40 or worse in the better eye, blindness as a visual acuity of 20/200 or worse in the better eye, and doubling of the visual angle (DVA) as the loss of 15 or more letters between the first and second visits. RESULTS: Over 6 years, 19 of 440 patients (4.3%) developed visual loss in the better eye, 3 of 472 patients (0.6%) became blind, 47 of 481 patients (9.8%) developed DVA in the better eye, and 65 of 481 (13.5%) developed DVA in either eye. Baseline older age, high glycosylated hemoglobin level, retinopathy severity, and proteinuria were characteristics significantly (P<.001 for all) and independently associated with DVA in either eye at follow-up. CONCLUSIONS: The 6-year incidence of DVA in either eye (13.5%) is high in African Americans with type 1 diabetes. Baseline poor glycemic control, diabetic retinopathy severity, proteinuria, and older age are predictors of visual loss in this population.

Telomere dynamics in macaques and humans.

In humans, telomere length in proliferating tissues shortens with age--a process accelerated with age-related diseases. Thus, telomere length and attrition with age in the nonhuman primate may serve as a useful paradigm for understanding telomere biology in humans. We examined telomere parameters in tissues of young and old Macaca fascicularis and compared them with several tissues from humans. Macaque telomeres were variable in length and exhibited partial synchrony (equivalence) within animals. They were longer than humans, partially because of longer subtelomeric segments. As skeletal muscle telomere length was unchanged with age, we used it as an internal reference to offset interanimal variation in telomere length. We identified age-dependent telomere attrition in lung, pancreas, skin, and thyroid. Similar to humans, telomerase activity was detected in spleen, thymus, digestive tract, and gonads. We conclude that factors that modify telomere attrition and aging in humans may also operate in the macaque.

Proliferation dynamics in cultured skin fibroblasts from Down syndrome subjects.

With a view to better understanding the role of oxidant/antioxidant variables in proliferation dynamics of somatic cells, we explored the relationships among superoxide dismutase (SOD) activity, glutathione peroxidase (Gpx) activity, reactive oxygen intermediates (ROI), and indices of cellular proliferation and senescence in cultured fibroblasts from Down syndrome and normal donors. We found that Down syndrome cells had a significantly slower proliferative rate, but attain replicative senescence at similar population doubling (PD) as control cells. Irrespective of donor origin, the number of PD until replicative senescence was positively correlated with Gpx activity (r = 0.784, P = 0.007). In addition, the presence of exogenous catalase in the growth medium significantly extended the number of PD until replicative senescence (P = 0.011). The loss of telomere repeats per PD was not different between Down syndrome cells and controls. However, SOD activity was inversely correlated with the loss of telomere repeats per PD. Collectively, these findings suggest that replicative senescence ultimately relates to mechanisms downstream to SOD (i.e., Gpx and catalase) and confirmed previous observations about inverse relationships between SOD activity and telomere repeat loss per cellular replication.

The F + 0 protocol for diuretic renography results in fewer interrupted studies due to voiding than the F - 15 protocol.

UNLABELLED: Timing of diuretic administration is not universally standardized in renography. Over the past year, our practice has changed from F-15 administration of furosemide to an F + 0 protocol. Therefore, we have retrospectively compared these 2 cohorts to assess if the shorter interval between diuretic administration and study completion in the F + 0 study results in a greater frequency of patients able to complete the subsequent 30-min dynamic acquisition without disruption due to voiding. METHODS: We identified 108 diuretic (99m)Tc-mercaptoacetyltriglycine renograms performed in the previous 18-mo period. Three patients were given furosemide at 30 min after the radiopharmaceutical and were excluded. Twenty studies in children under 3 y of age were excluded from consideration because voiding is neither restricted in this age group nor does voiding into a diaper cause disruption. Forty milligrams of furosemide were administered to adults, whereas 0.5 mg/kg was given to children. In the first cohort of 56 studies, radiopharmaceutical was administered 15 min after furosemide (F-15), whereas, in the second cohort of 29 patients, it was administered immediately thereafter (F + 0). In all cases, patients were asked to void proximal to radiopharmaceutical injection. Dynamic images and renogram curves were inspected for evidence of interruption or voiding midstudy. Statistical significance was determined by a 1-tailed Fisher exact test for proportions, with P < 0.05. RESULTS: The F-15 and F+0 groups of patients were comparable in terms of age, sex, and diuretic amount. In 17 of the F-15 patients, renography was interrupted because of voiding (30%), whereas this occurred in only 3 of the F + 0 patients (10%). This difference was significant at the P = 0.033 level. The mean time of voiding was 18.3 min (range, 12-25 min) for F-15 patients and 16 min (range, 12-19 min) for the F + 0 group. CONCLUSION: The F + 0 renal diuretic protocol is associated with a significantly lower rate of disruption because of voiding than the F-15 protocol, likely due to the shorter period between diuretic administration and study termination, which results in less bladder distention and discomfort. On the basis of these data, the F + 0 protocol appears to be a more tolerable procedure.

Ethnic differences in past hysterectomy for benign conditions.

BACKGROUND: Hysterectomy for a benign condition is common, particularly in the underserved. The objective was to determine if ethnic differences could be explained by known risk factors. METHODS: A phone survey was conducted at random on 15,160 women, ages 40-55, from seven US cities. Subjects were 49.9% Caucasian, 28.1% African American, 12.3% Hispanic, and 9.8% Asian American. RESULTS: Ethnicity was associated with past hysterectomy (odds ratio [OR]: Caucasian = 1.0, African American = 1.66; confidence interval [CI] = 1.46-1.88, Hispanic = 1.64, CI = 1.29-2.07; Asian American = 0.44, CI = 0.34-0.56), after adjustment for age, education, fibroids, body mass index, marital status, smoking, geographic site, and country of education. CONCLUSION: Because the highest rates occurred in the disadvantaged African American and Hispanic subgroups, and could not be explained by known risk factors, disparity in the form of overuse in these disadvantaged groups may exist.

Ethnic differences in insulin sensitivity and beta-cell function in premenopausal or early perimenopausal women without diabetes: the Study of Women's Health Across the Nation (SWAN).

OBJECTIVE: To assess differences in insulin sensitivity and beta-cell function between nondiabetic premenopausal or early perimenopausal non-Hispanic white women and African American, Chinese American, Japanese American, and non-Mexican-American Latino women. RESEARCH DESIGN AND METHODS: Homeostasis model assessments (HOMAs) of insulin sensitivity (HOMA%S) and beta-cell function (HOMA%beta) were used. Stepwise multivariable ethnic-specific ANCOVA models were used to compare HOMA%S and HOMA%beta between non-Hispanic whites and each of the four ethnic groups. RESULTS: HOMA%S was lower in African Americans, Chinese Americans, and Japanese Americans when compared with non-Hispanic white women after correcting for waist circumference, presence of impaired fasting glucose, and site. Significant differences persisted only between African Americans and non-Hispanic whites after inclusion of triglycerides in the model. Triglycerides indirectly corrected for the differences in HOMA%S in the other two groups. There were no differences in HOMA%S between the non-Mexican-American Latinos and the non-Hispanic whites. Japanese Americans and Chinese Americans had lower HOMA%beta than non-Hispanic whites, whereas African Americans had higher HOMA%beta than non-Hispanic whites after correcting for confounders. HOMA%beta was similar between non-Mexican-American Latinos and non-Hispanic whites. CONCLUSIONS: These data suggest that type 2 diabetes prevention strategies for African-American women should initially target decreased insulin sensitivity, whereas strategies for Japanese-American and Chinese-American women may initially need to target both decreased insulin sensitivity and beta-cell function. Previous studies of Mexican-American populations may not apply to non-Mexican-American Latino women.

Dendritic cell amplification of HIV type 1-specific CD8+ T cell responses in exposed, seronegative heterosexual women.

In the Heterosexual AIDS Transmission Study (HATS), the frequency of high-risk sexual activity and viral load in the seropositive partner were shown to correlate with HIV-1 transmission. However, these parameters could not account for the status of some exposed, seronegative (ESN) individuals who remained uninfected despite years of exposure. To test the hypothesis that antiviral immune responses are a correlate of nontransmission in this cohort, we developed two sensitive methods for assessing HIV-1-specific humoral and cell-mediated responses. To quantify T cell responses, autologous mature dendritic cells (DCs) were used as antigen-presenting cells to elicit HIV-1-specific IFN-gamma production by ELISPOT. Antibody responses to HIV-1 gp120 were assessed by combination immunoprecipitation-Western blot (IP-WB). Previous studies of this cohort, using limiting dilution analysis, did not reveal HIV-1-specific cytotoxic T lymphocyte activity. However, when autologous DCs were used to present HIV-1 antigens, T cells from three of eight ESN women (38%) responded by producing IFN-gamma. T cells from three of four seropositive partners responded to HIV-1 antigens, whereas five negative controls did not. The use of DCs as antigen-presenting cells increased sensitivity by 2- to 30-fold relative to standard ELISPOT. Using IP-WB, low levels of gp120-reactive antibodies were detected in plasma from 1 of 14 ESN women. These results support the hypothesis that HIV-1-specific T cell responses play a role in immune surveillance in this cohort of North American serodiscordant couples. This report also demonstrates the ability of dendritic cells to reveal T cell responses that might be overlooked by other methods.

Oncoproteins and proliferation markers in synovial sarcomas: a clinicopathologic study of 19 cases.

PURPOSE: The objective of this study was to evaluate synovial sarcomas for the expression of oncogenic proteins (Her2/neu, EGFR, Bcl-2, p53) and proliferation markers (Ki-67, Topoisomerase 2alpha), as possible markers of prognostic significance. METHODS: From 17 patients with synovial sarcomas 19 tumors (15 primary, 2 recurrent, and 2 metastatic) were selected on the basis of characteristic histology, the expression of at least one epithelial marker, and/or the presence of t(X;18). Adequate follow-up was available in all cases. RESULTS: The tumors were tested immunohistochemically and were found to express multiple oncogenic proteins. Four of 19 synovial sarcomas (21%) demonstrated nuclear over-expression of p53 protein; 18 of 19 tumors (94%) stained positive for Bcl-2; and 13 of 19 tumors (68%) were immunoreactive with EGFR. Of particular interest was the frequent expression of Her2/neu, an oncogenic protein more commonly observed in epithelial neoplasms. Ten of 19 tumors (52%, 7 monophasic and 3 biphasic) showed positive cytoplasmic and membranous staining with Her2/neu (HercepTest, DAKO). The staining intensity ranged from 1+ to 2+. Cellular expression of Her2/neu was independent of EGFR positivity and showed no association with proliferative activity of the tumors. FISH analysis of eight positive cases showed no evidence of Her2/neu gene amplification. Among the non-metastatic tumors, we found a significant correlation between Ki-67 and Topoisomerase 2alpha. Spearman's correlation co-efficient was 0.86 with P=0.001 ( n=17). CONCLUSIONS: In this relatively small series of cases, we found no definite correlation between the over-expression of Her2/neu and clinical outcome. The over-expression of p53 was significantly associated with clinical outcome (Fisher's exact test, P=0.02).

Urinary incontinence predictors and life impact in ethnically diverse perimenopausal women.

OBJECTIVE: To document prevalence of mild, moderate, and severe urinary incontinence among ethnically diverse perimenopausal women, identify risk factors, and assess the effect of severity on women's daily lives using treatment seeking, bother, and nighttime voiding as indicators. METHODS: Baseline data from the longitudinal cohort of the Study of Women's Health Across the Nation, a prospective, multiethnic, multisite study of the natural history of menopausal transition was used (n = 3302). Interview and self-completed questionnaires assessed most variables of interest. Body mass index and diabetes mellitus were measured clinically. Incontinence severity was derived by multiplying frequency by volume leaked. Risk factors and effect on treatment seeking, bother, and nighttime voiding were assessed by the construction of multiple logistic regression models for each ethnic group and the total population. RESULTS: Mean age was 46.4 years. Incontinence prevalence was 57%, with nearly 15% categorized as moderate and 10% as severe. Biologic factors constituted the most important risk for severity, specifically perimenopausal compared with premenepausal status (odds ratio [OR] 1.35), body mass index (OR 1.04), diabetes mellitus (OR 1.55), and current smoking (OR 1.38). Nonwhite groups had lower risk, but the relationship of ethnicity is complex. Severity was associated with likelihood of discussing with a health care provider, with bothersomeness, and with likelihood of nighttime voiding. CONCLUSION: Large numbers of perimenopausal women experience urinary incontinence with 25% wearing protection or changing undergarments on several days per week. Mutable factors predicting severity included body mass index and current smoking.

Microsleep and sleepiness: a comparison of multiple sleep latency test and scoring of microsleep as a diagnostic test for excessive daytime sleepiness.

STUDY OBJECTIVE: To compare multiple sleep latency test (MSLT) and scoring of microsleep (presence of sleep electroencephalograph between 3 and 15s in an epoch) as a diagnostic test for excessive daytime sleepiness (EDS). DESIGN: A retrospective study. SETTING: Sleep center at a tertiary care teaching hospital. SUBJECTS: Patients referred to a sleep center who had an MSLT and one or more of the following symptoms; tiredness, sleepiness, memory loss, accidents/near accidents and gap driving. INTERVENTIONS: Full night polysomnography (PSG) and next day MSLT were performed. Patients were classified as 'microsleep-positive' or 'microsleep-negative' according to presence or absence of microsleep. RESULTS: Patients (n=92) were divided into three groups according to their MSLT results; group A had an MSLT10min (n=28). The number of patients with symptoms of tiredness and memory loss were statistically higher in group A compared with groups B and C (P=0.036). The number of patients with symptoms of EDS, in groups B and C, was significantly higher in patients with microsleep than without microsleep (P<0.05). By a paired McNemar's test, the better performance of adding microsleep to MSLT (sensitivity 42.9%; specificity 63.6%) to assess EDS was statistically significant (P=0.0096). CONCLUSIONS: Microsleep determination during an MSLT is a more sensitive and specific test for EDS as compared to MSLT alone.

Increased risk of preterm birth in singleton pregnancies resulting from in vitro fertilization-embryo transfer or gamete intrafallopian transfer: a meta-analysis.

OBJECTIVE: To perform a systematic review of the literature to determine whether singleton pregnancies resulting from IVF-ET/GIFT are at higher risk for preterm birth (<37 weeks). DESIGN: Literature search and systematic review. SETTING: Medical school. INTERVENTION(S): A MEDLINE search (1965-2000) was performed using the terms "premature labor," "infertility," "pregnancy complications," "gonadotropins," "pregnancy outcome," "preterm delivery," and "in vitro fertilization." Criteria for inclusion were English language, original research article, study patients conceived using IVF-ET (with or without intracytoplasmic sperm injection) or GIFT, pregnancy outcome reported compared with a control group (e.g., naturally conceived singletons at their hospital or a national reference), and prematurity clearly defined. Incomplete articles (e.g., abstracts), reports of other studies, and studies that failed to separate multiple from singleton gestations were excluded. MAIN OUTCOME MEASURE(S): Summary of relative risks of preterm birth. RESULT(S): Twenty-seven articles met all inclusion/exclusion criteria and were analyzed by meta-analysis. The random-effects summary relative risk of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT was 1.98 (95% confidence interval, 1.77-2.22). CONCLUSION(S): The risk of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT is twice that of natural conceived pregnancies.