A Phase 2, Randomized, Control Trial of Group B Streptococcus (GBS) Type III Capsular Polysaccharide-tetanus Toxoid (GBS III-TT) Vaccine to Prevent Vaginal Colonization With GBS III.

BACKGROUND: Group B Streptococcus (GBS) frequently colonizes pregnant women and can cause sepsis and meningitis in young infants. If colonization was prevented through maternal immunization, a reduction in perinatal GBS disease might be possible. A GBS type III capsular polysaccharide (CPS)-tetanus toxoid conjugate (III-TT) vaccine was evaluated for safety and efficacy in preventing acquisition of GBS colonization. METHODS: Healthy, nonpregnant women aged 18-40 years and screened to be GBS III vaginal and rectal culture negative were randomized to receive III-TT conjugate or tetanus diphtheria toxoid vaccine in a multicenter, observer-blinded trial. GBS vaginal and rectal cultures and blood were obtained bimonthly over 18 months. Serum concentrations of GBS III CPS-specific antibodies were determined using enzyme-linked immunosorbent assay. RESULTS: Among 1525 women screened, 650 were eligible for the intent-to-treat analysis. For time to first acquisition of vaginal GBS III, vaccine efficacy was 36% (95% confidence interval [CI], 1%-58%; P = .044), and for first rectal acquisition efficacy was 43% (95% CI, 11% to 63%; P = .014). Two months post-immunization, geometric mean concentrations of serum GBS type III CPS-specific immunoglobulin G were 12.6 µg/mL (95% CI, 9.95 to 15.81) in GBS III-TT recipients, representing a 4-fold increase from baseline in 95% of women, which persisted. Both vaccines were well tolerated. CONCLUSIONS: GBS CPS III-TT conjugate vaccine significantly delayed acquisition of vaginal and rectal GBS III colonization. In addition to its use for maternal immunization to passively protect infants with maternally derived antibodies, a multivalent vaccine might also serve to reduce fetal and neonatal exposure to GBS. CLINICAL TRIALS REGISTRATION: NCT00128219.

Efficacy results of a trial of a herpes simplex vaccine.

BACKGROUND: Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. METHODS: We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 µg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. RESULTS: The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26). CONCLUSIONS: In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330.).

Correlate of immune protection against HSV-1 genital disease in vaccinated women.

BACKGROUND: Previously we conducted a double-blind controlled, randomized efficacy field trial of gD-2 HSV vaccine adjuvanted with ASO4 in 8323 women. Subjects had been previously selected to be seronegative for HSV-1 and HSV-2. We found that vaccine was 82% protective against HSV-1 genital disease, but offered no significant protection against HSV-2 genital disease. METHODS: To better understand the results of the efficacy study, post-vaccination anti-gD-2 antibody concentrations from all HSV infected subjects and matched uninfected controls were measured. Three models were used to determine whether thes responses correlated with protection against HSV infection or disease. Similarly, cellular immune responses from a subset of subjects and matched controls were evaluated for a correlation with HSV protection. RESULTS: Antibodies to gD-2 correlated with protection against HSV-1 infection with higher antibody concentration associated with higher efficacy. Cellular immune responses to gD-2 did not correlate with protection. CONCLUSIONS: The protection against HSV-1 infection observed in the Herpevac Trial for Women was associated with antibodies directed against the vaccine. Clinical Trials Registration NCT00057330.

HSV-1 and HSV-2 seroprevalence in the united states among asymptomatic women unaware of any herpes simplex virus infection (Herpevac Trial for Women).

OBJECTIVES: Recent evidence suggests that the epidemiology of herpes simplex viruses (HSVs) is changing because fewer HSV-1 infections are acquired in childhood and increased sexual transmission of HSV-1 is reported. The objective of the study was to assess the seroprevalence of type-specific antibodies to HSV-1 and HSV-2 in the United States. METHODS: We used the Western blot antibody screening data from a large phase III vaccine efficacy trial (Herpevac Trial for Women) to assess the seroprevalence of type-specific antibodies to HSV-1 and HSV-2 in the United States. RESULTS: The antibody status of 29,022 women (>31,000 women interviewed and then had their blood drawn for the HSV testing [29,022 women]) between the ages of 18 and 30 years in the United States revealed that increasing age was associated with increasing seroprevalence to HSV. Overall, in asymptomatic women unaware of any HSV infection, HSV-1/-2 status was positive/negative in 45%, negative/positive in 5%, positive/positive in 7%, negative/negative in 38%, and indeterminate in 5%. HSV-1 infections were more common in Hispanic and non-Hispanic black women and in the US northeast and in individuals living in urban areas. HSV-2 was more common in non-Hispanic black women, the US south, and in urban areas. CONCLUSIONS: Seronegative status for both HSV-1 and HSV-2 was the second most common finding after positive antibody to HSV-1 but negative antibody to HSV-2. Despite recent changes in genital herpes epidemiology, most women acquired HSV-1 but not HSV-2 infections before 18 years of age. Among participants screened for study participation and who were unaware of any HSV infection, progressively higher prevalence of the HSV-1 or HSV-2 antibody was observed in older subjects. Many women who test positive for HSV-1 and/or HSV-2 are unaware of their status.

Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women.

BACKGROUND: Herpes simplex virus infections type 1 (HSV-1) and type 2 (HSV-2) are common, but the epidemiology of HSV disease is changing. METHODS: HSV-seronegative women, aged 18-30 years, who were in the control arm of the HERPEVAC Trial for Women were followed for 20 months for primary HSV infections. RESULTS: Of the 3438 evaluable participants, 183 became infected with HSV: 127 (3.7%) with HSV-1 and 56 (1.6%) with HSV-2. The rate of infection for HSV-1 (2.5 per 100 person-years) was more than twice that for HSV-2 (1.1 per 100 person-years). Most infections (74% of HSV-1 and 63% of HSV-2) occurred without recognized signs or symptoms of herpes disease. The HSV-2 infection rate was 2.6 times higher in non-Hispanic black participants than in Hispanics and 5.5 times higher than in non-Hispanic whites (P < .001), while the HSV-1 infection rate was 1.7 times higher in non-Hispanic whites than non-Hispanic blacks. Younger participants (18-22 years) were more likely to acquire HSV-1 infections and less likely to develop recognized disease than older participants. Overall, 84% of recognized disease cases were genital. No differences were noted in the clinical manifestations of genital HSV-1 vs genital HSV-2 disease. The clinicians' assessment that cases were caused by HSV was good when they assessed cases as clinically confirmed or unlikely (validated in 83% and 100% of cases, respectively). CONCLUSIONS: HSV-1 is now more common than HSV-2 as a cause of oral and genital mucosal infections in young women, but there are important age and race differences.

Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels.

Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m(2)), and antithymocyte globulin was associated with excessive organ toxicity.

Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial.

BACKGROUND: Autologous haemopoietic stem-cell transplantation (HSCT) improves survival in patients with multiple myeloma, but disease progression remains an issue. Allogeneic HSCT might reduce disease progression, but can be associated with high treatment-related mortality. Thus, we aimed to assess effectiveness of allogeneic HSCT with non-myeloablative conditioning after autologous HSCT compared with tandem autologous HSCT. METHODS: In our phase 3 biological assignment trial, we enrolled patients with multiple myeloma attending 37 transplant centres in the USA. Patients (<70 years old) with adequate organ function who had completed at least three cycles of systemic antimyeloma therapy within the past 10 months were eligible for inclusion. We assigned patients to receive an autologous HSCT followed by an allogeneic HSCT (auto-allo group) or tandem autologous HSCTs (auto-auto group) on the basis of the availability of an HLA-matched sibling donor. Patients in the auto-auto group subsequently underwent a random allocation (1:1) to maintenance therapy (thalidomide plus dexamethasone) or observation. To avoid enrolment bias, we classified patients as standard risk or high risk on the basis of cytogenetics and ß2-microglobulin concentrations. We used the Kaplan-Meier method to estimate differences in 3-year progression-free survival (PFS; primary endpoint) between patients with standard-risk disease in the auto-allo group and the best results from the auto-auto group (maintenance, observation, or pooled). This study is registered with ClinicalTrials.gov, number NCT00075829. FINDINGS: Between Dec 17, 2003, and March 30, 2007, we enrolled 710 patients, of whom 625 had standard-risk disease and received an autologous HSCT. 156 (83%) of 189 patients with standard-risk disease in the auto-allo group and 366 (84%) of 436 in the auto-auto group received a second transplant. 219 patients in the auto-auto group were randomly assigned to observation and 217 to receive maintenance treatment, of whom 168 (77%) completed this treatment. PFS and overall survival did not differ between maintenance and observation groups and pooled data were used. Kaplan-Meier estimates of 3-year PFS were 43% (95% CI 36-51) in the auto-allo group and 46% (42-51) in the auto-auto group (p=0·671); overall survival also did not differ at 3 years (77% [95% CI 72-84] vs 80% [77-84]; p=0·191). Within 3 years, 87 (46%) of 189 patients in the auto-allo group had grade 3-5 adverse events as did 185 (42%) of 436 patients in the auto-auto group. The adverse events that differed most between groups were hyperbilirubinaemia (21 [11%] patients in the auto-allo group vs 14 [3%] in the auto-auto group) and peripheral neuropathy (11 [6%] in the auto-allo group vs 52 [12%] in the auto-auto group). INTERPRETATION: Non-myeloablative allogeneic HSCT after autologous HSCT is not more effective than tandem autologous HSCT for patients with standard-risk multiple myeloma. Further enhancement of the graft versus myeloma effect and reduction in transplant-related mortality are needed to improve the allogeneic HSCT approach. FUNDING: US National Heart, Lung, and Blood Institute and the National Cancer Institute.

Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response.

Patients with follicular lymphoma (FL) typically experience an indolent course; however, the disease is rarely curable with conventional chemotherapy. Autologous hematopoietic cell transplantation (HCT) can extend progression-free survival (PFS) and overall survival (OS), but relapse is the primary cause of failure. Allogeneic HCT confers lower relapse rates due to a graft-versus-lymphoma effect. Reduced-intensity conditioning (RIC) allows the performance of allogeneic HCT with lower toxicity. The Blood and Marrow Transplant Clinical Trials Network conducted a prospective multicenter trial comparing these two strategies in patients with relapsed, chemotherapy-sensitive FL. Patients were assigned to a treatment arm based on the availability of an HLA-matched sibling donor (MSD). Those with an MSD underwent allogeneic HCT (n = 8) with the FCR preparative regimen (fludarabine, cyclophosphamide [Cy], rituximab [RTX]) and received tacrolimus and methotrexate for graft-versus-host disease (GVHD) prophylaxis. Those without an MSD (n = 22) underwent mobilization with Cy, RTX, and filgrastim and received a conditioning regimen of either CBV (Cy, carmustine, Etoposide [VP16]) or total body irradiation with Cy and VP16. Patients undergoing autologous HCT received 4 doses of weekly maintenance RTX (375 mg/m²) starting on day +42 post-HCT. Sixteen patients were in complete remission, 10 patients were in partial remission, and 1 patient had stable disease after salvage therapy and before HCT. Median follow-up was 36 months (range, 1-51 months). OS was 73% in autologous HCT versus 100% in allogeneic HCT, and PFS was 63% in autologous HCT versus 86% in allogeneic HCT. No patient had grade II-IV acute GVHD; two patients developed extensive chronic GVHD. Three autologous recipients died from nonrelapse causes. This trial closed early because of slow accrual. We show that the FCR regimen is well tolerated, and that both allogeneic and autologous HCT result in promising 3-year OS and PFS in patients with relapsed FL.

Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE smallpox vaccine.

INTRODUCTION: Previous research shows immune response to vaccination differs by sex but this has not been explored for IMVAMUNE, a replication-deficient smallpox vaccine developed in response to the potential for bioterrorism using smallpox. METHODS: We conducted a participant-level meta-analysis (N=275, 136 men, 139 women) of 3 randomized trials of IMVAMUNE conducted at 13 centers in the US through a federally-funded extramural research program. Studies were eligible for inclusion if they tested the standard dose (1×10(8)TCID50/mL on Days 0 and 28) of liquid formulation IMVAMUNE, were completed at the time of our search, and enrolled healthy vaccinia-naïve participants. Models of the peak log2 ELISA and PRNT titers post-second vaccination were constructed for each study with sex as a covariate. Results from these models were combined into random effects meta-analyses of the sex difference in response to IMVAMUNE. We then compared this approach with fixed effects models using the combined participant level data. RESULTS: In each study the mean peak log2 ELISA titer was higher in men than women but no single study demonstrated a statistically significant difference. Combination of the adjusted study-specific estimates into the random effects model showed a higher mean peak log2-titer in men compared with women (absolute difference [men-women]: 0.32, 95% CI: 0.02-0.60). Fixed effects models controlling for study showed a similar result (log2 ELISA titer, men-women: 0.34, 95% CI: 0.04-0.63). This equates to a geometric mean peak titer that is approximately 27% higher in men than women (95% CI: 3-55%). Peak log2 PRNT titers were also higher (although not significantly) in men (men-women: 0.14, 95% CI: -0.30 to 0.58). CONCLUSION: Our results show statistically significant differences in response to IMVAMUNE comparing healthy, vaccinia-naïve men with women and suggest that sex should be considered in further development and deployment of IMVAMUNE and other MVA-based vaccines.

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study.

BACKGROUND: The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts. METHODS: In a multicentre phase 1-2 study, patients (aged ≤65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m(2) per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417. FINDINGS: 96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0·7% (credible interval 0-3·3) and 1·4% (0-4·9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively. INTERPRETATION: Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies. FUNDING: US National Heart, Lung, and Blood Institute and National Cancer Institute.

Phase II randomized trial of cisplatin and WR-2721 versus cisplatin alone for metastatic melanoma: an Eastern Cooperative Oncology Group Study (E1686).

This study was designed to evaluate the toxicity and efficacy of cisplatin and WR-2721 in contrast to cisplatin alone for the therapy of measurable metastatic melanoma. Ninety-four patients with metastatic melanoma were randomized to receive either cisplatin at a dose of 150 mg/m2 and WR-2721 at a dose of 910 mg/m2, or cisplatin alone at a dose of 120 mg/m2. WR-2721 did not mitigate the toxic effects of cisplatin, and toxicity was increased in the WR-2721 plus cisplatin arm compared with cisplatin alone. For patients receiving cisplatin alone, the response rate was 16.3%; for those receiving cisplatin plus WR-2721, the response rate was 23.3%. The duration of response was 7.3 months. Median survival in the intent-to-treat analysis was 7.58 months. The study was terminated after accrual of 94 patients, with inadequate power to define an effect of WR-2721 on the duration of response and survival. In conclusion, cisplatin with WR-2721 showed an improved response rate over cisplatin alone. The lack of improved duration of response or impact on survival may be the result of the limited improvement of efficacy with the higher dosage of cisplatin in conjunction with WR-2721, or the limited number of patients accrued to this study. These factors, coupled with the failure of the combination to diminish toxicity, dampen enthusiasm for this combination.

Use of biological assignment in hematopoietic stem cell transplantation clinical trials.

BACKGROUND: When comparing treatments for a specific illness, it is sometimes impractical or impossible to conduct a randomized clinical trial (RCT). Biological assignment trials are one alternative design. In hematopoietic stem cell transplantation (HCT) trials, a human leukocyte antigen (HLA)-matched sibling donor is considered optimal, but such donors are available for only 20-30% of otherwise eligible patients. Rather than randomizing only those with a matched sibling donor, in a recent multiple myeloma trial, the type of HCT each patient received was biologically based, i.e., chosen according to whether or not the patient had a matched sibling donor. PURPOSE: This article describes the design and implementation of biological assignment trials as well as their advantages and disadvantages. METHODS: We focus on several aspects of such trials, including efficiency of trial duration, ethical issues, and potential sources of bias. Statistical issues are considered including sample size calculations, monitoring for biased enrollment, and adjustments for imbalances in patient characteristics. A multiple myeloma trial is used as an illustration. RESULTS: Although they often require a larger sample size, biological assignment trials can provide substantial efficiency in terms of study duration over randomized trials when accrual to a randomized trial would be slow. Determination of sample size requires consideration of the anticipated proportion of patients with a biologically favored (HLA-matched sibling) donor. An add-on randomization of patients without a matched sibling donor may alleviate ethical concerns about applicability of study results to all patients regardless of whether the biological assignment groups differ with respect to outcome. LIMITATIONS: Prognostic factor imbalance and enrollment bias can occur in a biological assignment trial. Statistical adjustment for potential imbalance in prognostic factors is important, as is monitoring center accrual for enrollment bias and performing an appropriate intention-to-treat analysis. CONCLUSIONS: A biological assignment trial can be a reasonable way to compare treatments which are biologically based, such as HLA-matched sibling transplants, when the gold-standard randomized trial design is impractical or impossible. Implementing such a trial requires careful consideration of the ethical issues and potential biases.

Comparative immunogenicity of trivalent influenza vaccine administered by intradermal or intramuscular route in healthy adults.

The present study was undertaken with controls using equal doses ID and IM plus the standard full dose IM to assess the role of route of vaccine in immunogenicity of inactivated influenza vaccine. The study was a prospective, randomized, active-controlled, open label clinical trial conducted in healthy young adult outpatients to compare the effect of route (IM versus ID) on antibody responses to influenza vaccine. Volunteers received 3, 6 or 9 microg of vaccine by ID or IM route; 15 microg IM was also studied. Low doses of vaccine given by either route were almost as immunogenic as the standard 15 microg IM dose of influenza vaccine. ID route was not superior to IM vaccine at inducing antibodies. ID vaccine induced significantly more local inflammatory response than IM vaccine.

The effect of unrelated donor marrow transplantation on health-related quality of life: a report of the unrelated donor marrow transplantation trial (T-cell depletion trial).

The primary objective of this study was to compare health-related quality of life (HRQL) in adult patients undergoing either ex vivo T cell-depleted bone marrow transplantation or conventional marrow transplantation. Data on patients' HRQL were gathered as part of a multicenter randomized trial comparing the effect of ex vivo T-cell depletion versus methotrexate and cyclosporine immunosuppression on disease-free survival. HRQL assessments were conducted at baseline, day +100, 6 months, 1 year, and 3 years. There were no treatment arm differences 1 year after transplantation on the Functional Assessment of Cancer Therapy, Bone Marrow Transplantation, the Medical Outcomes Study Short-Form 36, and the Centers for Epidemiological Studies of Depression. The lack of treatment differences was robust across types of data analyses that took baseline functioning into account and that recognized the sensitivity of outcome measures to assumptions concerning missing data. The trajectory of recovery revealed an initial decrease in function and then a recovery to pretreatment levels that were similar for both treatment arms. Furthermore, the patients in both treatment groups returned to a functional level that approximated general US population norms. Even though the incidence of acute graft-versus-host disease was slightly higher in the conventional treatment arm, T-cell depletion did not differentially affect HRQL at 1 year after transplantation.

Twenty-four-hour urine insulin as a measure of hyperinsulinaemia/insulin resistance before onset of pre-eclampsia and gestational hypertension.

OBJECTIVE: To evaluate levels of 24-hour urine insulin excretion before the onset of pre-eclampsia and gestational hypertension. DESIGN: Nested case-control study within the Calcium for Preeclampsia Prevention (CPEP) study cohort. SETTING: Five university medical centres in the United States. SAMPLE: Cases had developed pre-eclampsia (n= 70) or gestational hypertension (n= 142) in the absence of gestational diabetes. Controls (n= 429) had remained normotensive without gestational diabetes. METHODS: Subjects were required to have had an adequate baseline 24-hour urine collection prior to CPEP enrolment at 13-21 weeks. Controls were matched to cases by enrolment site and specimen storage time, without regard to gestational age or CPEP treatment. Adjusted mean 24-hour urine insulin excretion was, however, calculated using analysis of covariance, with adjustment models for pre-eclampsia considering body mass index, race and smoking status; and for gestational hypertension, gestational age at specimen collection, height, body mass index and smoking. Urine insulin was measured by radio-immunoassay. MAIN OUTCOME MEASURES: Twenty-four-hour urine insulin excretion. RESULTS: Adjusted 24-hour urine insulin excretion at baseline (mean 17 weeks of gestation) was greater in women who developed pre-eclampsia than in normotensive controls (mean [SE]: 15.6 [1.5] vs 13.1 [1.2] x 10(3)microIU/24 hour, P= 0.06), but not in women who developed gestational hypertension (14.7 [0.9] vs 15.0 [0.6] x 10(3)microIU/24 hour, P= 0.79, in cases vs controls). Among women who developed pre-eclampsia, adjusted urine insulin excretion was greater than controls only in women with mild pre-eclampsia and not in severe pre-eclampsia (mild pre-eclampsia vs controls: 17.3 [2.0] vs 13.7 [1.6] x 10(3)microIU/24 hour, P= 0.04; severe pre-eclampsia vs controls: 12.3 [2.2] vs 11.5 [1.2], P= 0.69). CONCLUSION: The data suggest that early hyperinsulinaemia, a marker of insulin resistance, may predispose to mild pre-eclampsia.

Abortion, changed paternity, and risk of preeclampsia in nulliparous women.

A prior birth confers a strong protective effect against preeclampsia, whereas a prior abortion confers a weaker protective effect. Parous women who change partners in a subsequent pregnancy appear to lose the protective effect of a prior birth. This study (Calcium for Preeclampsia Prevention Trial, 1992-1995) examines whether nulliparous women with a prior abortion who change partners also lose the protective effect of the prior pregnancy. A cohort analysis was conducted among participants in this large clinical trial of calcium supplementation to prevent preeclampsia. Subjects were nulliparous, had one prior pregnancy or less, delivered after 20 weeks' gestation, and were interviewed at 5-21 weeks about prior pregnancies and paternity. Women without a history of abortion served as the reference group in logistic regression analyses. Women with a history of abortion who conceived again with the same partner had nearly half the risk of preeclampsia (adjusted odds ratio = 0.54, 95 percent confidence interval: 0.31, 0.97). In contrast, women with an abortion history who conceived with a new partner had the same risk of preeclampsia as women without a history of abortion (adjusted odds ratio = 1.03, 95 percent confidence interval: 0.72, 1.47). Thus, the protective effect of a prior abortion operated only among women who conceived again with the same partner. An immune-based etiologic mechanism is proposed, whereby prolonged exposure to fetal antigens from a previous pregnancy protects against preeclampsia in a subsequent pregnancy with the same father.