Gestational diabetes: Risk of recurrence in subsequent pregnancies. Am J Obstet Gynecol. 2010 Jul 12. [Epub ahead of print]

Objectives: We sought to examine the recurrence risk of gestational diabetes mellitus (GDM) in a subsequent pregnancy and determine whether recurrence risk is modified by race/ethnicity.

Study Design: We used the Kaiser Permanente Southern California longitudinally linked records (1991–2008) to study women with first 2 (n = 65,132) and first 3 (n = 13,096) singleton pregnancies. Adjusted odds ratios (ORs) were used to estimate the magnitude of recurrence.

Results: Risks of GDM in the second pregnancy among women with and without previous GDM were 41.3% and 4.2%, respectively (OR, 13.2; 95% confidence interval, 12.0–14.6). The recurrence risk of GDM in the third pregnancy was stronger when women had GDM in both prior pregnancies (OR, 25.9; 95% confidence interval, 17.4–38.4). Hispanics and Asian/Pacific Islanders have higher risks of recurrence.

Conclusion: A pregnancy complicated by GDM is at increased risk for subsequent GDM. The magnitude of risk increases with the number of prior episodes of GDM. These recurrence risks also showed heterogeneity by race-ethnicity. Copyright © 2010 Mosby, Inc. All rights reserved.

An intensive behavioral weight loss intervention and hot flushes in women. Arch Intern Med. 2010;170:1161–1167.

Background: Higher body mass index is associated with worse hot flushes during menopause but the effect of weight loss on flushing is unclear.

Methods: Self-administered questionnaires were used to assess bothersome hot flushes in a 6-month randomized controlled trial of an intensive behavioral weight loss program (intervention) vs a structured health education program (control) in 338 women who were overweight or obese and had urinary incontinence. Weight, body mass index, abdominal circumference, physical activity, calorie intake, blood pressure, and physical and mental functioning were assessed at baseline and at 6 months. Repeated-measures proportional odds models examined intervention effects on bothersome hot flushes and potential mediating factors.

Results: Approximately half of participants (n = 154) were at least slightly bothered by hot flushes at baseline. Among these women, the intervention was associated with greater improvement in bothersome flushes vs control (odds ratio [OR] for improvement by 1 Likert category, 2.25; 95% confidence interval [CI], 1.20–4.21). Reductions in weight (OR, 1.32; 95% CI, 1.08–1.61; per 5-kg decrease), body mass index (1.17; 1.05–1.30; per 1-point decrease), and abdominal circumference (1.32; 1.07–1.64; per 5-cm decrease) were each associated with improvement in flushing, but changes in physical activity, calorie intake, blood pressure, and physical and mental functioning were not related. The effect of the intervention on flushing was modestly diminished after adjustment for multiple potential mediators (OR, 1.92; 95% CI, 0.95–3.89).

Conclusion: Among women who were overweight or obese and had bothersome hot flushes, an intensive behavioral weight loss intervention resulted in improvement in flushing relative to control. Trial Registration clinicaltrials.gov Identifier: NCT00091988.

Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): An international, prospective, randomised, non-inferiority phase 3 trial. Lancet. 2010;376:91–102

Background: After breast-conserving surgery, 90% of local recurrences occur within the index quadrant despite the presence of multicentric cancers elsewhere in the breast. Thus, restriction of radiation therapy to the tumour bed during surgery might be adequate for selected patients. We compared targeted intraoperative radiotherapy with the conventional policy of whole breast external beam radiotherapy.

Methods: Having safely piloted the new technique of single-dose targeted intraoperative radiotherapy with Intrabeam, we launched the TARGIT-A trial on March 24, 2000. In this prospective, randomised, non-inferiority trial, women aged 45 years or older with invasive ductal breast carcinoma undergoing breast-conserving surgery were enrolled from 28 centres in nine countries. Patients were randomly assigned in a 1:1 ratio to receive targeted intraoperative radiotherapy or whole breast external beam radiotherapy, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy. Neither patients nor investigators or their teams were masked to treatment assignment. Postoperative discovery of predefined factors (eg, lobular carcinoma) could trigger addition of external beam radiotherapy to targeted intraoperative radiotherapy (in an expected 15% of patients). The primary outcome was local recurrence in the conserved breast. The predefined non-inferiority margin was an absolute difference of 2.5% in the primary endpoint. All randomised patients were included in the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00983684.

Findings: 1113 patients were randomly allocated to targeted intraoperative radiotherapy and 1119 were allocated to external beam radiotherapy. Of 996 patients who received the allocated treatment in the targeted intraoperative radiotherapy group, 854 (86%) received targeted intraoperative radiotherapy only and 142 (14%) received targeted intraoperative radiotherapy plus external beam radiotherapy. 1025 (92%) patients in the external beam radiotherapy group received the allocated treatment. At 4 years, there were six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group. The Kaplan-Meier estimate of local recurrence in the conserved breast at 4 years was 1.20% (95% CI 0.53–2.71) in the targeted intraoperative radiotherapy and 0.95% (0.39-2.31) in the external beam radiotherapy group (difference between groups 0.25%, −1.04 to 1.54; p = 0.41). The frequency of any complications and major toxicity was similar in the two groups (for major toxicity, targeted intraoperative radiotherapy, 37 [3.3%] of 1113 vs external beam radiotherapy, 44 [3.9%] of 1119; p = 0.44). Radiotherapy toxicity (Radiation Therapy Oncology Group grade 3) was lower in the targeted intraoperative radiotherapy group (six patients [0.5%]) than in the external beam radiotherapy group (23 patients [2.1%]; p = 0.002).

Interpretation: For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks.

Funding: University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research (BMBF). Copyright 2010 Elsevier Ltd. All rights reserved.

Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): A randomised placebo-controlled trial. Lancet. 2010;376:259–266. Epub 2010 Jun 26

Background: Results of several trials of antioxidant use during pregnancy have not shown a reduction in pre-eclampsia, but the effect in women with diabetes is unknown. We aimed to assess whether supplementation with vitamins C and E reduced incidence of pre-eclampsia in women with type 1 diabetes.

Methods: We enrolled women from 25 UK antenatal metabolic clinics in a multicentre randomised placebo-controlled trial. Eligibility criteria were type 1 diabetes preceding pregnancy, presentation between 8 weeks' and 22 weeks' gestation, singleton pregnancy, and age 16 years or older. Women were randomly allocated in a 1:1 ratio to receive 1000 mg vitamin C and 400 IU vitamin E (alpha-tocopherol) or matched placebo daily until delivery. The randomisation sequence was stratified by centre with balanced blocks of eight patients. All trial personnel and participants were masked to treatment allocation. The primary endpoint was pre-eclampsia, which we defined as gestational hypertension with proteinuria. Analysis was by modified intention to treat. This study is registered, ISRCTN27214045.

Findings: Between April, 2003, and June, 2008, 762 women were randomly allocated to treatment groups (379 vitamin supplementation, 383 placebo). The primary endpoint was assessed for 375 women allocated to receive vitamins, and 374 allocated to placebo. Rates of pre-eclampsia did not differ between vitamin (15%, n = 57) and placebo (19%, 70) groups (risk ratio 0.81, 95% CI 0.59–1.12). No adverse maternal or neonatal outcomes were reported.

Interpretation: Supplementation with vitamins C and E did not reduce risk of pre-eclampsia in women with type 1 diabetes. However, the possibility that vitamin supplementation might be beneficial in women with a low antioxidant status at baseline needs further testing.

Funding: The Wellcome Trust. Copyright 2010 Elsevier Ltd. All rights reserved.

Vasomotor symptoms and coronary artery calcium in postmenopausal women. Menopause. 2010 Jul 21. [Epub ahead of print]

Objective: We assessed whether vasomotor symptoms (VMS) are associated with coronary artery calcium (CAC) and how hormone therapy (HT) may influence this association.

Methods: Participants were a subset of women aged 50 to 59 years with a history of hysterectomy who were enrolled in the Women's Health Initiative (WHI) estrogen-alone clinical trial and underwent a CT scan of the chest at the end of the trial to determine CAC. Participants provided information about VMS (hot flashes and/or night sweats), as well as HT use, on self-administered questionnaires at trial baseline.

Results: The sample consisted of 918 women with a mean (SD) age of 55.1 (2.8) years at WHI randomization and 64.8 (2.9) years at CAC ascertainment. The prevalence of a CAC score higher than 0 was 46%, whereas the prevalence of a CAC score of 10 or higher and higher than 100 was 39% and 19%, respectively. At randomization, 77% reported a history of any VMS at any time before or at enrollment in the WHI, whereas 20% reported any VMS present only at enrollment. Compared with those without a history of any VMS and after adjustment for potential confounders, a history of any VMS at any time up to and including WHI enrollment was associated with significantly reduced odds for CAC higher than 0 (odds ratio, 0.66; 95% CI, 0.45–0.98). Moreover, as duration of HT increased, the inverse association between any VMS and CAC moved toward the null.

Conclusions: A history of any VMS was significantly associated with reduced odds for CAC independent of traditional cardiovascular disease risk factors and other relevant covariates. This association seems to be influenced by duration of HT.

Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer. J Natl Cancer Inst. 2010;102:942–949. Epub 2010 Jun 16

Background: Tamoxifen use has been associated with increased risk of thromboembolic events (TEs) in women with breast cancer and women at high risk for the disease. Factor V Leiden (FVL) is the most common inherited clotting factor mutation and also confers increased thrombosis risk. We investigated whether FVL was associated with TE risk in women with early-stage breast cancer who took adjuvant tamoxifen.

Methods: A case-control study was conducted among 34 Cancer and Leukemia Group B (CALGB) institutions. We matched each of 124 women who had experienced a documented TE while taking adjuvant tamoxifen for breast cancer (but who were not necessarily on a CALGB treatment trial) to two control subjects (women who took adjuvant tamoxifen but did not experience TE) by age at diagnosis (+/−5 years). DNA from blood was analyzed for FVL mutations. Conditional logistic regression was used to estimate odds ratios (ORs) and to evaluate other potential factors associated with TE and tamoxifen use. All P values are based on two-sided tests.

Results: FVL mutations were identified in 23 (18.5%) case and 12 (4.8%) control subjects (OR = 4.66, 95% confidence interval = 2.14 to 10.14, p < .001). In the multivariable model, FVL mutation was associated with TE (OR = 4.73, 95% confidence interval = 2.10 to 10.68, p < .001). Other statistically significant factors associated with TE risk were personal history of TE and smoking.

Conclusions: Among women taking adjuvant tamoxifen for early-stage breast cancer, those who had a TE were nearly five times more likely to carry a FVL mutation than those who did not have a TE. Postmenopausal women should be evaluated for the FVL mutation before prescription of adjuvant tamoxifen if a positive test would alter therapeutic decision making.

Treatment of Hyperthyroidism in Pregnancy and Birth Defects. J Clin Endocrinol Metab. 2010 Jul 28. [Epub ahead of print]

Context: Clinical hyperthyroidism is not uncommon in pregnancy, with a reported prevalence of 0.1 to 0.4%. The available antithyroid drugs are propylthiouracil and methimazole/carbimazole.

Objectives: In this report we examined the association of both drugs with congenital malformations using data from the International Clearinghouse for Birth Defects Surveillance and Research.

Design: The study used a case-affected control analysis and included 18,131 cases with malformations and reported first-trimester exposure to medication. A total of 127 subjects were born to mothers with known first-trimester antithyroid drug exposure.

Results: Among the 52 groups of malformations that were analyzed, situs inversus +/− dextrocardia, isolated unilateral kidney a/dysgenesis, and cardiac outflow tract defects were associated with prenatal exposure to propylthiouracil based on three, two, and five cases, respectively. Prenatal exposure to methimazole/carbimazole was significantly associated with choanal atresia, omphalocele, and total situs inversus +/− dextrocardia (p < 0.01).

Conclusions: Further studies are required to exhaustively evaluate the associations between propylthiouracil and birth defects because of the low number, the lack of biological plausibility, and the possibility of underdiagnosis. Association between methimazole/carbimazole exposure and omphalocele and choanal atresia is consistent with previous reports and definitely suggests that these malformations could be part of a specific, even if rare, embryopathy.

Tubal ligation and the risk of ovarian cancer: Review and meta-analysis. Hum Reprod Update. 2010 Jul 15. [Epub ahead of print]

Background: The reduction of ovarian cancer (OC) risk in women with a history of tubal ligation (TL) has been reported repeatedly, mostly on small populations. We have aimed to provide a critical overview of the studies available to date and to conduct a meta-analysis.

Methods: There were 40 relevant studies identified. The studies were divided into two groups for strict and extended meta-analysis, respectively. Subgroup analysis was performed for age, time dependency since TL, histological types of OC and BReast CAncer (BRCA) mutation.

Results: Meta-analysis of 13 strictly selected studies showed a reduced risk of epithelial OC by 34%. The protective effect of TL was confirmed even in a subgroup of women 10–14 years after the procedure. The risk reduction was confirmed for the endometrioid (RR = 0.40) and serous (RR = 0.73) cancers but not for mucinous.

Conclusions: The review of relevant articles, as well as the meta-analysis of selected studies, yields consistent data on a significant reduction of OC risk in women who had undergone TL. The results of this meta-analysis should provide an impulse for further research on the etiology of ovarian epithelial cancers, focusing particularly on the importance of retrograde transport of endometrial cells.

Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol. 2010;28:3582–3590. Epub 2010 Jun 21

Purpose: Emerging clinical evidence suggests intravenous bisphosphonates may inhibit breast cancer while oral bisphosphonates have received limited evaluation regarding breast cancer influence.

Patients and Methods: The association between oral bisphosphonate use and invasive breast cancer was examined in postmenopausal women enrolled onto the Women's Health Initiative (WHI). We compared a published hip fracture prediction model, which did not incorporate bone mineral density (BMD), with total hip BMD in 10,418 WHI participants who had both determinations. To adjust for potential BMD difference based on bisphosphonate use, the hip fracture prediction score was included in multivariant analyses as a BMD surrogate.

Results: Of the 154,768 participants, 2,816 were oral bisphosphonate users at entry (90% alendronate, 10% etidronate). As calculated hip fracture risk score was significantly associated with both BMD (regression line = 0.79 to 0.0478 log predicted fracture; p < .001; r = 0.43) and breast cancer incidence (p = .03), this variable was incorporated into regression analyses to adjust for BMD difference between users and nonusers of bisphopshonate. After 7.8 mean years of follow-up (standard deviation, 1.7), invasive breast cancer incidence was lower in bisphosphonate users (hazard ratio [HR], 0.68; 95% CI, 0.52 to 0.88; p < .01) as was incidence of estrogen receptor (ER)-positive invasive cancers (HR, 0.70; 95% CI, 0.52 to 0.94, p = .02). A similar but not significant trend was seen for ER-negative invasive cancers. The incidence of ductal carcinoma in situ was higher in bisphosphonate users (HR, 1.58; 95% CI, 1.08 to 2.31; p = .02).

Conclusion: Oral bisphosphonate use was associated with significantly lower invasive breast cancer incidence, suggesting bisphosphonates may have inhibiting effects on breast cancer. PMID: 20567009 [PubMed - indexed for MEDLINE]PMCID: PMC2917313 [Available on 2011/8/1].