Sub-4 nm mapping of donor-acceptor organic semiconductor nanoparticle composition.

We report, for the first time, sub-4 nm mapping of donor : acceptor nanoparticle composition in eco-friendly colloidal dispersions for organic electronics. Low energy scanning transmission electron microscopy (STEM) energy dispersive X-ray spectroscopy (EDX) mapping has revealed the internal morphology of organic semiconductor donor : acceptor blend nanoparticles at the sub-4 nm level. A unique element was available for utilisation as a fingerprint element to differentiate donor from acceptor material in each blend system. Si was used to map the location of donor polymer PTzBI-Si in PTzBI-Si:N2200 nanoparticles, and S (in addition to N) was used to map donor polymer TQ1 in TQ1:PC71BM nanoparticles. For select material blends, synchrotron-based scanning transmission X-ray microscopy (STXM), was demonstrated to remain as the superior chemical contrast technique for mapping organic donor : acceptor morphology, including for material combinations lacking a unique fingerprint element (e.g. PTQ10:Y6), or systems where the unique element is in a terminal functional group (unsaturated, dangling bonds) and can hence be easily damaged under the electron beam, e.g. F on PTQ10 donor polymer in the PTQ10:IDIC donor : acceptor blend. We provide both qualitative and quantitative compositional mapping of organic semiconductor nanoparticles with STEM EDX, with sub-domains resolved in nanoparticles as small as 30 nm in diameter. The sub-4 nm mapping technology reported here shows great promise for the optimisation of organic semiconductor blends for applications in organic electronics (solar cells and bioelectronics) and photocatalysis, and has further applications in organic core-shell nanomedicines.

Out-Of-Plane Ordered Laminate Borides and Their 2D Ti-Based Derivative from Chemical Exfoliation.

Exploratory theoretical predictions in uncharted structural and compositional space are integral to materials discoveries. Inspired by M5 SiB2 (T2) phases, the finding of a family of laminated quaternary metal borides, M'4 M″SiB2 , with out-of-plane chemical order is reported here. 11 chemically ordered phases as well as 40 solid solutions, introducing four elements previously not observed in these borides are predicted. The predictions are experimentally verified for Ti4 MoSiB2 , establishing Ti as part of the T2 boride compositional space. Chemical exfoliation of Ti4 MoSiB2 and select removal of Si and MoB2 sub-layers is validated by derivation of a 2D material, TiOx Cly , of high yield and in the form of delaminated sheets. These sheets have an experimentally determined direct band gap of ≈4.1 eV, and display characteristics suitable for supercapacitor applications. The results take the concept of chemical exfoliation beyond currently available 2D materials, and expands the envelope of 3D and 2D candidates, and their applications.

Boridene: Two-dimensional Mo4/3B2-x with ordered metal vacancies obtained by chemical exfoliation.

Extensive research has been invested in two-dimensional (2D) materials, typically synthesized by exfoliation of van der Waals solids. One exception is MXenes, derived from the etching of constituent layers in transition metal carbides and nitrides. We report the experimental realization of boridene in the form of single-layer 2D molybdenum boride sheets with ordered metal vacancies, Mo4/3B2-xTz (where Tz is fluorine, oxygen, or hydroxide surface terminations), produced by selective etching of aluminum and yttrium or scandium atoms from 3D in-plane chemically ordered (Mo2/3Y1/3)2AlB2 and (Mo2/3Sc1/3)2AlB2 in aqueous hydrofluoric acid. The discovery of a 2D transition metal boride suggests a wealth of future 2D materials that can be obtained through the chemical exfoliation of laminated compounds.

Electronic and optical characterization of 2D Ti2C and Nb2C (MXene) thin films.

Two-dimensional (2D) transition metal carbides and/or nitrides (MXenes) are a new class of 2D materials, with extensive opportunities for property tailoring due to the numerous possibilities for varying chemistries and surface terminations. Here, Ti2AlC and Nb2AlC MAX phase epitaxial thin films were deposited on sapphire substrates by physical vapor deposition. The films were then etched in LiF/HCl solutions, yielding Li-intercalated, 2D Ti2CT z and Nb2CT z films, whose terminations, transport and optical properties were characterized. The former exhibits metallic conductivity, with weak localization below 50 K. In contrast, the Nb-based film exhibits an increase in resistivity with decreasing temperature from RT down to 40 K consistent with variable range hopping transport. The optical properties of both films were determined from spectroscopic ellipsometry in the 0.75 to 3.50 eV range. The results for Ti2CT z films confirm the metallic behavior. In contrast, no evidence of metallic behavior is observed for the Nb2CT z film. The present work therefore demonstrates that one fruitful approach to alter the electronic and optical properties of MXenes is to change the nature of the transition metal.

2D Transition Metal Carbides (MXenes) for Carbon Capture.

Global warming caused by burning of fossil fuels is indisputably one of mankind's greatest challenges in the 21st century. To reduce the ever-increasing CO2 emissions released into the atmosphere, dry solid adsorbents with large surface-to-volume ratio such as carbonaceous materials, zeolites, and metal-organic frameworks have emerged as promising material candidates for capturing CO2 . However, challenges remain because of limited CO2 /N2 selectivity and long-term stability. The effective adsorption of CO2 gas (≈12 mol kg-1 ) on individual sheets of 2D transition metal carbides (referred to as MXenes) is reported here. It is shown that exposure to N2 gas results in no adsorption, consistent with first-principles calculations. The adsorption efficiency combined with the CO2 /N2 selectivity, together with a chemical and thermal stability, identifies the archetype Ti3 C2 MXene as a new material for carbon capture (CC) applications.

On the Structural Stability of MXene and the Role of Transition Metal Adatoms.

In the present communication, the atomic structure and coordination of surface adsorbed species on Nb2C MXene is investigated over time. In particular, the influence of the Nb adatoms on the structural stability and oxidation behavior of the MXene is addressed. This investigation is based on the plane-view geometry observations of single Nb2C MXene sheets by a combination of atomic-resolution scanning transmission electron microscopy (STEM), electron energy loss spectroscopy (EELS) and STEM image simulations.

Tailoring Structure, Composition, and Energy Storage Properties of MXenes from Selective Etching of In-Plane, Chemically Ordered MAX Phases.

The exploration of 2D solids is one of our time's generators of materials discoveries. A recent addition to the 2D world is MXenes that possses a rich chemistry due to the large parent family of MAX phases. Recently, a new type of atomic laminated phases (coined i-MAX) is reported, in which two different transition metal atoms are ordered in the basal planes. Herein, these i-MAX phases are used in a new route for tailoriong the MXene structure and composition. By employing different etching protocols to the parent i-MAX phase (Mo2/3 Y1/3 )2 AlC, the resulting MXene can be either: i) (Mo2/3 Y1/3 )2 C with in-plane elemental order through selective removal of Al atoms or ii) Mo1.33 C with ordered vacancies through selective removal of both Al and Y atoms. When (Mo2/3 Y1/3 )2 C (ideal stoichiometry) is used as an electrode in a supercapacitor-with KOH electrolyte-a volumetric capacitance exceeding 1500 F cm-3 is obtained, which is 40% higher than that of its Mo1.33 C counterpart. With H2 SO4 , the trend is reversed, with the latter exhibiting the higher capacitance (≈1200 F cm-3 ). This additional ability for structural tailoring will indubitably prove to be a powerful tool in property-tailoring of 2D materials, as exemplified here for supercapacitors.

Sodium hydroxide and vacuum annealing modifications of the surface terminations of a Ti3C2 (MXene) epitaxial thin film.

We investigate, and quantify, changes in structure and surface terminations of epitaxial thin films of titanium carbide (Ti3C2) MXene, when treated by sodium hydroxide solution followed by vacuum annealing at 550 °C. Using X-ray photoelectron spectroscopy and scanning transmission electron microscopy, we show that NaOH treatment produce an increase in the c-lattice parameter together with an increase in the O terminations and a decrease in the F terminations. There is also an increase in the percentage of the binding energy of Ti-species in Ti 2p XPS region, which suggests an increase in the overall oxidation state of Ti. After subsequent annealing, the c-lattice parameter is slightly reduced, the overall oxidation state of Ti is decreased, and the F surface terminations are further diminished, leaving a surface with predominantly O as the surface terminating species. It is important to note that NaOH treatment facilitates removal of F at lower annealing temperatures than previously reported, which in turn is important for the range of attainable properties.

Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes.

OBJECTIVE: To investigate associations between combined hormonal contraception and progestogen-only contraception and risks of venous thromboembolism by progestogen and carriership of genetic hemostatic variations. METHODS: This was a case-control study in Sweden carried out between 2003 and 2009, which included 948 patients with venous thromboembolism and 902 individuals in a control group, all aged 18-54 years. Information was obtained by telephone interviews and DNA analyses of blood samples. Radiologic referrals were used for case ascertainment. For comparisons, odds ratios were estimated by unconditional logistic regression analysis adjusting for smoking, body mass index (BMI), and immobilization. RESULTS: The odds ratio (OR) for current use of combined hormonal contraception was 5.3 (95% confidence interval [CI] 4.0-7.0). Desogestrel combinations had the highest OR (11.4, 95% CI 6.0-22.0). The OR for injection of medroxyprogesterone acetate was 2.2 (95% CI 1.3-4.0). In users of combined hormonal contraception with the factor V Leiden mutation, the OR was 20.6 (95% CI 8.9-58). In women who used progestogen-only contraception and carried the factor V Leiden mutation, the OR was 5.4 (95% CI 2.5-13). CONCLUSION: Risks of venous thromboembolism in association with combined hormonal contraception vary by type of progestogen and independently of BMI and smoking. Thrombophilic genotypes such as factor V Leiden increase risks of venous thromboembolism in users of combined hormonal contraception. Except for injection of medroxyprogesterone acetate, progestin-only contraception seems to be the least thrombogenic hormonal contraception for women carrying genetic hemostatic variations. LEVEL OF EVIDENCE: II.

Influenza H1N1 vaccination and adverse pregnancy outcome.

Although vaccines against influenza can reduce maternal morbidity and mortality, large-scale data on adverse effects in the offspring are scarce. Historical cohort study in Stockholm County, Sweden. We linked H1N1 vaccination data (Pandemrix(®), a mono-valent AS03 adjuvanted H1N1 vaccine) with pregnancy and birth data from 21,087 women with singleton offspring conceived between February 2009 and January 2010 (vaccinated during pregnancy: n = 13,297 vs. unvaccinated: n = 7,790). Data were analysed by conceptualizing the observational cohort as a series of nested cohorts defined at each week of gestation. Logistic regression estimated odds ratios (ORs) for low birth weight (LBW, <2,500 g), preterm birth (<37 completed weeks), small-for-gestational age (SGA, <10th percentile of the gestational age-specific birth weight within the cohort), low 5-min Apgar score (<7), and caesarean section. Data were adjusted for potential confounders, including maternal age, body mass index, smoking, parity, civil status and comorbidities. Compared with infants of non-vaccinated women, infants of vaccinated women had similar adjusted ORs (95 % CI) for LBW (0.91; 0.79-1.04), preterm birth (0.99; 0.89-1.10), SGA (0.97; 0.90-1.05), low Apgar score (1.05, 0.84-1.31), and a marginal risk reduction for caesarean section (0.94, 0.89-0.99). H1N1 vaccination during pregnancy, using an AS03-adjuvanted vaccine, does not appear to adversely influence offspring risks of LBW, preterm birth, SGA, or low Apgar score. Our results suggest that this vaccine is safe for the offspring when used in different stages of pregnancy.

Non-steroidal anti-inflammatory drugs and venous thromboembolism in women.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) might increase the risk of venous thromboembolism (VTE), and risks might differ by type of NSAID. Compared with men, women have a higher incidence of VTE at younger age, and they more often use NSAIDs. OBJECTIVES: To assess risks of VTE in young and middle-aged women in association with use of NSAIDs. PATIENTS/METHODS: In a nationwide case­control study (Thrombo Embolism Hormone Study) performed in Sweden 2003­2009, we included as cases 1433 women, 18 to 64 years of age with a first time VTE. Controls were 1402 randomly selected women, frequency matched by age. Information was obtained by telephone interviews and DNA analyses of blood samples. We calculated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) adjusting for degree of immobilization, chronic disease, smoking, body mass index, use of hormonal contraception, hormone therapy or other NSAIDs. RESULTS: Use of NSAIDs was not associated with increased risks of VTE (OR = 0.98, 95% CI 0.80­1.19). The OR was 0.88 for propionic acid derivatives (95% CI 0.72­1.10), 1.18 for acetic acid derivatives (95% CI 0.82­1.70) and 1.76 for coxibs (95% CI 0.73­4.27). For users of acetic acid derivatives and coxibs, the ORs increased by cumulative dose. Carriership of the prothrombin gene mutation or factor V Leiden had only minor effects on the results. CONCLUSIONS: We found no increased risks of VTE in association with use of NSAIDs. Users of high cumulative doses of acetic acid derivatives and coxibs had the highest risks, suggesting a relationship with cyclooxygenase selectivity and dose.

Risk factors for venous thromboembolism in pre-and postmenopausal women.

INTRODUCTION: Hemostasis in women is affected by changes of estrogen levels. The role of endogenous estrogens on risk of venous thromboembolism (VTE) remains unclear. The aim of this study was to investigate the importance of acquired and genetic risk factors for VTE in pre-and postmenopausal women. METHOD: In a nationwide case-control study we included as cases 1470 women, 18 to 64years of age with a first time VTE. The 1590 controls were randomly selected and matched by age to the cases. Information on risk factors was obtained by interviews and DNA-analyses. We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The ORs were generally of similar magnitude in pre- and postmenopausal women. The highest risk was for the combination of surgery and cast (adjusted OR 54.12, 95% CI 16.62-176.19) in postmenopausal women. The adjusted OR for use of menopausal hormone therapy was 3.73 (95% CI 1.86-7.50) in premenopausal and 2.22 (95% CI 1.54-3.19) in postmenopausal women. Overweight was linked to an increased risk and exercise to a decreased risk, regardless of menopausal status. CONCLUSION: Menopausal status had only minor influence on the risk levels. Acquired transient risk factors conveyed the highest risks for VTE.

European Medicines Agency review of post-authorisation studies with implications for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance.

PURPOSE: A review of post-authorisation studies requested in 2007 by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) was undertaken to determine compliance and the need for research capacity in the European Union (EU), with implications for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). METHODS: Information from the EMA's electronic records management systems was analysed. RESULTS: As of 31 January 2010, of the 60 relevant studies identified, 52 had been progressed to being able to start data collection (including six merged into a single study). Of the remaining eight studies, the agreement of the CHMP that a proposed study was no longer required is documented for six, with a final decision having not been reached for another study and an acknowledgement by the CHMP that a further study would not be progressed. Of the 47 studies that could therefore have commenced data collection or extraction, 38 were ongoing, four were complete and five had not yet started. Most studies were conducted within the EU. CONCLUSION: Compliance with the request of the CHMP to conduct studies is very good. The review identified the need for careful consideration of the necessity of studies and of timely dialogue on protocols in advance of a CHMP opinion. The need for expertise and capacity within the EU for the conduct of post-authorisation studies is confirmed. ENCePP as a transparency and excellence network and as an initiative to build research capacity will enhance post-authorisation medicines research.

Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden.

OBJECTIVE: To examine the risk of neurological and autoimmune disorders of special interest in people vaccinated against pandemic influenza A (H1N1) with Pandemrix (GlaxoSmithKline, Middlesex, UK) compared with unvaccinated people over 8-10 months. DESIGN: Retrospective cohort study linking individualised data on pandemic vaccinations to an inpatient and specialist database on healthcare utilisation in Stockholm county for follow-up during and after the pandemic period. SETTING: Stockholm county, Sweden. Population All people registered in Stockholm county on 1 October 2009 and who had lived in this region since 1 January 1998; 1,024,019 were vaccinated against H1N1 and 921,005 remained unvaccinated. MAIN OUTCOME MEASURES: Neurological and autoimmune diagnoses according to the European Medicines Agency strategy for monitoring of adverse events of special interest defined using ICD-10 codes for Guillain-Barré syndrome, Bell's palsy, multiple sclerosis, polyneuropathy, anaesthesia or hypoaesthesia, paraesthesia, narcolepsy (added), and autoimmune conditions such as rheumatoid arthritis, inflammatory bowel disease, and type 1 diabetes; and short term mortality according to vaccination status. RESULTS: Excess risks among vaccinated compared with unvaccinated people were of low magnitude for Bell's palsy (hazard ratio 1.25, 95% confidence interval 1.06 to 1.48) and paraesthesia (1.11, 1.00 to 1.23) after adjustment for age, sex, socioeconomic status, and healthcare utilisation. Risks for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged. The risks of paraesthesia and inflammatory bowel disease among those vaccinated in the early phase (within 45 days from 1 October 2009) of the vaccination campaign were significantly increased; the risk being increased within the first six weeks after vaccination. Those vaccinated in the early phase were at a slightly reduced risk of death than those who were unvaccinated (0.94, 0.91 to 0.98), whereas those vaccinated in the late phase had an overall reduced mortality (0.68, 0.64 to 0.71). These associations could be real or explained, partly or entirely, by residual confounding. CONCLUSIONS: Results for the safety of Pandemrix over 8-10 months of follow-up were reassuring -notably, no change in the risk for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, or rheumatoid arthritis. Relative risks were significantly increased for Bell's palsy, paraesthesia, and inflammatory bowel disease after vaccination, predominantly in the early phase of the vaccination campaign. Small numbers of children and adolescents with narcolepsy precluded any meaningful conclusions.

Increased risk of abdominal wall hernia associated with combination anti-retroviral therapy in HIV-infected patients-results from a Swedish cohort-study.

PURPOSE: To determine if anti-retroviral therapy (ART) in HIV-infected patients is associated with an increased risk for development of abdominal wall hernia. METHODS: A cohort study of 1072 HIV-infected patients in Sweden. Information was collected by questionnaires to patients and treating physicians, chart reviews by study physicians and regular blood tests for metabolic disorders. Adjusted relative risks were estimated by Cox proportional hazards models. RESULTS: Sixty-three patients (5.9%) developed abdominal wall hernia during the study period, 34 inguinal and 29 midline. Compared to the male general population, inguinal hernia was twice as common in the male study population, standardized incidence ratio (SIR) 2.0 (95% confidence interval (CI) 1.4-2.8). An increased incidence rate of abdominal wall hernia was found in patients exposed to ART, 11.3 per 1000 person-years (PY) compared with therapy naïves, 2.1 per 1000 PY. When adjusting for confounding risk-factors, ART containing protease inhibitors (PIs) during the 2nd and 3rd year of treatment was associated with the development of midline hernia with a hazard ratio (HR) of 10.7 (95%CI 1.3-85.7), and of inguinal hernia with an HR of 4.4 (95%CI 1.1-16.6). Other independent risk factors were age and diabetes/impaired fasting glucose for midline hernia, and age and a previous diagnosis of AIDS for inguinal hernia. CONCLUSIONS: We found an increased risk of developing abdominal wall hernia associated with PI-containing ART. The size of the study-population did not permit any conclusions regarding non-PI-containing ART.

Reductions in use of hormone replacement therapy: effects on Swedish breast cancer incidence trends only seen after several years.

Studies from Western countries have found evidence of a recent decline in breast cancer incidence rates in postmenopausal women, findings which have been hypothesized to reflect a reduced use of hormonal replacement therapy (HRT). We examined breast cancer incidence trends in Sweden between 1997 and 2007, a period characterized by a drop in the use of HRT. Incidence trends were assessed using data from three population-based Regional Clinical Registries on breast cancer covering 2/3 of the Swedish population. Information on HRT sales was obtained from national pharmacy data. The prevalence of HRT use in age group 50-59 years decreased from a peak of 36% in 1999 to 27% in 2002 and further to 9% in 2007. Incidence rates of breast cancer in women 50 years and older increased between 1997 and 2003. A significant decrease in incidence between 2003 and 2007 was confined to women 50-59 years of age, the group in which the prevalence of HRT use has been highest and the decrease in use most pronounced. As opposed to the immediate effects reported from the United States and other regions, there was a time lag between the drop in HRT use and clear reductions in breast cancer incidence. This may reflect between country differences with regard to types of HRT used, and the rate, magnitude and pattern of change in use. The present findings give further support to the notion that HRT use is a driver of breast cancer incidence trends on the population level.

Evaluation of post-authorization safety studies in the first cohort of EU Risk Management Plans at time of regulatory approval.

BACKGROUND: Since November 2005, an EU Risk Management Plan (EU-RMP) has had to be submitted as part of a marketing application for all new chemical entities in the EU. In the EU-RMP, the safety profile of the medicine has to be described and pharmacovigilance activities should be proposed to study further safety concerns during use of the drug in the real-world setting. These activities include, for example, collection of spontaneously reported adverse events and post-authorization safety studies (PASS). Since the submission of an EU-RMP is a relatively new requirement, there is limited knowledge on the quality and completeness of the study protocols of PASS at the time of approval and there are no data on the influence of certain drug characteristics on the proposed pharmacovigilance activities. OBJECTIVE: To examine the types of proposed pharmacovigilance activities in a sample of EU-RMPs, describe and evaluate the methodology of PASS, identify problems and propose remedies, and compare characteristics between biologicals and small molecules. METHODS: Eighteen EU-RMPs (nine for biologicals, nine for small molecules) given a positive decision regarding the marketing application by the Committee for Medicinal Products for Human Use between November 2005 and May 2007 were included in this descriptive cohort study. The EU-RMPs were selected over time and different therapeutic areas. Classification of the safety concerns ('important identified risks', 'important potential risks', 'important missing information' within the EU-RMP was studied. For PASS, data source (registry, population-based database, sponsor-owned clinical trial database), source of study population to be included in PASS and comprehensiveness of study protocol (full protocol, limited protocol, study synopsis, short description, commitment without further information) were studied. RESULTS: Compared to small molecules, safety concerns for biologicals were less frequently classified as important identified risks (relative risk [RR] 0.6; 95% CI 0.3, 1.0) and more frequently as important missing information (RR 1.6; 95% CI 1.0, 2.7). Forty-seven PASS were proposed; 31 for biologicals and 16 for small molecules. Compared with studies proposed in population-based databases (4 for biologicals, 8 for small molecules), studies in registries (18 for biologicals, 4 for small molecules) were more frequently proposed for biologicals than for small molecules (RR 2.5; 95% CI 1.1, 5.7). About 60% of the proposed PASS will include EU inhabitants. No full study protocols were submitted; 26% involved a limited study protocol, 33% a study synopsis, 37% a short description and 4% a commitment without further information. CONCLUSION: Approximately 40% of the study proposals for PASS were classified as a short description or a commitment to perform a study without further information, precluding an adequate scientific assessment. Studying non-EU populations may give rise to difficulties with generalizability of the results to the EU due to differences in patient characteristics, differences in the indication for the medicine and different healthcare systems. This study emphasizes the need for more complete study proposals to be submitted earlier on in the evaluation period and for the inclusion of EU inhabitants in PASS. In addition, differences in the characteristics between biologicals and small molecules, e.g. in the data source proposed, support the need for individualized tailored PASS depending on the type of drug.

Breast cancer incidence after hormonal infertility treatment in Sweden: a cohort study.

OBJECTIVE: To assess the impact of infertility treatment with causes of infertility on incidence of breast cancer. STUDY DESIGN: Historical prospective cohort study of 1135 women attending major university clinics for treatment of infertility in Sweden, 1961-1976. Women were classified as users of clomiphene citrate or gonadotropins, or a combination of both therapies. Standardized incidence ratios were calculated to estimate relative risk of breast cancer. RESULTS: We observed 54 cases of breast cancer during 1961-2004, which did not significantly exceed those expected. Users of high-dose clomiphene citrate had an almost 2-fold increased risk (standardized incidence ratio, 1.90; 95% confidence interval, 1.08-3.35). This association was more pronounced among women referred for nonovulatory factors, with 3-fold increased risk (standardized incidence ratio, 3.00; 95% confidence interval, 1.35-6.67). CONCLUSION: No overall increased risk for breast cancer was shown with infertility treatment. Women with nonovulatory causes treated with high-dose clomiphene citrate therapy may have an elevated risk for breast cancer.

Limited knowledge on progestogen-only contraception and risk of venous thromboembolism.

OBJECTIVE: To assess the current knowledge concerning progestogen-only contraception (POC) and risks of venous thromboembolism (VTE). DESIGN AND SETTING: Systematic review of the literature on observational and analytical studies reporting risk estimates for VTE in women exposed to POCs. METHODS AND MAIN OUTCOME MEASURES: We performed a computerized literature search in the Pub Med, Embase, and the Cochrane Library for studies published between 1966 and February 13, 2008. Based on the evaluated studies we calculated an overall risk estimate for VTE in association with POC. RESULTS: Four case-control studies and one cohort study were included. Of the case-control studies, three reported an increased risk and one a decreased risk of VTE. The cohort study found divergent results depending on the type of statistical analysis used. None of the results was statistically significant. The overall odds ratio for POC-associated VTE in the four case-control studies was 1.45 (95% CI=0.92-2.26). CONCLUSIONS: The risk of VTE associated with use of POCs is poorly investigated. The slightly elevated overall risk estimate might suggest an association between POC and an increased risk for VTE. The results must, however, be interpreted with caution due to the possibility of residual confounding. Well-designed studies with sufficient statistical power to evaluate risks of VTE with POC are warranted.