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Where possible, we tried to account for potential modifying and confounding variables when reporting on these associations and we used meta-regression techniques to explore heterogeneity among studies. We performed a systematic review and meta-analysis following a predetermined protocol in accordance with the Meta-analysis of Observational Studies in Epidemiology MOOSE 6. All searches were carried out without any language restrictions, using free text and medical subject headings.

We performed our search using two themes. The first theme included terms related to the exposure: The second theme included terms related to the outcome: These terms were identified from exemplar articles identified in a scout search.


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A theme was not used for study design in our initial search. To identify articles that were yet to be cited or yet to be indexed in the electronic databases mentioned above, we handsearched major neurology and internal medicine journals published after December and the reference lists of all identified relevant publications. We also searched abstracts of major national and international Neurology, Internal Medicine, and Neurosurgery conferences from January until June using Conference Papers Index. In addition, we contacted local experts in stroke for information about other potential ongoing or unpublished studies.

Abstracts or papers in languages other than English were translated. Articles were independently evaluated for eligibility using a two-stage procedure.

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Both primary authors Farnaz Amoozegar, Bijoy K. Menon initially reviewed all citations for original articles related to the primary study question in a broad sense. Inter-rater agreement was measured using the kappa statistic. Disagreements were resolved by consensus. Potentially relevant articles then underwent full text review. We included studies that met our explicit population, exposure, outcome, and design criteria. Studies were excluded if the study population included: The exposure was any form of hormonal contraception, such as oral contraceptives pills, patches Evra , or injections depo-provera.

The outcome was CVST, objectively confirmed by imaging: As CVST is a rare outcome, case—control studies were the most commonly employed study design to measure this association. However, cohort studies have also been performed in this area.

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Given that randomized controlled trials are not feasible, we limited our review to case—control and cohort designs. The same reviewers Farnaz Amoozegar, Bijoy K. Menon independently extracted data from all included studies. If missing data were identified for a given study, attempts were made to contact the authors to obtain the data.

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When multiple papers published the same data, we used the latest publication, and supplemented it, if necessary, with data from earlier publications. The odds ratio OR was used as the common measure of association across studies. When studies only reported on stratum-specific OR for the relationship between the use of hormonal contraceptives and occurrence of CVST stratified by potential confounding variables, we calculated the assumed common OR across all stratifying variables using the Mantel—Haenszel method. A higher prevalence of hormonal contraceptive use in the population could potentially result in over-reporting of use.

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In addition, a higher prevalence of poverty, anemia, poor nutritional status, dehydration, and other residual confounding factors in developing countries may increase the incidence of CVST, when compared to developed countries. Statistical heterogeneity for the pooled OR was evaluated using the I 2 statistic and the Cochran Q statistic. In order to assess the nature of cumulative evidence over time on our research question, we performed a cumulative meta-analysis using the Der-Simonian and Laird random effects model.

An additional four studies were identified by handsearching the literature. The two reviewers agreed We excluded articles after initial screening of titles and abstracts. Of the 50 studies selected for full text review, 11 studies were included in the systematic review 8 — Thus only 9 of 11 studies contained sufficient information for a meta-analysis to calculate the pooled odds of CVST.

These nine studies were in the English language. Study period ranged from to All were case—control studies. Two studies were multi-center and three were from developing countries. Total subjects enrolled in the studies ranged from 32 to All studies reported only on the use of oral contraceptives. Only two studies reported on the duration of exposure to oral contraceptives.


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Flow diagram for studies included in systematic review and meta-analysis. Four studies had well-defined cases, and five studies had well-defined controls. Controls were matched to case characteristics in five studies. Potential confounders and modifiers were discussed in five studies to varying extents. Variable adjustment for these factors occurred in the same five studies. A study is defined as being of high quality if it satisfies at least four of the five criteria above.

Among the nine studies that reported OR, the pooled odds of developing CVST in women of reproductive age taking oral contraceptives was 7. De Bruijn et al. The actual number of healthy controls taking OCPs and third-generation OCPs were not available to us, despite contacting study authors. The incidence rate IR for non-exposed women was 0. The authors, when contacted, had person time data for exposure and non-exposure; however, the study design was such that we could not calculate our summary estimate, i. In addition, original clinical records to confirm the diagnosis of CVST could not be obtained in this study.

Forest plot with pooled odds ratio for relationship between oral contraceptive use and cerebral venous sinus thrombosis random effects model. Despite these findings, the confidence intervals around the estimates were wide. In this systematic review and meta-analysis, we found that the odds of CVST in women of reproductive age exposed to oral contraceptives was about sevenfold higher than the odds of CVST in those not taking oral contraceptives. In addition, our review showed that there was insufficient evidence on the relative safety of third generation OCPs when compared to previous generation OCPs in increasing the odds of CVST.

In addition, the odds of CVST with OCP use is not significantly different in developing countries when compared to developed countries. These latter issues were not assessed in detail in the prior systematic review. We found moderate to high heterogeneity between studies included in our meta-analysis. Given varying quality of studies included in our meta-analysis, study quality itself could be responsible for this heterogeneity.

We did not, however, find any statistical evidence that study quality was responsible for this heterogeneity. Variables such as age, smoking, and prothrombotic genetic mutations can certainly contribute to the risk of CVST and influence the results obtained 3 , 5. Meta-regression, however, did not identify these variables as contributing to study heterogeneity either.

The prevalence of CVST is reported to be high in developing countries when compared to developed countries 4 , A caveat to this conclusion would be that none of our included studies were from Sub-Saharan Africa or South Asia, regions of the world where malnutrition and anemia are more prevalent 20 , Available for download now. Only 20 left in stock more on the way.

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