Hormonal contraceptives and the brain: A systematic review on 60 years of neuroimaging, EEG, and biochemical studies in humans and animals.

Hormonal contraception has been widely prescribed for decades. Although safety and efficacy are well-established, much uncertainty remains regarding brain effects of hormonal contraception. We systematically review human and animal studies on the brain effects of hormonal contraception which employed neuroimaging techniques such as MRI, PET and EEG, as well as animal studies which reported on neurotransmitter and other brain biochemical effects. We screened 1001 articles and ultimately extracted data from 70, comprising 51 human and 19 animal studies. Of note, there were no animal studies which employed structural or functional MRI, MRS or PET. In summary, our review shows hormonal contraceptive associations with changes in the brain have been documented. Many questions remain and more studies are needed to describe the effects of hormonal contraception on the brain.

High thrombin-activatable fibrinolysis inhibitor expression in thrombi from stroke patients in elevated estrogen states.

BACKGROUND: The risk of acute ischemic stroke (AIS) associated with high estrogen states, including pregnant patients and those using oral contraceptives, has been well documented. We described the histological composition of thrombi collected in these cases. METHODS: From a prospective tissue registry (STRIP registry) of thrombi retrieved during mechanical thrombectomy for AIS, we identified 5 patients with high estrogen states: 1 post-partum patient, 1 undergoing hormone replacement therapy and 3 consuming oral contraceptive pills. Five male control patients were randomly chosen matched by age. Immunohistochemistry for CD42b (platelets), von Willebrand factor (vWF), thrombin-activatable fibrinolysis inhibitor (TAFI), fibrinogen and plasminogen activator inhibitor-1 (PAI-1) was performed. Expression was quantified using Orbit Image Software. Student's t-test was performed as appropriate. RESULTS: Mean TAFI content for the high estrogen state group was higher than controls (25.6 ± 11.9% versus 9.3 ± 9.0%, p = 0.043*). Mean platelet content for the high estrogen state group was lower than controls (41.7 ± 10.6% versus 61.8 ± 12.9%, p = 0.029*). No significant difference was found in vWF, fibrinogen and PAI-1 expression. Mean time to recanalize was higher in the high estrogen state group compared to the control group (57.8 ± 27.6 versus 22.6 ± 11.4 min, p = 0.0351*). The mean number of passes required was higher in the high estrogen group compared to controls 4.6 versus 1.2, p = 0.0261*). CONCLUSIONS: TAFI expression, a powerful driver of thrombosis, was significantly higher in stroke thrombi among patients with high estrogen states compared to controls.

Differential Adsorption of Dissolved Organic Matter and Phosphorus on Clay Mineral in Water-Sediment System.

Lake sediments connection to the biogeochemical cycling of phosphorus (P) and carbon (C) influences streamwater quality. However, it is unclear whether and how the type of sediment controls P and C cycling in water. Here, the adsorption behavior of montmorillonite (Mt) with different interlayer cations (Na+, Ca2+, or Fe3+) on dissolved organic matter (DOM) and P was investigated to understand the role of Mt in regulating the organic carbon-to-phosphate (OC/P) ratio within freshwater systems. The adsorption capacity of Fe-Mt for P was 3.2-fold higher than that of Ca-Mt, while it was 1/3 lower for DOM. This dissimilarity in adsorption led to an increased OC/P in Fe-Mt-dominated water and a decreased OC/P in Ca-Mt-dominated water. Moreover, an in situ atomic force microscope and high-resolution mass spectrometry revealed molecular fractionation mechanisms and adsorptive processes. It was observed that DOM inhibited the nucleation and crystallization processes of P on the Mt surface, and P affected the binding energy of DOM on Mt through competitive adsorption, thereby governing the interfacial P/DOM dynamics on Mt substrates at a molecular level. These findings have important implications for water quality management, by highlighting the role of clay minerals as nutrient sinks and providing new strategies for controlling P and C dynamics in freshwater systems.

Diffusion of organochlorine (OCPs) and cypermethrin pesticides from rohu (Labeo rohita) internal organs to edible tissues during ice storage: a threat to human health.

The migration of organochlorine pesticides (OCPs) and cypermethrin residues from internal organs to edible tissues of ice-held Labeo rohita (rohu) was investigated in this study. The liver (246 µg/kg) had the highest level of ∑OCP residues, followed by the gills (226 µg/kg), intestine (167 µg/kg), and muscle tissue (54 µg/kg). The predominant OCPs in the liver and gut were endosulfan (53-66 µg/kg), endrin (45-53 µg/kg), and dichloro-diphenyl-trichloroethane (DDT; 26-35 µg/kg). The ∑OCP residues in muscle increased to 152 µg/kg when the entire rohu was stored in ice, but they decreased to 129 µg/kg in gill tissues. On days 5 and 9, the total OCPs in the liver increased to 317 µg/kg and 933 µg/kg, respectively. Beyond day 5 of storage, total internal organ disintegration had led to an abnormal increase in OCP residues of liver-like mass. Despite a threefold increase in overall OCP residues by day 9, accumulation of benzene hexachloride (BHC) and heptachlor was sixfold, endrin and DDT were fourfold, aldrin was threefold, and endosulfan and cypermethrin were both twofold. Endosulfan, DDT, endrin, and heptachlor were similarly lost in the gills at a rate of 40%, while aldrin and BHC were also lost at 60 and 30%, respectively. The accumulation of OCP residues in tissues has been attributed to particular types of fatty acid derivatives. The study concluded that while pesticide diffusion to edible tissues can occur during ice storage, the levels observed were well below the allowable limit for endosulfan, endrin, and DDT.

Assessment of organochlorine pesticide contamination in Astyanax altiparanae from the Alagados Dam, Southern Brazil.

Organochlorine pesticides (OCPs) are persistent pollutants previously used in agriculture, known for their ability to bioaccumulate and pose health risks. This study analyzed samples of roe, viscera, and muscle from Astyanax altiparanae fish collected from the Alagados reservoir in Paraná, Brazil. Samples were prepared through extraction and purification, then analyzed using gas chromatography with an electron capture detector (GC/ECD), chosen for its sensitivity in detecting OCPs. The method was validated for precision, accuracy, and detection limits. Detected OCPs included Aldrin (17.1 to 50.6 ng/g in roe), α-endosulfan (3.4 to 23.5 ng/g), p, p'-DDE (4.2 to 134.7 ng/g), Dieldrin (84.7 to 183.1 ng/g), ß-endosulfan (6.0 to 51.6 ng/g), and p, p'-DDT (56.6 to 286.8 ng/g). In viscera, concentrations ranged from Aldrin (19.8 to 93.3 ng/g) to p, p'-DDT (52.3 to 89.2 ng/g). Muscle samples showed similar trends. Principal component analysis indicated a link between higher OCP concentrations and increased abdominal width of the fish. While OCP levels were below FAO and WHO limits, risk quotient calculations suggest potential health risks from consuming these fish.

Prescribing Information: Elizabeth B. Connell, the Pill, and the (Woman) Patient's Peace of Mind.

Throughout the 1970s and 1980s, commercialized reproductive technologies experienced a reputational crisis as news about the hormonal birth control pill's possible side effects reportedly caused 18-30% of women to stop taking it. While secondary literature has followed patients' and legislatures' actions, few histories have focused on physicians' responses. How did physicians manage this public crisis of confidence? This article contributes to existing literature through a backstage look at the work of Elizabeth B. Connell (1925-2018), whose wide-ranging career in medicine, academia, government, industry consulting, and popular writing embroiled her at the center of these controversies. To counter critique from legislatures and consumer reformers, Connell became a mediator for medicine in the public sphere, dispensing select information and arguing for limits on others - for the patient's sake. If legislative inquiry's primary havoc was unleashing information, Connell would help the profession moderate it. Because Connell was a woman doctor whom health feminists who were her contemporaries denied was a feminist doctor, the existing scholarship has occluded her. This article reconstructs the contributions of this important and flawed doctor, illuminating how she contorted herself to suit her various public messages, constrained by her conflicting, dual identities as woman and doctor.

Quantum dots decorated photoanodes in bioelectrochemical fuel cells: Enhanced electricity generation using green algae.

The power performance of the bio-electrochemical fuel cells (BEFCs) depends mainly on the energy harvesting ability of the anode material. The anode materials with low bandgap energy and high electrochemical stability are highly desirable in the BEFCs. To address this issue, a novel anode is designed using indium tin oxide (ITO) modified by chromium oxide quantum dots (CQDs). The CQDs were synthesized using facile and advanced pulsed laser ablation in liquid (PLAL) technique. The combination of ITO and CQDs improved the optical properties of the photoanode by exhibiting a broad range of absorption in the visible to UV region. A systematic study has been performed to optimize the amount of CQDs and green Algae (Alg) film grown using the drop casting method. Chlorophyll (a, b, and total) content of algal cultures (with different concentrations) were optimized to investigate the power generation performance of each cell. The BEFC cell (ITO/Alg10/Cr3//Carbon) with optimized amounts of Alg and CQDs demonstrated enhanced photocurrent generation of 120 mA cm-2 at a photo-generated potential of 24.6 V m-2 . The same device exhibited a maximum power density of 7 W m-2 under continuous light illumination. The device also maintained 98% of its initial performance after 30 repeated cycles of light on-off measurements.

The role of the protein tyrosine phosphatase SHP2 in ossification.

SHP2, encoded by the PTPN11 gene, participates in multiple cell functions including cell proliferation, movement, and differentiation. PTPN11 loss-of-function and gain-of-function mutations are both associated with diseases, such as Noonan syndrome, whose manifestations include bone defects, suggesting a crucial role for SHP2 in the skeleton. However, the exact mechanisms by which SHP2 regulates bone development remain unclear. This review focuses on the current understanding of the regulation of SHP2 and highlights the vital roles of SHP2 in skeletal development, especially its roles in ossification. Overall, a better understanding of the functions of SHP2 in ossification will provide a new avenue to treat-related skeletal diseases.

Probing the spectral signatures of orange carotenoid protein by orthogonal translation with aromatic non-canonical amino acids.

Orange Carotenoid Protein (OCP) is a water-soluble photoreceptor involved in photoprotection of cyanobacteria. The photoactive OCP contains a bound ketocarotenoid cofactor held in a protein matrix with a hydrogen bonding network. We have developed a system to replace essential residues of the photoactive OCP with non-canonical aromatic analogues that produce well-defined chemical or steric changes. Preliminary spectroscopic evaluation of the generated OCP variants demonstrates the potential of this "molecular surgery" to disentangle protein-chromophore interaction networks that are critical for photoreceptor function. In this way, the number and strength of key contacts with non-canonical amino acids could be controlled and manipulated. We have illustrated this principle here by replacing hydrogen bond donating residues with aromatic non-canonical amino acids that alter the state preference of OCP.

Arterial stiffness and blood pressure are similar in naturally menstruating and oral contraceptive pill-using women during the higher hormone phases.

NEW FINDINGS: What is the central question of this study? Are there differences in blood pressure, arterial stiffness and indices of pressure waveforms between young oral contraceptive pill-using and naturally menstruating women during lower and higher hormone phases of their cycles? What is the main finding and its importance? Blood pressure, arterial stiffness and indices of pressure waveforms are influenced similarly by exogenous and endogenous hormones. However, lower levels of exogenous hormones moderately increase blood pressure among oral contraceptive pill-using women. ABSTRACT: Elevations in blood pressure (BP) are understood as having a bidirectional relationship with stiffening of central and peripheral arteries. Arterial stiffness is mitigated by oestrogen, which aides in arterial vasorelaxation. To evaluate whether BP, stiffness, and pressure waveforms were different between young healthy naturally menstruating (non-OCP) and oral contraceptive pill (OCP)-using women, we measured brachial and aortic BPs, carotid-to-femoral pulse wave velocity, carotid ß-stiffness, elastic modulus, central augmentation index and augmentation index normalized to a heart rate of 75 bpm, and forward and backward pressure waveforms in 22 women (22 (1) years, OCP: n = 12). To assess phasic differences, women were studied during the early follicular (≤5 days of menstruation onset) and early luteal (4 (2) days post-ovulation) phases of non-OCP and compared to the placebo pill (≤5 days of onset) and active pill (≤5 days of highest-dose active pill) phases of OCP. During the lower hormone phases, OCP users had significantly higher brachial systolic blood pressure (SBP) (119.3 (8.3) vs. 110.2 (8.3) mmHg, P = 0.02) and aortic SBP (104.10 (7.44) vs. 96.80 (6.39) mmHg, P = 0.03) as compared to non-OCP users; however, during the higher hormone phases, there were no differences in measures of brachial or aortic BP, arterial stiffness, or indices of BP waveforms between OCP and non-OCP users (P ≥ 0.05). In conclusion, exogenous and endogenous hormones have similar influences on BP and arterial stiffness; however, lower levels of exogenous hormones augment both central and peripheral BPs.

Integrated Structural Studies for Elucidating Carotenoid-Protein Interactions.

Carotenoids are ancient pigment molecules that, when associated with proteins, have a tremendous range of functional properties. Unlike most protein prosthetic groups, there are no recognizable primary structure motifs that predict carotenoid binding, hence the structural details of their amino acid interactions in proteins must be worked out empirically. Here we describe our recent efforts to combine complementary biophysical methods to elucidate the precise details of protein-carotenoid interactions in the Orange Carotenoid Protein and its evolutionary antecedents, the Helical Carotenoid Proteins (HCPs), CTD-like carotenoid proteins (CCPs).

Low-Cost Potentiometric Sensor for Chloride Measurement in Continuous Industrial Process Control.

Recently, the new updates in legislation about drinking water control and human health have increased the demand for novel electrochemical low-cost sensors, such as potentiometric ones. Nowadays, the determination of chloride ion in aqueous solutions has attracted great attention in several fields, from industrial processes to drinking water control. Indeed, chloride plays a crucial role in corrosion, also influencing the final taste of beverages, especially coffee. The main goal is to obtain devices suitable for continuous and real-time analysis. For these reasons, we investigated the possibility to develop an easy, low-cost potentiometric chloride sensor, able to perform analysis in aqueous mediums for long immersion time and reducing the need of periodic calibration. We realized a chloride ion selective electrode made of Ag/AgCl sintered pellet and we tested its response in model solutions compatible with drinking water. The sensor was able to produce a stable, reproducible, and accurate quantification of chloride in 900 s, without the need for a preliminary calibration test. This opens the route to potential applications of this sensor in continuous, in situ, and real time measurement of chloride ions in industrial processes, with a reduced need for periodic maintenance.

An oral combined contraceptive user with elevated D-dimer post COVID-19: a case report.

BACKGROUND: This case discusses the challenges created by COVID-19 (coronavirus disease 2019) in the area of hormonal contraception, highlighting the contraception knowledge gap for women in their post COVID-19 period, especially if they had high D-dimer levels. CASE PRESENTATION: This case involves a thirty-eight-year-old woman taking combined oral contraception (desogestrel/ethinyl oestradiol tablets) with a history of varicose veins. She recovered from a COVID-19 infection in November 2020. She presented to the emergency room with right lower-limb pain below the knee and progressive swelling for five days in February 2021. Physical examination of the lower limb showed mild swelling and tenderness of the right leg compared to the left leg. D-Dimer was elevated (1.06 mcg/mL FEU). COVID-19 screening was negative. A Doppler scan to exclude DVT was performed considering the clinical picture and high D-dimer level. There was no evidence of DVT in the right limb. She was reassured and discharged with instructions on when to visit the emergency room. The D-dimer had decreased to 0.53 mcg/mL FEU in March 2021. She booked an appointment with family medicine clinics because she was concerned about the continuation of combined oral contraception (desogestrel/ethinyl oestradiol tablets) with high D-dimer and risk of thrombosis. The follow-up D-dimer level in May 2021 was normal (0.4 mcg/mL FEU). The patient preferred to continue taking oral contraception. CONCLUSION: An evidence-based consensus is needed to guide clinicians in providing contraception counselling for such patients.

Effects of oral contraceptive for different responder women before GnRH antagonists: a systematic review and meta-analysis.

This analysis aimed to compare the efficacy of oral contraceptive pill (OCP) pretreatment for gonadotropin-releasing hormone antagonist (GnRH-ant) protocol, especially for different responder women. The PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases were searched for trials on with and without OCP pretreatment before stimulation with gonadotropins. The standardized mean differences (SMDs) or pooled risk ratios (RRs) with 95% confidence intervals (CIs) were used for statistical analysis. Fifteen studies with 5326 in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles were summarized. The clinical pregnancy rate, moderate or severe ovarian hyper-stimulation syndrome (OHSS) rate, and miscarriage rate was not found to be significantly different between patients with and those without OCP pretreatment, even after sensitivity analyses. In addition, there were still no statistically significant differences for the subgroups analyses of hyper-responders, poor responders, and normal responders. No significant differences were detected in the duration of ovarian stimulation, gonadotropin dose consumed, endometrial thickness on day of oocyte collection, or number of oocytes. This meta-analysis did not find an unequivocally beneficial effect of OCP pretreatment for different responder women with using a GnRH-ant protocol. The clinician should weigh the advantages and disadvantages of OCP pretreatment and guide the treatment scheduling considering the patient's own situation.

Analysis of Intrinsic and Extrinsic Coagulation Pathway Factors in OCP Treated PCOS Women.

Human polycystic ovary syndrome (PCOS)-a cluster of diseases displays various symptoms associated with endocrine and gynecological disorders in childbearing women. Oral contraceptive pills (OCP) being a drug of choice minimizes symptoms and complications associated with the disorder. But, the controversial data available in literature regarding use of OCPs compels us to setup a study design regarding effect of OCP treatment in PCOS subjects and the possible outcomes specifically regarding coagulation pathways. Two PCOS study groups have been selected according to Rotterdam Criteria: one with OCP treatment (n = 50) and other without any drug treatment i.e., drug naive (n = 50). Anthropometry, Biochemistry, Hormones, Insulin and various clotting factors like Factor XI, Factor V, tPA, TAT-III and D-dimer were analyzed in both groups. The results showed worsening of IR, Metabolic parameters and coagulopathy in OCP group comparative to drug naive group indicating adverse effects of the OCP treatment which puts these women at risk for number of future clinical implications especially Cardiovascular and metabolic complications.

Simplifying contraception requirements for iPLEDGE: A decision analysis.

BACKGROUND: For persons of childbearing potential prescribed isotretinoin, the iPLEDGE program requires use of 2 simultaneous methods of contraception or commitment to abstinence. OBJECTIVE: To model the relative effectiveness of a variety of contraception strategies for patients taking isotretinoin, including those that are acceptable according to iPLEDGE. METHODS: We performed a decision analysis modeling the estimated rate of pregnancy with various contraception strategies during a typical 6-month course of isotretinoin. RESULTS: Tier 1 contraception options (eg, subdermal hormonal implant, intrauterine devices) each had effectiveness of >99.5% alone. When combined with a secondary form of contraception, tier 2 contraception options (eg, depot medroxyprogesterone injections, combined oral contraceptives) each had effectiveness >99%. LIMITATIONS: Sensitivity analyses were conducted to evaluate the impact of uncertain parameters on the results. CONCLUSION: There may be opportunities to simplify iPLEDGE by recognizing the high effectiveness of tier 1 contraception options and increasing use of secondary forms of contraception among those using tier 2 contraception options as their primary form of contraception. Future studies are needed to understand the most effective strategies in clinical practice to prevent unintended pregnancy for patients taking isotretinoin to improve outcomes and provide patient-centered care.

Macrophage colony-stimulating factor pretreatment of bone marrow progenitor cells regulates osteoclast differentiation based upon the stage of myeloid development.

Osteoclasts (OCs) are large, multinucleated bone resorbing cells originating from the bone marrow myeloid lineage, and share a common progenitor with macrophages and dendritic cells. Bone marrow cells (BMCs) are a common source for in vitro osteoclastogenesis assays but are a highly heterogeneous mixture of cells. Protocols for in vitro osteoclastogenesis vary considerably thus hindering interpretation and comparison of results between studies. Macrophage colony-stimulating factor (M-CSF) pretreatment is commonly used to expand OC progenitors (OCPs) in BMC cultures before in vitro differentiation. However, the failure of osteoclastogenesis of M-CSF primed bone marrow myeloid blasts has been reported. In this study, we used a simple method of differential adherence to plastic to enrich OCP from mouse BMCs. We found that M-CSF pretreatment of plastic-adherent BMCs (adBMCs) increased the number of CD11b-F4/80+ macrophages and decreased the number of CD11b+ monocytes resulting in decreased OC formation. M-CSF pretreatment of purified c-Kit+ progenitors weakly inhibited OC formation, whereas M-CSF pretreatment of purified c-Kit-CD11b+ progenitors promoted the formation of large OC. M-CSF pretreatment increased the proliferation of both purified c-Kit+ and c-Kit-CD11b+ cells and increased the percentage of CD11b-F4/80+ cells from c-Kit+ progenitors. In addition, M-CSF pretreatment increased the percentage of CD11b+ F4/80- cells from purified c-Kit-CD11b+ cells. M-CSF pretreatment increased the percentage of CD14 + CD16 + intermediate monocytes and subsequent OC formation from human 2adBMCs, and increased OC formation of purified CD14 + cells. Together, these results indicate that in vitro OCP expansion in the presence of M-CSF and bone marrow stromal cells is dependent upon the developmental stage of myeloid cells, in which M-CSF favors macrophage differentiation of multipotent progenitors, promotes monocyte maturation and supports differentiation of late-stage OCP cells.

Optimization of expression of orange carotenoid protein in Escherichia coli.

Naturally-occurring orange carotenoid protein (OCP) is synthesized in cyanobacteria and red algae for photoprotection. Holo-OCP can be produced with three plasmids in E. coli, which needs two inducers (arabinose and isopropyl ß-D-thiogalactoside) to initiate two processes: one for generation of carotenoid and the other for generation of apo-OCP, so takes about two days. Afterwards, a two-plasmid method using two plasmids in E. coli is established, in which E. coli cells are induced only by isopropyl ß-D-thiogalactoside, so can yield different holo-OCPs from several cyanobacteria within three days. In this work, we optimized the two-plasmid method as follows: (1) re-organization of the two plasmids, letting carotenoid-generating gene, crtW, be arranged together with apo-OCP-generating gene, ocp, in a single plasmid, which causes that both carotenoid and apo-protein were properly produced, (2) modification of several amino acids at the N-terminus of apo-OCP, in this way increasing the yield and purity of holo-OCP. After these optimizations, we can generate much more amount of holo-OCP within shorter time of only 16 h, and pure holo-OCP be conveniently prepared after routine purification. Comparing with the reported data, the general yield of holo-OCP is increased by ∼10-fold under similar conditions. The high quality of the prepared holo-OCPs is verified by fluorescence quenching of the phycobilisomes.

Vascularized Bone-Mimetic Hydrogel Constructs by 3D Bioprinting to Promote Osteogenesis and Angiogenesis.

Bone is a highly vascularized tissue with a unique and complex structure. Long bone consists of a peripheral cortical shell containing a network of channels for vascular penetration and an inner highly vascularized bone marrow space. Bioprinting is a powerful tool to enable rapid and precise spatial patterning of cells and biomaterials. Here we developed a two-step digital light processing technique to fabricate a bone-mimetic 3D hydrogel construct based on octacalcium phosphate (OCP), spheroids of human umbilical vein endothelial cells (HUVEC), and gelatin methacrylate (GelMA) hydrogels. The bone-mimetic 3D hydrogel construct was designed to consist of a peripheral OCP-containing GelMA ring to mimic the cortical shell, and a central GelMA ring containing HUVEC spheroids to mimic the bone marrow space. We further demonstrate that OCP, which is evenly embedded in the GelMA, stimulates the osteoblastic differentiation of mesenchymal stem cells. We refined the design of a spheroid culture device to facilitate the rapid formation of a large number of HUVEC spheroids, which were embedded into different concentrations of GelMA hydrogels. It is shown that the concentration of GelMA modulates the extent of formation of the capillary-like structures originating from the HUVEC spheroids. This cell-loaded hydrogel-based bone construct with a biomimetic dual ring structure can be potentially used for bone tissue engineering.

Risk of Stroke Associated With Use of Estrogen Containing Contraceptives in Women With Migraine: A Systematic Review.

OBJECTIVE: Migraine with aura has been associated with increased risk of ischemic and hemorrhagic stroke. Prior studies have shown a further increase in risk in women using combined hormonal contraceptives (CHCs). This has led to guidelines recommending against use of CHCs in this population. We sought to assess whether the risk of stroke is associated with the dose of estrogen and whether there is evidence of synergism between migraine and CHCs. We also sought to assess whether an interaction effect exists between migraine and CHCs. METHODS: We searched PubMed, the Cochrane Library, and EMBASE from inception through January 2016 for relevant English-language studies of adults, of any design. We included studies that examined exposure to CHCs and reported outcomes of ischemic or hemorrhagic stroke. Data extraction and assessment of study quality were conducted independently by reviewer pairs and quality was assessed with the GRADE and Newcastle Ottawa scales. RESULTS: Of 2480 records, 15 studies met inclusion criteria and six provided odds ratios for the relevant population. The point estimates for the odds ratios for ischemic stroke in women with migraine who used CHCs with any dose of estrogen ranged from 2.08 to 16.9. Studies were generally small and confidence intervals were wide. No studies reported odds ratios for stroke risk as a function of estrogen dose in women with migraine, largely due to insufficient sample sizes. No interaction effect between migraine and CHCs was seen in the seven studies that assessed this. One study differentiated risk by presence or absence of migraine aura and found an increased risk in the migraine with aura population (OR 6.1; CI 3.1 to 12.1 in migraine with aura vs 1.8; CI 1.1 to 2.9 in the migraine without aura group). Studies generally had high Newcastle Ottawa scores and low GRADE levels of evidence. No studies met all three supplementary quality criteria (assessed migraine subtype, used International Classification of Headache Disorders criteria for diagnosis of migraine, and stratified risk by estrogen dose). CONCLUSIONS: This systematic review shows a lack of good quality studies assessing risk of stroke associated with low dose estrogen use in women with migraine. Further study in this area is needed. The available evidence is consistent with an additive increase in stroke risk with CHC use in women with migraine with aura. Since the absolute risk of stroke is low even in the presence of these risk factors, use of CHCs in women who have migraine with aura should be based on an individualized assessment of harms and benefits.