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The chances for a history of symptoms of STI/pelvic inflammatory women with oligomenorrhea becoming pregnant disease (PID) and sometimes chronic abdominal are less aygestin 5mg discount breast cancer inspirational quotes. If you can make an ultrasound you • Polycystic ovary syndrome (PCOS): this is a disease often can see hydrosalpinges (see Figure 6) buy aygestin 5 mg line women's health gynecological problems. You in which many small follicles grow (you can see can test the patency of the tubes in several ways (see it on ultrasound, per definition >12 follicles of section on Investigations on subfertility). Women will have oligomenorrhea (cycle of more than During the growth and development of a dominant 35 days) and are often (but not always) obese. An example of this mucus becomes very clear and forms threads. This questionnaire can be seen in the Appendix at the only happens around ovulation. You can also develop your own change in mucus is so that the sperm cells can swim form. The important questions are: up via the cervical mucus inside the uterus. In some • Duration of fertility problem: the longer the women, cervical mucus does not change and stays duration of the subfertility, the less likely it is white and is full of leukocytes: the sperm cells can- that you could help this couple. For example, if not use the mucus to swim up towards the follicle. In older women not mean that if sperm is of lower quality that it is (this does not count for men) fertility becomes a completely impossible to make a woman pregnant. Do not waste time and your patients’ Production of sperm cells takes 3 months and is money tackling infertility problems in women negatively influenced by high temperatures as in over the age of 42 years. If you find a poor sperm sample, you should • Ever pregnant before? Unexplained subfertility N Intrauterine fetal death (IUFD). We diagnose unexplained infertility if all the tests N Abortion (spontaneous, induced or dilatation are normal: the woman is ovulating, the tubes are and curettage, D&C). Any history of infec- patent, the cervical mucus is good, the post-coital tion around that abortion? Then the other tube semen; however, the woman has still not become could be damaged as well. This could be because there are many • Periods and cycle aspects in human fertility which are still not under- N Cycle: from first day of period until first day stood. However, other factors may play a role: of next period infrequent or wrongly timed intercourse, sexual N Regular: women with a cycle between 25 problems, intravaginal application of spermicide and 35 days will have in 91–97% of cases an (washing of the vagina, often with traditional herbs, ovulatory cycle directly after intercourse). The service provider can N Oligomenorrhea: cycle >35 days detect such fertility-hindering factors through N Amenorrhea: cycle >6 months thorough history taking. N The amount of blood loss: heavy bleeding could be a sign of fibroids. Women with galactorrhea often A detailed history will give you directions about have an anovulatory cycle. It is recommended to • Secondary dysmenorrhea (see Chapter 7). After PID (Chapter 17) or endometriosis (Chapter 6). Table 2 WHO criteria for normal semen • Sexual intercourse N Frequency. Pain (deep dys- rapid progressive motile pareunia, see Chapter 6) could be a sign of Morphology ≥30% normal PID (Chapter 17) or endometriosis (Chapter White blood count <1 million per ml 6). Signs of chronic diseases like tuberculosis or AIDS? Ex- cessive weight gain will also give anovulatory cycles and PCOS (see section on causes of subfertility). HIV with chronic infec- tions could lead to anovulation and amenorrhea (read about special considerations for HIV- positive infertility patients in Chapter 18). When women have already changed partners frequently because of sub- Figure 5 An example of a post-coital test under the fertility it will be more likely that the cause of microscope. Use the 40 × ocular and look if progressive infertility is either anovulation or blocked tubes motile sperm cells are present and not poor sperm quality. Production only around period of insertion of cervical mucus is stimulated by hormones (estro- N Depo-Provera: it could take up to 1 year gen produced in growing follicle). Examine cervical mucus for progressive motile • Stress: both mental and physical stress reduce spermatozoa using a microscope with the ocular on ovulation. You can remove some mucus from • History of abdominal operations or hydrocele/ the cervix by using a tuberculin syringe (without a herniography in men. In women abdominal needle, suck some mucus into your syringe) or use operations can cause adhesions. Unfortunately, a sponge-holding forceps (just grasp some mucus in many doctors still perform curettages because your forceps). Put the mucus on a microscope slide they think this will cure subfertility.
Consistent with preclinical models cheap aygestin 5 mg with visa menstrual like cramps at 33 weeks, marked differentia- such as quizartinib (AC220) and crenolanib buy 5mg aygestin mastercard menstrual hygiene management, are already being tion of myeloblasts into mature forms was associated with response. When used as single agents, they have limited antileukemic activity, mostly showing MLL-rearranged AML and DOT1L inhibition. Deregulation in only transient reduction of blood and BM blasts; ﬁrst randomized several epigenetic regulators that modify DNA or histones have trials evaluating these agents have been disappointing. Polo-like kinases (Plks) are a family of 5 highly conserved serine/threonine protein kinases that have been shown to The second-generation compounds such as quizartinib have im- play a key role in mitotic checkpoint regulation and cell division. This is associated with higher rates Plk1 is overexpressed in a range of human cancers, including of BM blast clearance, however, mostly without achieving formal AML. In addition, response duration is limited by the development of competitive kinase inhibitor that potently inhibits Plk1. Crenolanib is another highly selective ineligible for intensive therapy, the combination therapy doubled and potent FLT3 inhibitor exhibiting strong activity against FLT3- the response rate and even showed a signal for a survival beneﬁt. Phase 2 trials are ongoing A pivotal placebo-controlled phase 3 trial in this patient population (www. In fully transformed cells with endogenous BET inhibition. Further therapeutic targets of potential relevance IDH1 mutations, the selective R132H-IDH1 inhibitor AGI-5198 in AML are represented by the bromodomain and extraterminal showed a near-complete R-2HG inhibition. Preclinical data in AML suggest efﬁcacy primary IDH2 R140 AML cells with the small molecule AGI-6780, of BET inhibition across several AML subtypes. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence A new era of clinical research in AML has been entered. With the of relapse, and overall survival in adult patients with de novo acute rapid development in novel genomics technologies, comprehensive myeloid leukemia: results from Cancer and Leukemia Group B (CALGB molecular proﬁling will now become integral part of our clinical 8461). Molecular proﬁling will move away from the analysis of 5. Reﬁnement of cytogenetic more precise diagnosis and the identiﬁcation of patient subsets with classiﬁcation in acute myeloid leukemia: determination of prognostic distinct gene signatures, particularly among patients with intermedi- signiﬁcance of rare recurring chromosomal abnormalities among 5876 ate-risk cytogenetics. Such an integrative mutational analysis will younger adult patients treated in the United Kingdom Medical Research be instrumental to identifying patients who will beneﬁt from novel Council trials. Genomic and epigenomic rapid progress will only be achieved if the physicians caring for landscapes of adult de novo acute myeloid leukemia. Wouters BJ, Lo¨wenberg B, Erpelinck-Verschueren CA, et al. Double recommended to further specify the intermediate-risk AML group CEBPA mutations, but not single CEBPA mutations, deﬁne a subgroup as deﬁned by cytogenetics and to guide treatment decisions. BM of acute myeloid leukemia with a distinctive gene expression proﬁle that aspirates should been preferentially used for the molecular analyses; is uniquely associated with a favorable outcome. Acute myeloid leukemia proportion of circulating blasts. In NPM1-mutated AML, minimal with biallelic CEBPA gene mutations and normal karyotype represents a residual disease monitoring is clinically relevant because NPM1 distinct genetic entity associated with a favorable clinical outcome. Prognostic signiﬁcance of CEBPA patients at a high risk of relapse. Applicability of NPM1 minimal mutations in a large cohort of younger adult patients with acute myeloid residual disease monitoring for preemptive therapy is currently leukemia: impact of double CEBPA mutations and the interaction with under investigation. Diagnostic testing for other molecular markers FLT3 and NPM1 mutations. However, it is likely that the accumulating concurrent genetic mutations, and gene expression features of AML data on the novel molecular markers will affect upcoming revisions with CEBPA mutations in a cohort of 1182 cytogenetically normal of risk classiﬁcation systems. A better understanding of the role of AML patients: further evidence for CEBPA double mutant AML as a these molecular lesions in AML biology will hopefully result in the distinctive disease entity. Prognostic relevance of clinical outcome for our AML patients. Cytoplasmic nucleophosmin in acute myelogenous This work was supported in part by Grant BU 1339/5-1 from the leukemia with a normal karyotype. Deutsche Forschungsgemeinschaft and Grant 109675 by the Deut- 13. We thank Daniela Spa¨th for support with creating (NPM1) predicts favorable prognosis in younger adults with acute the ﬁgures in this manuscript and Hartmut Do¨hner for critically myeloid leukemia and normal cytogenetics: interaction with other gene reviewing the manuscript. Mutations and treatment Disclosures outcome in cytogenetically normal acute myeloid leukemia. Age-related risk proﬁle and Off-label drug use: None disclosed. Favorable prognostic impact of Konstanze Do¨hner, MD, Department of Internal Medicine III, NPM1 mutations in older patients with cytogenetically normal de novo University Hospital of Ulm, Albert-Einstein-Allee 23, D-89081 acute myeloid leukemia and associated gene- and microRNA- Ulm, Germany; Phone: 49-731-500-45001; Fax: 49-731-500- expression signatures: a Cancer and Leukemia Group B study. Schlenk RF, Do¨hner K, Kneba M, et al; German-Austrian AML Study References Group (AMLSG).
Obesity is becoming an dom chromosomal abnormality of embryos cheap 5mg aygestin with amex women's health past issues. Accumulating evidence has shown obesity is a risk factor for infertility aygestin 5mg with mastercard pregnancy and headaches, sporadic and recurrent RISK FACTORS FOR RECURRENT miscarriage, as well as obstetrics complications and MISCARRIAGE 22–25 perinatal morbidities. Epidemiological factors Maternal age Antiphospholipid syndrome Risk of miscarriage increases with advancing Antiphospholipid syndrome (APS) is the most im- maternal age, secondary to the increase in chromo- portant treatable cause of recurrent miscarriage. It somally abnormal conceptions15 and decline in refers to the association between antiphospholipid ovarian function. The risk increases steeply after 35 antibodies, most commonly lupus anticoagulant years of age from 11% at 20–24 years to 25% at and anticardiolipin antibodies26,27. Advanced nancy outcomes in APS include: paternal age has also been identified as a risk factor • Three or more consecutive miscarriages before with the highest risk in couples with maternal age 16 10 weeks of gestation. Previous reproductive history • One or more preterm births before the 34 weeks of gestation due to placental disease. Reproductive history is an independent predictor of future pregnancy outcome and history of pre- ‘Primary APS’ affects patients with no identifiable vious miscarriage is the single most important underlying systemic connective tissue disease, factor7. Risk of a further miscarriage increases after whereas APS in patients with chronic inflamma- each successive pregnancy loss, reaching 45% after tory diseases, such as systemic lupus erythematosus, three and 54% after four consecutive pregnancy is referred to as ‘secondary APS’. However, a previous live birth does not Worldwide, antiphospholipid antibodies are preclude women from experiencing recurrent mis- present in ~15% of women with recurrent mis- carriage in the future17. Adverse pregnancy out- comes may be due to the inhibition of tropho- Environmental factors 28–32 blastic function and differentiation , activation Most data on environmental risk factors are based of complement pathways at maternal fetal interface on studies with women having sporadic rather than resulting in a local inflammatory response33, and, in recurrent miscarriage. The results are conflicting later pregnancy, thrombosis of the uteroplacental and understandably biased with difficulties in con- vasculature34–36. Live birth rate in pregnancies with trolling for confounding factors and inaccuracy in no pharmacological intervention has been reported quantifying the dose of exposure. The a balanced reciprocal or Robertsonian transloca- malformation ranges from the mildest form with tion13,38,39 (Figure 1). Carriers of balanced transloca- slight indentation at the fundus (arcuate uterus) to tion are usually phenotypically normal and unaware the most extreme form with complete duplication of the condition. However, up to 70% of their (uterus didelphys) (Figure 2). This leads to alies in both the general population and women with a much higher risk of miscarriage, or rarely result- recurrent miscarriages is not clear. Wide variation of ing in live birth with multiple congenital malfor- prevalence from 1. A retrospective review of reproductive performance in patients with untreated uterine The risk of miscarriage resulting from chromo- anomalies suggested that these women have high somal abnormality increases with maternal age. In rates of miscarriage and preterm delivery, resulting in couples with recurrent miscarriage, chromosomal 42 a term delivery rate of only 50%. However, with increasing Cervical incompetence number of miscarriages, the risk of euploid preg- nancy loss increases, suggesting some other under- Cervical incompetence is defined as the inability lying pathology accounting for the loss. Reprinted with permission of Dr Jonathan Wolfe, Department of Biology, Galton Laboratory, University College London, UK 136 Recurrent Miscarriage including Cervical Incompetence Figure 2 The American Society for Reproductive Medicine classification of Müllerian anomalies. Copyright 2012 by the American Society for Reproductive Medicine. No part of this presentation may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording or by any informa- tion storage and retrieval system without permission in writing from the American Society for Reproductive Medicine, 1209 Montgomery Highway, Birmingham, AL 35216. It is a well-recognized cause pact on pregnancy outcomes, whereas subserosal of late miscarriage but the true incidence is un- lesions do not46–51. Epidemiological studies suggest an approxi- fibroids is more controversial. The result from uterine trauma after vigorous intra- cervix is the main mechanical barrier separating the uterine curettage or intrauterine infection. This has pregnancy from the vaginal bacterial flora. Many been implicated in recurrent miscarriage presum- patients who have asymptomatic mid-trimester ably due to the reduced uterine cavity volume as cervical dilation also have evidence of subclinical 44 well as fibrosis and inflammation of the endo- intrauterine infection. It is unclear whether this metrium leading to defective implantation and high rate of microbial invasion is the result or the pregnancy loss. Dilatation and curettage (D&C) cause of premature cervical dilation. Uterine fibroids have long been associated with a variety of reproductive problems, including preg- Endocrine factors nancy loss. Presumed mechanisms include mechani- Systemic endocrine factors cal distortion of the uterine cavity, abnormal vascularization, abnormal endometrial develop- Diabetes and thyroid disease have been associated ment, endometrial inflammation, abnormal endo- with sporadic miscarriage but there is no direct crine milieu and structural and contractile evidence that they contribute to recurrent mis- myometrial abnormalities45, any or all of which carriage. Women with well-controlled diabetes may impede embryonic implantation. It is well mellitus and treated thyroid dysfunction do not 137 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS carry higher risks for recurrent miscarriage52,53. The Empirical use of antibiotics in pregnancy should prevalence of diabetes and thyroid dysfunction in be avoided due to lack of evidence of benefit and women with recurrent miscarriage is similar to that potential harm with increased risk of cerebral reported in the general population54,55.
The selection of drugs included in this review was influenced by the specific programmatic interests of the organizations participating in the Drug Effectiveness Review Project and are not meant to be read as a usage guideline discount aygestin 5 mg without a prescription menstrual 10 days. Of the drugs studied purchase 5mg aygestin overnight delivery menstrual girls, trials differed with respect to dosing regimens limiting any conclusions about optimal dose. Studies Pending Review We identified no trials in progress that would meet inclusion criteria for this review and would potentially change conclusions. Summary of the evidence Key Question Strength of evidence Conclusion Key Question 1. For adults with acute coronary syndromes or coronary revascularization via stenting or bypass grafting, prior ischemic stroke or transient ischemic attack, or symptomatic peripheral vascular disease do antiplatelet agents differ in effectiveness? No difference between placebo/aspirin and placebo/aspirin: Moderate clopidogrel/aspirin at reducing all-cause mortality and cardiovascular mortality at 12 Clopidogrel/aspirin vs. Significant difference in reduction of MI at 12 placebo/aspirin: Moderate months Clopidogrel/aspirin vs. No significant difference in reduction of placebo/aspirin: Low cardiovascular mortality at median 28 months Clopidogrel vs aspirin: Low No significant difference in reduction of cardiovascular mortality at mean 1. Prasugrel reduces risk of target-vessel clopidogrel/aspirin: High revascularization at 15 months when compared to clopidogrel Prasugrel/aspirin vs. No difference in risk of all-cause mortality and clopidogrel/aspirin: Mod-High cardiovascular mortality at 15 months Ticlopidine/aspirin vs. No difference in risk of target-vessel clopidogrel/aspirin: Low- revascularization at 30 days and 6 months Moderate Ticlopidine/aspirin vs. No difference in risk for cardiovascular mortality at clopidogrel/aspirin: Low 30 days Stroke/transient ischemic Extended-release No significant difference for all-cause mortality, attack dipyridamole/aspirin vs. No significant difference for all-cause mortality, aspirin alone: Low cardiovascular mortality, and revascularization Key Question 2. For adults with acute coronary syndromes or coronary revascularization via stenting or bypass grafting, prior ischemic stroke or transient ischemic attack, or symptomatic peripheral vascular disease do antiplatelet agents differ in harms? Increased risk of major bleeding at 12 months placebo/aspirin: Moderate ACS coronary interventions Prasugrel/aspirin vs. Increased risk of major bleeding with prasugrel and clopidogrel/aspirin: Moderate no difference in withdrawal due to adverse events at 15 months Ticlopidine/aspirin vs. Increased withdrawals due to adverse events with clopidogrel/aspirin: Low ticlopidine and no difference in risk of major bleeding at 6 months Stroke/transient ischemic Extended-release Lower rate of major bleeding and withdrawal due to attack dipyridamole/aspirin vs. No significant difference for major bleeding aspirin alone: Low Key Question 3. For adults with acute coronary syndromes or coronary revascularization via stenting or bypass grafting, prior ischemic stroke or transient ischemic attack, or symptomatic peripheral vascular disease do antiplatelet agents differ in effectiveness and harms based on duration of therapy? Significantly lower risk of revascularization with 6 clopidogrel 6 months: months of therapy, no significant increase in Moderate bleeding risk, and nonsignificant benefit for all- cause mortality and cardiovascular mortality Clopidogrel 1 month vs. Smaller, nonsignificant benefit for revascularization clopidogrel/average 8 with 8 months of therapy compared with 1 month months: Moderate and a trend toward increase in bleeding risk Clopidogrel 1 month vs. Further reduction in benefit for revascularization Clopidogrel 12 months: Low with 12 months of therapy and further, but nonsignificant increase in risk of bleeding Newer antiplatelet agents 54 of 98 Final Update 2 Report Drug Effectiveness Review Project Key Question Strength of evidence Conclusion Key Question 4. Are there subgroups of patients based on demographics (age, racial groups, gender), socioeconomic status, other medications (drug-drug interactions), comorbidities (drug-disease interactions), or pregnancy for which one antiplatelet agent is more effective or associated with fewer harms? Genotype Clopidogrel, prasugrel: Low Compared to CYP2C19*17 noncarriers, carriers of the CYP2C19*17 allele did not have a significantly greater risk of major bleeding during treatment with clopidogrel Carriage of the ABCB1 3435 TT genotype also does not significantly impact the combined risk of major or minor bleeding in patients taking either clopidogrel or prasugrel Abbreviations: ACS, acute coronary syndrome; MI, myocardial infarction. Newer antiplatelet agents 55 of 98 Final Update 2 Report Drug Effectiveness Review Project CONCLUSIONS High-strength evidence indicated that in coronary revascularization, prasugrel reduces target- vessel revascularization more than clopidogrel at 15 months, while moderate-strength evidence indicated that there was more major bleeding with prasugrel. Evidence was moderate strength that the use of clopidogrel for 6 months after coronary revascularization resulted in lower risk of revascularization compared with 1 month, with no increase in bleeding (moderate strength). The benefit lessened after 8 and 12 months and bleeding risk gradually increased (moderate to low strength). In patients with acute coronary syndrome who are managed medically, there was moderate-strength evidence of no significant difference in reduction of mortality out to at least 12 months, significantly fewer myocardial infarctions and increased major bleeding between clopidogrel plus aspirin compared with aspirin alone. Following stroke or transient ischemic attack, high-strength evidence indicated that extended-release dipyridamole plus aspirin did not meet criteria for being noninferior to clopidogrel for the primary outcome of recurrent stroke and had higher risks of major bleeding and withdrawals due to adverse events. Evidence was insufficient to draw strong conclusions about the benefit-risk ratio of using a proton pump inhibitor for any patients taking clopidogrel. Newer antiplatelet agents 56 of 98 Final Update 2 Report Drug Effectiveness Review Project REFERENCES 1. Heart disease and stroke statistics – 2011 update: a report from the American Heart Association. Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction). King SI, Smith SJ, Hirshfeld JJ, Jacobs A, Morrison D, et al. Popma JJ, Berger P, Ohman EM, Harrington RA, Grines C, Weitz JI.