Septum resection versus expectant management in women with a septate uterus: an international multicentre open-label randomized controlled trial.

STUDY QUESTION: Does septum resection improve reproductive outcomes in women with a septate uterus? SUMMARY ANSWER: Hysteroscopic septum resection does not improve reproductive outcomes in women with a septate uterus. WHAT IS KNOWN ALREADY: A septate uterus is a congenital uterine anomaly. Women with a septate uterus are at increased risk of subfertility, pregnancy loss and preterm birth. Hysteroscopic resection of a septum may improve the chance of a live birth in affected women, but this has never been evaluated in randomized clinical trials. We assessed whether septum resection improves reproductive outcomes in women with a septate uterus, wanting to become pregnant. STUDY DESIGN, SIZE, DURATION: We performed an international, multicentre, open-label, randomized controlled trial in 10 centres in The Netherlands, UK, USA and Iran between October 2010 and September 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a septate uterus and a history of subfertility, pregnancy loss or preterm birth were randomly allocated to septum resection or expectant management. The primary outcome was conception leading to live birth within 12 months after randomization, defined as the birth of a living foetus beyond 24 weeks of gestational age. We analysed the data on an intention-to-treat basis and calculated relative risks with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: We randomly assigned 80 women with a septate uterus to septum resection (n = 40) or expectant management (n = 40). We excluded one woman who underwent septum resection from the intention-to-treat analysis, because she withdrew informed consent for the study shortly after randomization. Live birth occurred in 12 of 39 women allocated to septum resection (31%) and in 14 of 40 women allocated to expectant management (35%) (relative risk (RR) 0.88 (95% CI 0.47 to 1.65)). There was one uterine perforation which occurred during surgery (1/39 = 2.6%). LIMITATIONS, REASONS FOR CAUTION: Although this was a major international trial, the sample size was still limited and recruitment took a long period. Since surgical techniques did not fundamentally change over time, we consider the latter of limited clinical significance. WIDER IMPLICATIONS OF THE FINDINGS: The trial generated high-level evidence in addition to evidence from a recently published large cohort study. Both studies unequivocally do not reveal any improvements in reproductive outcomes, thereby questioning any rationale behind surgery. STUDY FUNDING/COMPETING INTEREST(S): There was no study funding. M.H.E. reports a patent on a surgical endoscopic cutting device and process for the removal of tissue from a body cavity licensed to Medtronic, outside the scope of the submitted work. H.A.v.V. reports personal fees from Medtronic, outside the submitted work. B.W.J.M. reports grants from NHMRC, personal fees from ObsEva, personal fees from Merck Merck KGaA, personal fees from Guerbet, personal fees from iGenomix, outside the submitted work. M.G. reports several research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the scope of the submitted work. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: Dutch trial registry: NTR 1676. TRIAL REGISTRATION DATE: 18 February 2009. DATE OF FIRST PATIENT'S ENROLMENT: 20 October 2010.

Single- versus double-layer closure of the caesarean (uterine) scar in the prevention of gynaecological symptoms in relation to niche development - the 2Close study: a multicentre randomised controlled trial.

BACKGROUND: Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility. METHODS: Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective. DISCUSSION: This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound. TRIAL REGISTRATION: Dutch Trial Register ( NTR5480 ). Registered 29 October 2015.

Hysteroscopic resection of a uterine caesarean scar defect (niche) in women with postmenstrual spotting: a randomised controlled trial.

OBJECTIVE: To compare the effectiveness of a hysteroscopic niche resection versus no treatment in women with postmenstrual spotting and a uterine caesarean scar defect. DESIGN: Multicentre randomised controlled trial. SETTING: Eleven hospitals collaborating in a consortium for women's health research in the Netherlands. POPULATION: Women reporting postmenstrual spotting after a caesarean section who had a niche with a residual myometrium of ≥3 mm, measured during sonohysterography. METHODS: Women were randomly allocated to hysteroscopic niche resection or expectant management for 6 months. MAIN OUTCOME MEASURES: The primary outcome was the number of days of postmenstrual spotting 6 months after randomisation. Secondary outcomes were spotting at the end of menstruation, intermenstrual spotting, dysuria, sonographic niche measurements, surgical parameters, quality of life, women's satisfaction, sexual function, and additional therapy. Outcomes were measured at 3 months and, except for niche measurements, also at 6 months after randomisation. RESULTS: We randomised 52 women to hysteroscopic niche resection and 51 women to expectant management. The median number of days of postmenstrual spotting at baseline was 8 days in both groups. At 6 months after randomisation, the median number of days of postmenstrual spotting was 4 days (interquartile range, IQR 2-7 days) in the intervention group and 7 days (IQR 3-10 days) in the control group (P = 0.04); on a scale of 0-10, discomfort as a result of spotting had a median score of 2 (IQR 0-7) in the intervention group, compared with 7 (IQR 0-8) in the control group (P = 0.02). CONCLUSIONS: In women with a niche with a residual myometrium of ≥3 mm, hysteroscopic niche resection reduced postmenstrual spotting and spotting-related discomfort. TWEETABLE ABSTRACT: A hysteroscopic niche resection is an effective treatment to reduce niche-related spotting.

The randomised uterine septum transsection trial (TRUST): design and protocol.

BACKGROUND: A septate uterus is a uterine anomaly that may affect reproductive outcome, and is associated with an increased risk for miscarriage, subfertility and preterm birth. Resection of the septum is subject of debate. There is no convincing evidence concerning its effectiveness and safety. This study aims to assess whether hysteroscopic septum resection improves reproductive outcome in women with a septate uterus. METHODS/DESIGN: A multi-centre randomised controlled trial comparing hysteroscopic septum resection and expectant management in women with recurrent miscarriage or subfertility and diagnosed with a septate uterus. The primary outcome is live birth, defined as the birth of a living foetus beyond 24 weeks of gestational age. Secondary outcomes are ongoing pregnancy, clinical pregnancy, miscarriage and complications following hysteroscopic septum resection. The analysis will be performed according to the intention to treat principle. Kaplan-Meier curves will be constructed, estimating the cumulative probability of conception leading to live birth rate over time. Based on retrospective studies, we anticipate an improvement of the live birth rate from 35% without surgery to 70% with surgery. To demonstrate this difference, 68 women need to be randomised. DISCUSSION: Hysteroscopic septum resection is worldwide considered as a standard procedure in women with a septate uterus. Solid evidence for this recommendation is lacking and data from randomised trials is urgently needed. TRIAL REGISTRATION: Dutch trial registry ( NTR1676 , 18th of February 2009).

The HysNiche trial: hysteroscopic resection of uterine caesarean scar defect (niche) in patients with abnormal bleeding, a randomised controlled trial.

BACKGROUND: A caesarean section (CS) can cause a defect or disruption of the myometrium at the site of the uterine scar, called a niche. In recent years, an association between a niche and postmenstrual spotting after a CS has been demonstrated. Hysteroscopic resection of these niches is thought to reduce spotting and menstrual pain. However, there are no randomised trials assessing the effectiveness of a hysteroscopic niche resection. METHODS/DESIGN: We planned a multicentre randomised trial comparing hysteroscopic niche resection to no intervention. We study women with postmenstrual spotting after a CS and a niche with a residual myometrium of at least 3 mm during sonohysterography. After informed consent is obtained, eligible women will be randomly allocated to hysteroscopic resection of the niche or expectant management for 6 months. The primary outcome is the number of days with postmenstrual spotting during one menstrual cycle 6 months after randomisation. Secondary outcomes are menstrual characteristics, menstruation related pain and experienced discomfort due to spotting or menstrual pain, quality of life, patient satisfaction, sexual function, urological symptoms, medical consultations, medication use, complications, lost productivity and medical costs. Measurements will be performed at baseline and at 3 and 6 months after randomisation. A cost-effectiveness analysis will be performed from a societal perspective at 6 months after randomisation. DISCUSSION: This trial will provide insight in the (cost)effectiveness of hysteroscopic resection of a niche versus expectant management in women who have postmenstrual spotting and a niche with sufficient residual myometrium to perform a hysteroscopic niche resection. TRIAL REGISTRATION: Dutch Trial Register NTR3269 . Registered 1 February 2012. ZonMw Grant number 80-82305-97-12030.

Isolation and characterization of subcellular membranes of Entamoeba invadens.

A method is described for the isolation of subcellular membranes of Entamoeba invadens. Plasma membranes were obtained by rate centrifugation followed by isopycnic centrifugation on a sucrose gradient. Intact phagolysosomes floated in a 10% sucrose solution providing a simple technique for isolation. Phagolysosomal membranes were collected by isopycnic centrifugation, after lysis of the phagolysosomes. Microsomes were obtained by differential centrifugation. Membrane fractions were examined by electron microscopy, and the contamination of each fraction was determined with marker enzymes. Mg2+-ATPase is associated with the plasma membrane. Acid phosphatase (beta-glycerophosphate) was associated mainly with phagolysosmal membranes. Plasma membranes also contained acid phosphatase activity which hydrolyzes p-nitrophenylphosphate but not beta-glycerophosphate. The localization of the two phosphatases was confirmed cytochemically. Isolated plasma membranes were contaminated with phagolysosomal membranes (15%) and with microsomes (25%). No more than 5% of the phagolysosomal membrane fraction consisted of plasma membranes. Contamination of the microsomes by plasma and phagolysosomal membranes was 10% and 7%, respectively. Plasma membranes and phagolysosomal membranes had a high ratio of cholesterol to phospholipid (0.93 and 1.05 mumol/mumol, respectively). Microsomes were relatively poor in cholesterol (0.39 mumol/mumol). Microsomes, plasma, and phagolysosomal membranes contained increasing amounts of spingolipids (12%, 17%, and 28%). Phagolysosomal membranes had a high percentage of phosphatidylserine but little phosphatidylcholine. Microsomes were rich in phosphatidylcholine (45%). Differences in phospholipid composition between plasma and phagolysosomal membranes are discussed in view of the phagocytic process.

Effects of the contraceptive patch, the vaginal ring and an oral contraceptive on APC resistance and SHBG: a cross-over study.

INTRODUCTION: The transdermal patch (20 microg ethinylestradiol+150 microg norelgestromin daily) and the vaginal ring (15 microg ethinylestradiol+120 microg etonogestrel daily) are new contraceptives, designed to deliver a low dose of hormones, suggesting a low exposure. However, few data are available about their risk of venous thrombosis. The objective was to investigate the effect of the patch, the ring, and an oral contraceptive (30 microg ethinylestradiol+150 microg levonorgestrel daily) on activated protein C sensitivity ratio (APC-sr) and on sex hormone-binding globulin (SHBG) levels in plasma. MATERIALS AND METHODS: After a two month wash-out, 13 volunteers were randomly assigned to either the patch followed by the oral contraceptive or vice versa, or the ring followed by the oral contraceptive or vice versa. All treatments lasted two cycles and were separated by a wash-out of two cycles. APC-sr and SHBG levels were determined on day 18-21 of the second cycle of the wash-out and of each treatment period. RESULTS: Compared to the oral contraceptive, both the patch and the ring led to higher APC resistance (mean difference APC-sr 1.1; 95% CI 0.67-1.52 and 0.55; 95% CI 0.11-1.00, respectively) and higher SHBG levels (mean difference 210 nmol/l; 95% CI 134-286 and 148 nmol/l; 95% CI 48-248, respectively). CONCLUSION: The activity of the protein C system in plasma was impaired more by contraceptive patch and vaginal ring than by an oral contraceptive containing the second generation progestagen levonorgestrel.

Vasectomy occlusion techniques for male sterilization.

BACKGROUND: Vasectomy is an increasingly popular and effective family planning method. A variety of vasectomy techniques are used worldwide, including various vas occlusion techniques (excision and ligation, thermal or electrocautery, and mechanical and chemical occlusion methods), as well as vasectomy with vas irrigation or with fascial interposition. Vasectomy guidelines largely rely on information from observational studies. Ideally, the choice of vasectomy techniques should be based on the best available evidence from randomized controlled trials. OBJECTIVES: The objective of this review was to compare the effectiveness, safety, acceptability and costs of vasectomy techniques for male sterilization. SEARCH STRATEGY: We searched the computerized databases of CENTRAL, MEDLINE, EMBASE, POPLINE and LILACS. In addition, we searched the reference lists of relevant articles and book chapters. SELECTION CRITERIA: We included randomized controlled trials comparing vasectomy techniques. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts located in the literature searches. Two reviewers independently extracted data from articles identified for inclusion. Outcome measures include contraceptive efficacy, safety, discontinuation, and acceptability. MAIN RESULTS: Six studies met the inclusion criteria. One trial compared vas occlusion with clips versus a conventional vasectomy technique. No difference was found in failure to reach azoospermia. Three trials examined vasectomy with vas irrigation. Two studies looked at irrigation with water versus no irrigation, while one examined irrigation with water versus the spermicide euflavine. None found a difference between the groups for time to azoospermia. However, one trial reported that the median number of ejaculations to azoospermia was lower in the euflavine group compared to the water irrigation group. One high-quality trial compared vasectomy with fascial interposition versus vasectomy without fascial interposition. The fascial interposition group was less likely to have vasectomy failure. Fascial interposition had more surgical difficulties, but the groups were similar in side effects. Lastly, one trial found that an intra-vas was less likely to produce azoospermia than was no-scalpel vasectomy. More men were satisfied with the intra-vas device, however. AUTHORS' CONCLUSIONS: For vas occlusion with clips or vasectomy with vas irrigation, no conclusions can be made as those studies were of low quality and underpowered. Fascial interposition reduced vasectomy failure. An intra-vas device was less effective in reducing sperm count than was no-scalpel vasectomy. Randomized controlled trials examining other vasectomy techniques were not available. More and better quality research is needed to examine vasectomy techniques.

Scalpel versus no-scalpel incision for vasectomy.

BACKGROUND: Currently, the two most common surgical techniques for approaching the vas during vasectomy are the incisional method and the no-scalpel technique. Whereas the conventional incisional technique involves the use of a scalpel to make one or two incisions, the no-scalpel technique uses a sharp-pointed, forceps-like instrument to puncture the skin. The no-scalpel technique aims to reduce adverse events, especially bleeding, bruising, hematoma, infection and pain and to shorten the operating time. OBJECTIVES: The objective of this review was to compare the effectiveness, safety, and acceptability of the incisional versus no-scalpel approach to the vas. SEARCH STRATEGY: We searched the computerized databases of CENTRAL, MEDLINE, EMBASE, POPLINE and LILACS in May 2006. In addition, we searched the reference lists of relevant articles and book chapters. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials were included in this review. No language restrictions were placed on the reporting of the trials. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts located in the literature searches and two authors independently extracted data from the articles identified for inclusion. Outcome measures included safety, acceptability, operating time, contraceptive efficacy, and discontinuation. MAIN RESULTS: Two randomized controlled trials evaluated the no-scalpel technique and differed in their findings. The larger trial demonstrated less perioperative bleeding (Odds ratio (OR) 0.49; 95% Confidence Interval (CI) 0.27 to 0.89) and pain during surgery (OR 0.75; 95% CI 0.61 to 0.93), scrotal pain (OR 0.63; 95% 0.50 to 0.80), and incisional infection (OR 0.21; 95% CI 0.06 to 0.78) during follow up than the standard incisional group. Both studies found less hematoma with the no-scalpel technique (OR 0.23; 95% CI 0.15 to 0.36). Operations using the no-scalpel approach were faster and had a quicker resumption of sexual activity. The smaller study did not find these differences; however, the study could have failed to detect differences due to a small sample size as well as a high loss to follow up. Neither trial found differences in vasectomy effectiveness between the two approaches to the vas. AUTHORS' CONCLUSIONS: The no-scalpel approach to the vas resulted in less bleeding, hematoma, infection, and pain as well as a shorter operation time than the traditional incision technique. No difference in effectiveness was found between the two approaches.

Hormonal versus non-hormonal contraceptives in women with diabetes mellitus type 1 and 2.

BACKGROUND: Adequate contraceptive advice is important in women with diabetes mellitus type 1 and 2 to reduce the risk of maternal and infant morbidity and mortality in unplanned pregnancies. A wide variety of contraceptives are available for these women. However hormonal contraceptives might influence carbohydrate and lipid metabolism and increase micro- and macrovascular complications. So caution in selecting a contraceptive method is required. OBJECTIVES: To investigate whether progestogen-only, combined estrogen/progestogen or non-hormonal contraceptives differ in terms of effectiveness in preventing pregnancy, in their side effects on carbohydrate and lipid metabolism and in long-term complications such as micro- and macrovascular disease, when used in women with diabetes mellitus. SEARCH STRATEGY: The search was performed in MEDLINE, EMBASE, CENTRAL/CCTR, POPLINE, CINAHL, WorldCat, ECO, ArticleFirst, the Science Citation Index, the British Library Inside, and reference lists of relevant articles. Last search was performed in May 2005. In addition, experts in the field and pharmaceutical companies marketing contraceptives were contacted to identify published, unpublished or ongoing studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that studied women with diabetes mellitus comparing: 1. hormonal versus non-hormonal contraceptives. 2. progestogen-only versus estrogen/progestogen contraceptives. 3. contraceptives containing <50 microg estrogen versus contraceptives containing > or = 50 microg estrogen. 4. contraceptives containing 'first'-, 'second'- and 'third'-generation progestogens, drospirenone and cyproterone acetate. Principal outcomes were contraceptive effectiveness, diabetes control, lipid metabolism and micro- and macrovascular complications. DATA COLLECTION AND ANALYSIS: Two investigators evaluated the titles and abstracts from the literature search. Quality assessment was performed independently with discrepancies resolved by discussion or consulting a third reviewer. Because the trials differed in studied contraceptives, participant characteristics and methodological quality, we could not combine the data in a meta-analysis. The trials were therefore examined on an individual basis and narrative summaries were provided. MAIN RESULTS: Three randomised controlled trials were included. Only one was of good methodological quality. It compared the influence of levonorgestrel-releasing IUD versus copper-IUD on carbohydrate metabolism in women with type 1 diabetes mellitus. No difference was found in daily insulin requirement, glycosylated hemoglobin (HbA1c) or fasting blood sugar after twelve months. The other two trials were of limited methodological quality. Both compared progestogen-only pills with different estrogen/progestogen combinations. The trials reported blood glucose levels to remain stable during treatment with most regimens. Only high-dose combined oral contraceptives were found to slightly impair glucose homeostasis. Combined oral contraceptives also appeared to have a minor adverse effect on lipid metabolism whereas progestogen-only contraceptives slightly improved lipid-metabolism. Only one study reported on micro- and macrovascular complications. No signs or symptoms of thromboembolic incidents or visual disturbances were observed. However study duration was short. Minor adverse effects were reported in one study. The trial found progestogen-only pills to cause more bleeding irregularities when compared with combined oral contraceptives. Unintended pregnancies were not observed during any of the studies. AUTHORS' CONCLUSIONS: The three included randomised controlled trials in this systematic review provided insufficient evidence to assess whether progestogen-only and combined contraceptives differ from non-hormonal contraceptives in diabetes control, lipid metabolism and complications. Two of the three studies were of limited methodological quality, sponsored by pharmaceutical companies and described surrogate outcomes. Ideally, an adequately reported, high-quality randomised controlled trial analysing both intermediate outcomes (i.e. glucose and lipid metabolism) and true clinical endpoints (micro- and macrovascular disease) in users of combined, progestogen-only and non-hormonal contraceptives should be conducted. However, due to the low incidence of micro- and macrovascular disease and accordingly the large sample size and follow-up period needed to observe differences in risk, a randomised controlled trial might not be the ideal design.

Biphasic versus triphasic oral contraceptives for contraception.

BACKGROUND: Side effects caused by oral contraceptives discourage compliance with, and continuation of, oral contraceptives. A suggested disadvantage of biphasic compared to triphasic oral contraceptive pills is an increase in breakthrough bleeding. We conducted this systematic review to examine this potential disadvantage. OBJECTIVES: To compare biphasic with triphasic oral contraceptives in terms of efficacy, cycle control, and discontinuation due to side effects. SEARCH STRATEGY: We searched MEDLINE, EMBASE, POPLINE, LILACS and CENTRAL. We searched the reference lists of relevant articles and book chapters. We also contacted the authors of relevant studies and pharmaceutical companies in Europe and the USA. SELECTION CRITERIA: We included randomized controlled trials comparing any biphasic with any triphasic oral contraceptive when used to prevent pregnancy. DATA COLLECTION AND ANALYSIS: We examined the studies found during the searches for possible inclusion and assessed methodological quality using Cochrane guidelines. We contacted the authors of included studies and of possibly randomized studies for supplemental information about the methods and outcomes. We entered the data into RevMan. We calculated Peto odds ratios for incidence of discontinuation due to medical reasons, intermenstrual bleeding, and absence of withdrawal bleeding. MAIN RESULTS: Only two trials of limited quality met our inclusion criteria. Larranaga 1978 compared two biphasic pills and one triphasic pill, each containing levonorgestrel and ethinyl estradiol. No important differences emerged, and the frequency of discontinuation due to medical problems was similar with all three pills. Percival-Smith 1990 compared a biphasic pill containing norethindrone (Ortho 10/11) with a triphasic pill containing levonorgestrel (Triphasil) and with another triphasic containing norethindrone (Ortho 7/7/7). The biphasic pill had inferior cycle control compared with the levonorgestrel triphasic. The odds ratio of cycles with intermenstrual bleeding was 1.7 (95% CI 1.3 to 2.2) for the biphasic compared with the triphasic levonorgestrel pill. The odds ratio of cycles without withdrawal bleeding was 6.5 (95% CI 3.1 to 13). In contrast, cycle control with the biphasic pill was comparable to that of the triphasic containing the same progestin (norethindrone). AUTHORS' CONCLUSIONS: The available evidence is limited and the internal validity of these trials is questionable. Given the high losses to follow up, these reports may even be considered observational. Given that caveat, the biphasic pill containing norethindrone was associated with inferior cycle control compared with the triphasic pill containing levonorgestrel. The choice of progestin may be more important than the phasic regimen in determining bleeding patterns.

Biphasic versus monophasic oral contraceptives for contraception.

BACKGROUND: Side effects caused by oral contraceptives discourage compliance with, and continuation of, oral contraceptives. Three approaches have been used to decrease these adverse effects: reduction of steroid dose, development of new steroids, and new formulas and schedules of administration. The third strategy led to the biphasic oral contraceptive pill. OBJECTIVES: To compare biphasic with monophasic oral contraceptives in terms of efficacy, cycle control, and discontinuation due to side effects. Our a priori hypotheses were: (a) biphasic oral contraceptives are less effective than monophasic oral contraceptives in preventing pregnancy; (b) biphasic oral contraceptives cause more side effects, give poorer cycle control, and have lower continuation rates. SEARCH STRATEGY: We searched the computerized databases MEDLINE, EMBASE, POPLINE, LILACS and CENTRAL. In addition, we searched the reference lists of all potentially relevant articles and book chapters. We also contacted the authors of relevant studies and pharmaceutical companies in Europe and the USA. SELECTION CRITERIA: We included randomized controlled trials comparing any biphasic with any monophasic oral contraceptive when used to prevent pregnancy. DATA COLLECTION AND ANALYSIS: We examined the studies found during the various literature searches for possible inclusion and assessed their methodology using Cochrane guidelines. We contacted the authors of all included studies and possibly randomized studies for supplemental information about methodology and outcome. We entered the data into RevMan, and calculated Peto odds ratios for the incidence of intermenstrual bleeding, absence of withdrawal bleeding, and study discontinuation due to intermenstrual bleeding. MAIN RESULTS: Only one trial of limited quality compared a biphasic and monophasic preparation. Percival-Smith 1990 examined 533 user cycles of a biphasic pill (500 microg norethindrone/35 microg ethinyl estradiol for 10 days, followed by 1000 microg norethindrone/35 microg ethinyl estradiol for 11 days; Ortho 10/11) and 481 user cycles of a monophasic contraceptive pill (1500 microg norethindrone acetate/30 microg ethinyl estradiol daily; Loestrin). The study found no significant differences in intermenstrual bleeding, amenorrhea and study discontinuation due to intermenstrual bleeding between the biphasic and monophasic oral contraceptive pills. AUTHORS' CONCLUSIONS: Conclusions are limited by the identification of only one trial, the methodological shortcomings of that trial, and the absence of data on accidental pregnancies. However, the trial found no important differences in bleeding patterns between the biphasic and monophasic preparations studied. Since no clear rationale exists for biphasic pills and since extensive evidence is available for monophasic pills, the latter are preferred.

Scalpel versus no-scalpel incision for vasectomy.

BACKGROUND: Currently, the two most common surgical techniques for approaching the vas during vasectomy are the incisional method and the no-scalpel technique. Whereas the conventional incisional technique involves the use of a scalpel to make one or two incisions, the no-scalpel technique uses a sharp-pointed, forceps-like instrument to puncture the skin. The no-scalpel technique aims to reduce adverse events, especially bleeding, bruising, hematoma, infection and pain and to shorten the operating time. OBJECTIVES: The objective of this review was to compare the effectiveness, safety, and acceptability of the incisional versus no-scalpel vasectomy approach to the vas. SEARCH STRATEGY: We searched the computerized databases of CENTRAL, MEDLINE, EMBASE, POPLINE and LILACS in May 2006. In addition, we searched the reference lists of relevant articles and book chapters. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials were included in this review. No language restrictions were placed on the reporting of the trials. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts located in the literature searches and two authors independently extracted data from the articles identified for inclusion. Outcome measures included safety, acceptability, operating time, contraceptive efficacy, and discontinuation. MAIN RESULTS: Two randomized controlled trials evaluated the no-scalpel technique and differed in their findings. The larger trial demonstrated less perioperative bleeding (Odds ratio (OR) 0.49; 95% Confidence Interval (CI) 0.27 to 0.89) and pain during surgery (OR 0.75; 95% CI 0.61 to 0.93), scrotal pain (OR 0.63; 95% 0.50 to 0.80), and incisional infection (OR 0.21; 95% CI 0.06 to 0.78) during follow up than the standard incisional group. Both studies found less hematoma with the no-scalpel technique (OR 0.23; 95% CI 0.15 to 0.36). Operations using the no-scalpel approach were faster and had a quicker resumption of sexual activity. The smaller study did not find these differences; however, the study could have failed to detect differences due to a small sample size as well as a high loss to follow up. Neither trial found differences in vasectomy effectiveness between the two approaches to the vas. AUTHORS' CONCLUSIONS: The no-scalpel approach to the vas resulted in less bleeding, hematoma, infection, and pain as well as a shorter operation time than the traditional incision technique. Although no difference in effectiveness was found between the two approaches, the sample sizes might have been too small to detect actual differences. Additional well-conducted randomized trials would help answer this question.

Triphasic versus monophasic oral contraceptives for contraception.

BACKGROUND: Side effects of oral contraceptive pills (OCs) discourage adherence to and continuation of OC regimens. Strategies to decrease adverse effects led to the introduction of the triphasic OC in the 1980s. Whether triphasic OCs have higher accidental pregnancy rates than monophasic pills is unknown. Nor is it known if triphasic pills give better cycle control and fewer side effects than the monophasic pills. OBJECTIVES: To compare triphasic OCs with monophasic OCs in terms of efficacy, cycle control, and discontinuation due to side effects. SEARCH STRATEGY: We searched the computerized databases of MEDLINE, EMBASE, POPLINE, LILACS and CENTRAL. Additionally, we searched the reference lists of relevant articles and book chapters. We also contacted researchers and pharmaceutical companies in Europe and the U.S. to identify other trials not found in our search. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing any triphasic OC with any monophasic pill used to prevent pregnancy. Interventions had to include at least three treatment cycles. DATA COLLECTION AND ANALYSIS: We assessed the studies found in the literature searches for possible inclusion and for their methodological quality. We contacted the authors of all included studies and of possibly randomized trials for supplemental information about the methods and outcomes studied. We entered the data into RevMan 4.2 and calculated odds ratios for the outcome measures of efficacy, breakthrough bleeding, spotting, withdrawal bleeding and discontinuation. MAIN RESULTS: Of 21 trials included, 18 examined contraceptive effectiveness: the triphasic and monophasic preparations did not differ significantly. Several trials reported favorable bleeding patterns, i.e. less spotting, breakthrough bleeding or amenorrhea, in triphasic versus monophasic OC users. However, meta-analysis was generally not possible due to differences in measuring and reporting the cycle disturbance data as well as differences in progestogen type and hormone dosages. No significant differences were found in the numbers of women who discontinued due to medical reasons, cycle disturbances, intermenstrual bleeding or adverse events. AUTHORS' CONCLUSIONS: The available evidence is insufficient to determine whether triphasic OCs differ from monophasic OCs in effectiveness, bleeding patterns or discontinuation rates. Therefore, we recommend monophasic pills as a first choice for women starting OC use. Large, high-quality RCTs that compare triphasic and monophasic OCs with identical progestogens are needed to determine whether triphasic pills differ from monophasic OCs. Future studies should follow the WHO recommendations on recording menstrual bleeding patterns and the CONSORT reporting guidelines.

[Anxiety disorders and epilepsy: not unknown, but sometimes unexpected. A case study]. / Angstklachten en epilepsie: niet onbekend, maar soms onverwacht.

Epileptic disorders can manifest themselves with symptoms of anxiety and panic. In clinical practice it is not always easy to achieve a correct diagnosis. The subject of this case study is an adult with symptoms of anxiety and panic who was referred to the mental health care service but who was diagnosed as having epilepsy when subjected to a supplementary examination. Psychological and in particular anxiety symptoms in epilepsy are discussed. The psychiatrist needs to consider the possibility of epilepsy in a patient presenting with anxiety symptoms.

Intra-uterine insemination versus timed intercourse for cervical hostility in subfertile couples.

BACKGROUND: The postcoital test has poor diagnostic and prognostic characteristics. Nevertheless, some physicians believe it can identify scanty or abnormal mucus that might impair fertility. One way to avoid 'hostile' cervical mucus is intrauterine insemination. With this technique, the physician injects sperm directly into the uterine cavity through a small catheter passed through the cervix; the theory is to bypass the "hostile" cervical mucus. Although most gynaecological societies do not endorse use of intrauterine insemination for hostile cervical mucus, some physicians consider it an effective treatment for women with infertility thought due to cervical mucus problems. OBJECTIVES: The aim of this review was to determine the effectiveness of intrauterine insemination with or without ovarian stimulation in women with cervical hostility who failed to conceive. SEARCH STRATEGY: We searched Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library Issue 2, 2005, MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), POPLINE (to June 2005) and LILACS (to June 2005). In addition, we contacted experts and searched the reference list of relevant articles and book chapters. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials comparing intrauterine insemination with intercourse timed at the presumed fertile period. Participants were women with cervical hostility who failed to conceive for at least one year. DATA COLLECTION AND ANALYSIS: We assessed the titles and abstracts of 386 publications and two reviewers independently abstracted data on methods and results from five studies identified for inclusion. The main outcome is pregnancy rate per couple. MAIN RESULTS: We did not pool the outcomes of the included five studies in a meta-analysis due to the methodological quality of the trials and variations in the patient characteristics and interventions. Narrative summaries of the outcomes are provided. Each study was too small for a clinically relevant conclusion. None of the studies provided information on important outcomes such as spontaneous abortion, multiple pregnancies, and ovarian hyperstimulation syndrome. AUTHORS' CONCLUSIONS: There is no evidence from the published studies that intrauterine insemination is an effective treatment for cervical hostility. Given the poor diagnostic and prognostic properties of the postcoital test and the observation that the test has no benefit on pregnancy rates, intrauterine insemination (with or without ovarian stimulation) is unlikely to be a useful treatment for putative problems identified by postcoital testing.

Cardiovascular determinants of carotid artery disease. The Rotterdam Elderly Study.

The objective of the present study was to assess the prevalence of moderate and severe stenosis of the right carotid artery in the elderly and its associations with smoking, blood pressure, serum lipid levels, and hemostatic factors. The Rotterdam Elderly Study is a recently started single-center prospective follow-up study of a cohort of 11,854 elderly people aged 55 years or more. In 1990, 954 participants of the Rotterdam Elderly Study underwent ultrasonic duplex examination of the right internal carotid artery. A reduction of the lumen diameter of 16-49% was found in 29 people (3.0%). Severe stenosis (50% or more) was observed in 13 people (1.4%). With differences in age, sex, and body mass index taken into account, subjects with moderate-to-severe carotid artery disease had, compared with participants without stenosis, lower mean high density lipoprotein cholesterol levels (mean difference, 0.10 mmol/l; 95% confidence interval, 0, 0.20) and higher mean fibrinogen levels (difference, 0.24 g/l; 0.04, 0.45). Among them were more people with hypertension (mean difference, 16%) and more current smokers (mean difference, 13%). Factor VIIc and factor VIIIc activity was higher in subjects with carotid artery disease, without, however, reaching statistical significance (mean difference, 0.06 IU/ml [-0.01, 0.12] and 0.21 IU/ml [-0.05, 0.47], respectively). Our data suggest that hypertension, smoking, and reduced serum high density lipoprotein cholesterol levels, combined with unfavorable increases in hemostatic factors, may be related to carotid artery disease in the elderly.

Transient neurologic and ocular manifestations in primary thrombocythemia.

We report the presenting neurologic and visual symptoms in 17 patients with primary thrombocythemia. Poorly localizing symptoms occurred in 14 patients: transient unsteadiness in 13, dysarthria in eight, and scintillating scotomata in four. Nine patients had focal symptoms: transient monocular blindness in two patients, transient mono- or hemiparesis in six, and both of these in one patient. The attacks all had a sudden onset, occurred sequentially rather than simultaneously, lasted for a few seconds to several minutes, and were usually associated with a dull or pulsatile headache. A causal platelet-mediated arterial thrombosis was evident in 15 patients. There were no recurrences of thrombotic or ischemic events during long-term treatment of 12 patients with aspirin and during cytostatic reduction of platelet count to normal in seven patients. We conclude that low-dose aspirin and reduction of platelet count to normal are effective, but coumarin is ineffective, in the treatment and prevention of arterial thrombosis in thrombocythemia.

Coffee, caffeine and hemostasis: results from two randomized studies.

The influence of coffee and caffeine consumption on hemostatic factors was studied in 2 randomized trials. Both studies were conducted in young, healthy adults. In the first study, 107 participants were randomly allocated to one or 3 intervention groups, drinking filtered coffee, boiled coffee or no coffee at all, respectively, for a period of 9 weeks. In the second study, 69 subjects received either 4-6 tablets containing 75 mg caffeine or the same amount of placebo tablets, while using decaffeinated coffee. In this double-blind study caffeine intake from any other source was not allowed. Blood samples for hemostatic factors were obtained at baseline and after 9 weeks of intervention. The findings indicate no effect of coffee consumption on fibrinogen, clotting factor VII activity, factor VIII antigen, protein C and protein S and also no effect of caffeine consumption on fibrinogen and factor VII activity.

Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management.

Acquired von Willebrand syndrome (AVWS) associated with hypothyroidism is of type I, results from a decreased synthesis of factor VIII and von Willebrand factor (VWF), responds to desmopressin with normal half-life times for factor VIII and VWF parameters, and disappears after treatment with I-thyroxine. AVWS type I or III, which occurs in a minority of patients with Wilms' tumour in the complete absence of an inhibitor against VWF and no absorption of factor VIII or VWF onto nephroblastoma cells, responds to chemotherapy and/or tumour resection. Hyaluronic acid produced by nephroblastoma cells may be the causative factor in atypical AVWS in Wilms' tumour. AVWS associated with thrombocythaemia of various myeloproliferative disorders is characterized by normal factor VIII and von Willebrand factor antigen (VWF: Ag) levels and a selective deficiency of functional ristocetin co-factor activity (VWF: RCo) and collagen-binding activity (VWF: CBA). AVWS type II in thrombocythaemia is caused by a platelet-dependent proteolysis of large VWF multimers, given the inverse relationship between platelet count and large VWF multimers in plasma and specific increases in the number of proteolytic VWF fragments in plasma. The laboratory findings of AVWS associated with systemic lupus erythematosus or IgG benign monoclonal gammopathy are characterized by a prolonged bleeding time and activated partial thromboplastin time, decreased or absent ristocetin-induced platelet activity, low to very low levels of factor VIII coagulant activity (mean 15%), VWF: Ag (mean 10.7%) and VWF: RCo (mean 6.2%), and a type II multimeric pattern of VWF. Neutralizing and non-neutralizing anti-VWF autoantibodies, usually IgG, have been detected in patient plasma either free or tightly bound to the intermediate and high molecular weight VWF factor VIII particles. The bound auto antibody-antigen complex is rapidly cleared from the circulation, resulting in low levels of factor VIII, VWF parameters as documented by a poor response to desmopressin and VWF factor VIII concentrate. High-dose intravenous immunoglobulin transiently corrects the factor VIII coagulant and VWF levels, lasting for a few weeks in AVWS type II associated with systemic lupus erythematosus or IgG benign monoclonal gammopathy. Prednisolone is effective in AVWS associated with autoimmune disorder. Prednisolone and chemotherapy will not affect AVWS associated with IgG benign monoclonal gammopathy because the monoclonal IgG protein remains to act as an anti-VWF autoantibody. An absorption of VWF to malignant cells has been documented in a few patients with various lymphoproliferative disorders or adrenal carcinoma and suggested to result in a depletion of VWF. The clinical picture of AVWS associated with early-stage IgG multiple myeloma, chronic lymphocytic leukaemia or non-Hodgkin's lymphoma without a paraprotein or no detectable underlying disorder is similar to that of AVWS type II in IgG benign monoclonal gammopathy but poorly documented with regard to the underlying immune mechanism of AVWS. The mechanical destruction of large VWF multimers may be of relevance in conditions in which the shear rate of flowing blood is increased, as may occur in cases of aortic stenosis, other heart valve defects or stenosed vessels. Drug-induced AVWS has been described in association with the use of pesticides valproic acid, ciprofloxacin, griseofulvin, tetracycline, thrombolytic agents and hydroxyethyl starch.