Thyroid function, activated protein C resistance and the risk of venous thrombosis in users of hormonal contraceptives.

INTRODUCTION: Use of combined hormonal contraceptives is associated with a three- to eight-fold increased risk of venous thrombosis compared with non-use. The thrombotic risk depends on the estrogen dose as well as the progestogen type. Use of hormonal contraceptives leads to resistance to activated protein C (APC), which may serve as marker for the risk of venous thrombosis. Hyperthyroidism is also associated with an increased risk of venous thrombosis, due to increased free Thyroxine (FT4) levels which cause a hypercoagulable state. MATERIALS AND METHODS: The objective of this study was to evaluate the effects of hormonal contraceptives on levels of FT4, thyroid stimulating hormone (TSH) and thyroxine binding globulin (TBG), and to investigate the effects on APC resistance per contraceptive group. We measured FT4, TBG and TSH levels and APC resistance in 231 users of oral contraceptives. RESULTS: Users of the most thrombogenic hormonal contraceptives, i.e. containing desogestrel, cyproterone acetate or drospirenone, had higher TBG levels than users of less thrombogenic hormonal contraceptives, i.e. the levonorgestrel-containing intrauterine device. TSH levels were not significantly elevated and FT4 levels did not change. TBG levels were also associated with APC resistance. CONCLUSION: Use of hormonal contraceptives lead to elevated TBG levels, slightly elevated TSH levels and unchanged FT4 levels without causing a hyperthyroid state. Thus, the increased thrombotic risk during the use of hormonal contraceptives cannot be explained by a hyperthyroid state caused by use of these hormonal contraceptives.

The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy.

BACKGROUND: Oral contraception (OC) and postmenopausal hormone therapy (HT) can be used to alleviate menopausal symptoms. However, the risk of venous thrombosis (VT) associated with OC use in women over 50 years old has never been assessed and the two preparations have not been directly compared. OBJECTIVES: To determine and compare the risk of VT associated with OC and HT use. METHODS: From a large case-control study, 2550 women aged over 50 years old, 1082 patients with a first VT and 1468 controls, were included. Odds ratios (ORs) and 95% confidence intervals for VT were calculated for OC-users (164 patients and 54 controls) and HT-users (88 patients and 102 controls) compared with non-hormone users (823 patients and 1304 controls). RESULTS: OC-users had a 6.3-fold (4.6-9.8) increased risk of VT. This ranged from 5.4 (3.3-8.9) for preparations containing levonorgestrel to 10.2 (4.8-21.7) for desogestrel. The VT-risk associated with oral HT use was 4.0 (1.8-8.2) for conjugated equine estrogen combined with medroxyprogesterone acetate and 3.9 (1.5-10.7) for micronized estradiol combined with norethisterone acetate. Non-oral HT did not increase the risk of VT: OR 1.1 (0.6-1.8). Relative risk estimates were further increased in hormone users with factor V Leiden, prothrombin G20210A or blood group non-O and hormone users with a family history of VT. CONCLUSIONS: In this study, non-oral HT seemed to be the safest hormonal preparation in women over 50 years old. OC use increased the VT risk the most, especially in women with inherited thrombophilia or a family history of VT.

Sex hormone-binding globulin levels are not causally related to venous thrombosis risk in women not using hormonal contraceptives.

BACKGROUND: Oral contraceptive use increases the risk of venous thrombosis as well as sex hormone-binding globulin (SHBG) levels. Furthermore, increased SHBG levels are positively associated with activated protein C (APC) resistance and thrombotic risk in oral contraceptive users. OBJECTIVES: To determine whether increased SHBG levels are causally related to venous thrombosis in women not using hormonal contraceptives. METHODS: Premenopausal women were selected from a case-control study on venous thrombosis, the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study (23 patients; 258 controls). Women using hormonal contraceptives were excluded. First, the risk of venous thrombosis with SHBG levels above the normal reference range (70 nm) was determined. Second, because multiple regulatory factors affect SHBG levels and residual confounding may remain, we determined six single-nucleotide polymorphisms (SNPs) in the SHBG gene and assessed the risk of venous thrombosis in a different case-control study, the Leiden Thrombophilia Study (LETS) (20 patients; 74 controls), and in the MEGA study. Finally, the association between SHBG levels and the normalized activated partial thromboplastin time-based APC resistance (an intermediate endpoint for venous thrombosis) was determined. RESULTS: Elevated SHBG levels (> 70.0 nm) were associated with venous thrombosis (odds ratio 1.92; 95% confidence interval [CI] 0.74-5.00). However, this finding can be explained by residual confounding. Two SNPs in the SHBG gene affected SHBG levels, but not venous thrombosis risk. Furthermore, SHBG levels in controls were not associated with APC resistance (SHBG level, > 70.0 vs. ≤ 70.0 nm: mean difference in normalized APC sensitivity ratio, 0.03; 95% CI -0.05 to 0.10). Exclusion of women with FV Leiden did not materially change these results. CONCLUSIONS: Increased SHBG levels are not causally related to the risk of venous thrombosis.

Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort.

BACKGROUND: Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown. METHODS: We identified a nationwide historic cohort of 19,146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997-1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group. RESULTS: After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16-2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62-6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25-14.33 and 2.14; 95% CI = 1.07-4.25, respectively, adjusted for age, parity and subfertility cause). CONCLUSIONS: Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.

PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis.

BACKGROUND: Patients with polycystic ovary syndrome (PCOS) are at risk of arterial disease. We examined the risk of (non)fatal coronary heart disease (CHD) or stroke in patients with PCOS and ovulatory women without PCOS, and assessed whether obesity might explain a higher risk of CHD or stroke. METHODS: We performed a systematic review and meta-analysis of controlled observational studies. Four definitions of PCOS were considered: World Health Organization type II anovulation, National Institutes of Health criteria, Rotterdam consensus and Androgen-excess criteria. Obesity was defined as BMI > 30 kg/m(2) and/or waist circumference >88 cm. Study quality was assessed using the Newcastle-Ottawa Scale. Primary outcome was fatal/non-fatal CHD or stroke. Definitions of CHD and stroke were based on criteria used by the various authors. The effect measure was the pooled relative risk in a random effects model. Risk ratios and rate ratios were combined here. RESULTS: After identifying 1340 articles, 5 follow-up studies published between 2000 and 2008 were included. The studies showed heterogeneity in design, definitions and quality. In a random effects model the relative risk for CHD or stroke were 2.02 comparing women with PCOS to women without PCOS (95% confidence interval 1.47, 2.76). Pooling the two studies with risk estimates adjusted for BMI showed a relative risk of 1.55 (1.27, 1.89). CONCLUSIONS: This meta-analysis showed a 2-fold risk of arterial disease for patients with PCOS relative to women without PCOS. BMI adjustment did not affect this finding, suggesting the increased risk for cardiovascular events in PCOS is not completely related to a higher BMI in patients with PCOS.

Sex difference in risk of recurrent venous thrombosis and the risk profile for a second event.

BACKGROUND: The risk of recurrent venous thrombosis is higher in men than in women, and this is so far unexplained. We set out to determine the influence of age, time between first and second event, type of first event, oral contraception, pregnancy and surgery. METHODS: We performed a prospective follow-up study of 474 patients with a first objective diagnosis of deep vein thrombosis, aged 18-70 years (Leiden Thrombophilia Study cohort). RESULTS: During 3477 person-years of follow-up, 90 recurrences occurred. The overall incidence rates of recurrence (IRs) were 40.9 per 1000 person-years in men and 15.8 per 1000 person-years in women. Men with an unprovoked first event had the highest risk of recurrence, with almost one-third experiencing a second unprovoked event within 8 years (IR 41.2 per 1000 person-years). This risk was three-fold lower in women [IR 14.2 per 1000 person-years; hazard ratio 2.8 (95% confidence interval 1.4-5.7)]. Age at diagnosis had little effect on recurrence rate, and nor had time elapsed since the first event. In women, almost half of the recurrences were provoked and were mainly related to oral contraceptive use or pregnancy. CONCLUSIONS: The higher recurrence rate in men than in women is not the result of differences in the environmental or transient risk factors that we studied. The risk profile for a second thrombotic event is clearly different from that of a first.

The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study.

OBJECTIVE: To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands. DESIGN: Population based case-control study. SETTING: Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht). PARTICIPANTS: Premenopausal women <50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls. MAIN OUTCOME MEASURES: First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf's method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model. RESULTS: Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives. CONCLUSIONS: Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.

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.

Decidual vascularization and the expression of angiogenic growth factors and proteases in first trimester spontaneous abortions.

BACKGROUND: Decidual vascular development is important for implantation. This study analysed decidual vascular adaptation to implantation in correlation with miscarriage in decidual secretory endometrium (DSE), decidua parietalis (DP) and decidua basalis (DB) of miscarriage patients and matched controls. METHODS: Decidua was obtained during first trimester termination of pregnancy (controls) and vacuum aspiration in case of missed abortion (cases). Vascularization and the expression of VEGF-A, placental growth factor, Flt-1, KDR, angiopoietin (Ang)-1, Ang-2, TIE-2, and membrane-type matrix metalloproteinases MT1-, MT2-, MT3- and MT5-MMP were determined at mRNA and protein level. Uterine natural killer cells (CD56), macrophages (CD68), proliferation (Ki67) and apoptosis (activated caspase-3) were evaluated in consecutive sections. RESULTS: Decidual vascularization showed differences between cases and controls, i.e. fewer vessels with larger circumference in cases. This correlated with the differential expressions of various factors at mRNA/antigen level and with increased endothelial flt1, KDR, MT2- and MT5-MMP expression in miscarriage patients. The differences between cases and controls were probably not based on altered proliferation and/or apoptosis, since Ki67 and active Caspase-3 showed comparable expression levels in both groups. Although DB of cases and controls showed similar amounts of CD56- and CD68-positive cells, the case group did show elevated levels of CD56 in DSE (P < 0.05) and of CD68 in DP compared with the control group (P < 0.05). CONCLUSIONS: The differences in vascularization and in the expression of angiogenic factors and proteases between groups suggest a correlation between decidual vascularization and the occurrence of miscarriages.

Angiogenic growth factors and their receptors in first-trimester human decidua of pregnancies further complicated by preeclampsia or fetal growth restriction.

Disturbances in decidual and placental vascular development may play a role in the pathogenesis of pregnancy complications. This study focused on the role of angiogenic factors in the first trimester in the pathogenesis of preeclampsia (PE) and/or fetal growth restriction (FGR). First-trimester decidua was obtained during chorionic villous sampling.The expression of the angiogenic factors was determined by reverse transcriptase polymerase chain reaction and related to the pregnancy outcome. First-trimester decidua expressed all angiogenic factors.The differential expression of angiogenic factors appeared to be more prominent in FGR than in PE. These first-trimester samples provided a unique opportunity to obtain information regarding the onset of PE and FGR. First-trimester changes in angiogenic factor expression may well occur as a compensatory mechanism. This, in turn, may unintentionally set the stage for increased angiogenesis and altered decidual/placental vascular adaptation, which may be part of the pathogenesis of PE and/or FGR.

Oral contraceptives containing drospirenone for premenstrual syndrome.

BACKGROUND: Premenstrual syndrome (PMS) is a common problem. Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Combined oral contraceptives (COCs), which have both progestin and estrogen, have been examined for their ability to relieve premenstrual symptoms. A COC containing drospirenone and low estrogen has been approved for treating PMDD in women who choose COCs for contraception. OBJECTIVES: To review all randomized controlled trials comparing combined oral contraceptives containing drospirenone versus a placebo or another COC for effect on premenstrual symptoms. SEARCH STRATEGY: We searched the computerized databases MEDLINE, POPLINE, CENTRAL, EMBASE, LILACS, PsycINFO, and CINAHL for studies of drospirenone and premenstrual syndrome. We also examined references lists of relevant articles, and wrote to known investigators to find other trials. SELECTION CRITERIA: We included randomized controlled trials in any language that compared a COC containing drospirenone versus a placebo or another COC for effect on premenstrual symptoms. Primary outcome was the prospective recording of premenstrual symptoms (affective and physical). Adverse events related to COC use were examined. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed study quality. MAIN RESULTS: We included five trials with a total of 1600 women. Two placebo-controlled trials of women with PMDD showed less severe premenstrual symptoms after three months with drospirenone (plus ethinyl estradiol (EE) 20g) than with the placebo (WMD -7.83; 95% CI -10.91 to -4.75). The drospirenone group had greater decreases in impairment of productivity (WMD -0.42; 95% CI -0.64 to -0.20), social activities (WMD -0.39; 95% CI -0.62 to -0.15), and relationships (WMD -0.38; 95% CI -0.61 to -0.51). Side effects more common with COC use were nausea, intermenstrual bleeding, and breast pain. Little effect was found on less severe symptoms when comparing drospirenone plus more estrogen to another COC. A six-month study showed fewer symptoms with drospirenone, while a two-year trial found the groups to be similar. AUTHORS' CONCLUSIONS: Drospirenone plus EE 20 mug may help treat premenstrual symptoms in women with PMDD. The placebo also had a large effect. We do not know whether the COC works after three cycles, for women with less severe symptoms, or better than other COCs. Larger and longer trials of higher quality are needed to address these issues. Trials should follow CONSORT reporting guidelines.

Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor.

BACKGROUND: Oral contraceptives (OC) containing different types of progestogens induce different sensitivities to activated protein C (APC) measured with the thrombin generation-based APC-resistance test. These differences in APC resistance may be the biological explanation for the differences in thrombotic risk of the various pills. The mechanistic basis of APC resistance observed in OC users is unknown. Our objective was to study the effect of OC on the two main determinants of the APC-resistance test, free protein S and free tissue factor pathway inhibitor (TFPI). PATIENTS/METHODS: We measured free protein S and free TFPI in 156 users of various types of OC. RESULTS: Users of desogestrel-containing OC, known to double the risk of thrombosis compared with levonorgestrel-containing OC, had lower free protein S (24 vs. 33 U dL(-1)) and TFPI free antigen (2.9 vs. 3.6 ng mL(-1)) levels than users of OC containing levonorgestrel. Women using cyproterone acetate-containing OC, known to confer a high thrombotic risk, had the lowest free protein S (19 U dL(-1)) and free TPFI antigen (2.5 ng mL(-1)) levels. Users of OC containing drospirenone had lower free protein S (23 U dL(-1)) and TFPI antigen levels (3.2 ng mL(-1)) than users of levonorgestrel-containing OC. Low free protein S and low free TFPI antigen levels were associated with an increased resistance to APC, an established risk factor for thrombosis. CONCLUSIONS: This study observed that the differences in APC resistance induced by OC containing different progestogens can at least in part be explained by different effects of OC on free protein S and TFPI.

Copper containing, framed intra-uterine devices for contraception.

BACKGROUND: Intrauterine devices (IUD) are safe and effective methods of long term reversible contraception. The design, and copper content as well as placement of the copper on IUDs could affect their effectiveness and side-effect profile. OBJECTIVES: We compared different copper IUDs for their effectiveness and side effects. SEARCH STRATEGY: Multiple electronic databases were searched with appropriate key words and names of the IUDs known to be in the market. We searched the reference lists of papers identified and contacted trialists when possible. There was no language restriction. SELECTION CRITERIA: Randomised controlled trials comparing different IUDs were considered. Trials needed to report on clinical outcomes. DATA COLLECTION AND ANALYSIS: Data on outcomes and trial characteristics were extracted in duplicate and independently by two reviewers. Meta-analysis results are expressed as rate difference (RD) using a fixed-effects model with 95% confidence interval (CI). In the presence of significant heterogeneity a random-effects model was applied. MAIN RESULTS: We included 35 trials, resulting in 18 comparisons of 10 different IUDs in approximately 48,000 women. TCu380A was more effective in preventing pregnancy than MLCu375 (RD 1.70%, 95% CI 0.07% to 2.95% after 4 years of use). TCu380A was also more effective than MLCu250, TCu220 and TCu200. There tended to be fewer pregnancies with TCu380S compared to TCu380A after the first year of use, a difference which was statistically significant in the fourth year (RD -1.62%, 95% CI -3.00% to -0.24%). This occurred despite more expulsions with TCu380S (RD 3.50%, 95% CI 0.36% to 6.63% at 4 years). MLCu375 was no more effective than TCu220 at 1 year of use, or MLCu250 and NovaT up to 3 years. Compared to TCu380A or TCu380S, none of the IUDs showed any benefits in terms of bleeding or pain, or any of the other reasons for early discontinuation. None of the trials that reported events at insertion found one IUD easier to insert than another or caused less pain at insertion. There is no evidence that uterine perforation rates vary by type of device. There are minimal randomised data on IUD use in nulliparous women. AUTHORS' CONCLUSIONS: TCu380A or TCu380S appear to be more effective than other IUDs. No IUD showed consistently lower removal rates for bleeding and pain in comparison to other IUDs. There is no evidence that any particular framed copper device is better suited to women who have not had children.

[New recommendations as regards forgetting to take the contraceptive pill]. / Nieuwe adviezen bij het vergeten van de anticonceptiepil.

Guidelines from the Dutch College of General Practitioners (NHG), the Scientific Institute of Dutch Pharmacists (WINAp), the Dutch Association for Obstetrics & Gynaecology (NVOG) and the Dutch Expert Centre on Sexuality (Rutgers Nisso Groep) all gave different recommendations on the use of the morning after pill in the event of the contraceptive pill being missed. This is an undesirable situation. Using the 2004 WHO-recommendations on missed pills as a starting point, new Dutch guidelines were drawn up. The consensus is that in the case of only one pill being missed, no extra precautions are necessary. This is by far the most frequent situation. The forgotten pill should be taken as soon as possible. Forgetting to take the pill more than once is a rare occurrence. Iftwo or more pills have been missed, advice will be given in accordance with the existing NHG guideline. The WHO has been requested to initiate research in order to establish if its current recommendations on forgetting more than one contraceptive pill can be supported by better data. The new recommendations will be implemented into harmonized guidelines thus enabling women to be given the same simple advice at every advisory centre.

Matched follow-up study of 5 8-year-old ICSI singletons: child behaviour, parenting stress and child (health-related) quality of life.

BACKGROUND: Psychosocial follow-up of ICSI children is scarce. We compared child behaviour, parenting stress and quality of life for singletons aged 5-8 years born after ICSI, IVF and natural conception (NC). METHODS: All singletons born between June 1996 and December 1999 after ICSI in the Leiden University Medical Center were invited (n = 110). Matched singletons born after IVF and NC were recruited. Parents completed the Child Behaviour Checklist (measures problem behaviour), the Parenting Stress Index (Nijmeegse Ouderlijke Stress Index) and two quality of life questionnaires (Dux25 and TACQOL). Children completed the Dux25 Child form. RESULTS: Eighty-seven ICSI children (79%), 92 IVF children (73%) and 85 NC children enrolled. Prevalence of behavioural disorders-as reported by the parents-was comparable in the three groups. Three of 87 ICSI children had autism or an autistic spectrum disorder (ASD). Problem behaviour scores were similar for ICSI and NC children; IVF children (mainly girls) scored less problem behaviour (P < 0.05) and their scores were less often in the (borderline) clinical range. Parenting stress was similar for ICSI and IVF, but lower for NC than ICSI parents, mainly on the child scale. Quality of life scores were similar in the three conception groups. CONCLUSIONS: Prevalence of autism/ASD seemed higher after ICSI, but this unexpected finding should be confirmed by future studies with larger group sizes. ICSI parents experienced more stress than NC parents, although selection bias cannot be ruled out. The majority of ICSI singletons assessed at age 5-8 years showed a normal psychosocial well-being.