Huib Aam Van Vliet

Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography

In a study population consisting of healthy men (n = 8), women not using oral contraceptives (OC) (n = 28) and women using different kinds of OC (n = 187) we used calibrated automated thrombography (CAT) in the absence and presence of added activated protein C (APC) to compare parameters that can be obtained from thrombin generation curves, i.e. lag time, time to peak, peak height and endogenous thrombin potential (ETP). Both with and without APC, plasmas of OC users exhibited the shortest lag time and time to peak, and the highest peak height and ETP. In the absence of APC none of these parameters differed between users of OC containing different progestogens. In contrast, in the presence of APC shorter lag times and time to peak, and higher peak height and ETP were observed in plasma of users of gestodene-, desogestrel-, drospirenone- and cyproterone acetate-containing OC than in plasma of users of levonorgestrel- containing OC. The ETP determined in the absence of APC (ETP(-APC)) had no predictive value for the APCsr (r = 0.11; slope 0.9 x 10(-3); 95% CI: -0.1 x 10(-3) to 2.0 x 10(-3)) whereas the ETP measured in the presence of APC (ETP+APC) showed an excellent correlation with the APCsr (r = 0.95; slope 6.6 x 10(-3); 95% CI: 6.3 x 10(-3) to 6.9 x 10(-3)) indicating that the APCsr is entirely determined by the ETP+APC. In conclusion, OC use increases thrombin generation, but differential effects of second and third generation OCs on the protein C system likely determine the differences in the risk of venous thrombosis between these kinds of OC.

Intrauterine insemination versus timed intercourse for cervical hostility in subfertile couples.

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 gynecologic societies do not endorse use of intrauterine insemination for hostile cervical mucus, some physicians consider it an effective treatment for women with infertility thought the result of cervical mucus problems. 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. 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. We included randomized and quasirandomized, 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 1 year. We assessed the titles and abstracts of 386 publications and 2 reviewers independently abstracted data on methods and results from 5 studies identified for inclusion. The main outcome is pregnancy rate per couple. We did not pool the outcomes of the included 5 studies in a meta-analysis resulting from 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. 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. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to recall that there is a lack of adequate studies that support that intrauterine insemination (IUI) is an effective treatment of cervical hostility, explain that the postcoital test has poor diagnostic and prognostic properties, and state that the use of both tests has no benefit on pregnancy rates. Editors Note: Although many assisted reproductive technology (ART) programs no longer perform postcoital tests, many perform intrauterine insemination (IUI), often with gonadotropins or clomiphene citrate, in their subfertile patients. Therefore, this review article will be of value to our readers who treat subfertile patients with IUI, whether or not they perform postcoital tests. For additional explanations of the statistical tests employed in this review, see D. Grimes, KF Schulz, Obstetrical and Gynecologic Survey, 57; Supplement 3: S35, September 2002; and D. Grimes, KF Schulz, Obstetrical and Gynecologic Survey, Supplement 2, S53–S69, September 2005.—RBJ

The effect of the levonorgestrel-releasing intrauterine system on the resistance to activated protein C (APC)

Exogenously administered estrogens and progestogens as during combined oral contraceptive use increase the risk of venous thrombosis. The thrombin generation-based APC resistance assay is a global coagulation test that enables quantification of the net prothrombotic effect of combined oral contraceptives and that predicts the risk of thrombosis. The thrombotic risk of the levonorgestrel-releasing intrauterine system is unknown. It was the objective of this study to evaluate the thrombotic risk by comparing the APC resistance before and after insertion of a levonorgestrel-releasing or a copper-containing intrauterine device. We measured normalized APC-sensitivity ratios (nAPCsr) before and three months after insertion of the levonorgestrel-intrauterine system in 56 women and the copper-intrauterine device in 18 women. In women without hormonal contraceptive use or a pregnancy in the three months before collection of the baseline samples, nAPCsr were lower three months after insertion of the levonorgestrel-intrauterine system than at baseline (difference -0.29; 95% CI -0.04 to -0.53) and hardly changed after insertion of the copper-intrauterine device (difference -0.11; 95% CI -1.03 to 0.82). In women who switched from a combined oral contraceptive to the levonorgestrel-system the difference was more pronounced (-1.48; 95% CI -0.85 to -2.11). In this study we observed that the levonorgestrel-intrauterine system decreases the resistance to APC which indicates that the levonorgestrel-intrauterine system does not have a prothrombotic effect.

The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI

Use of combined oral contraceptives is associated with a three- to six-fold increased risk of venous thrombosis. Hormonal contraceptives induce acquired resistance to activated protein C (APC), which predicts the risk of venous thrombosis. The biological basis of the acquired APC resistance is unknown. Free protein S (PS) and free tissue factor pathway inhibitor (TFPI) are the two main determinants of APC. Our objective was to assess the effect of both hormonal and non-hormonal contraceptives with different routes of administration on free TFPI and free PS levels. We conducted an observational study in 243 users of different contraceptives and measured APC sensitivity ratios (nAPCsr), free TFPI and free PS levels. Users of contraceptives with the highest risk of venous thrombosis as reported in recent literature, had the lowest free TFPI and free PS levels, and vice versa, women who used contraceptives with the lowest risk of venous thrombosis had the highest free TFPI and free PS levels. An association was observed between levels of free TFPI and nAPCsr, and between free PS and nAPCsr. The effect of oral contraceptives on TFPI and PS is a possible explanation for the increased risk of venous thrombosis associated with oral contraceptives.

Effects of the contraceptive vaginal ring, the contraceptive transdermal patch and combined oral contraceptives on markers of hemostasis

This letter to the editor compares the results of two studies assessing the effect of switching from combined oral contraceptives to the combined contraceptive vaginal ring or transdermal patch on markers of hemostasis that have been related to the risk of venous thrombosis. One study found beneficial as well as unfavorable changes in markers and in contrast one study found only unfavorable prothrombotic effects. It states that the differences in outcomes between the studies might be explained by: difference in comparator oral contraceptive difference in laboratory methods and methodological differences. Copyright

Growth-restricted preterm newborns are predisposed to functional adrenal hyperandrogenism in adult life.

BACKGROUND The long-term effects of perinatal growth and corticosteroid exposure on adrenal steroid concentrations in adults born very preterm are uncertain. OBJECTIVES To examine the effect of birth weight, early postnatal growth, and pre- and postnatal corticosteroid administration on serum adrenal steroids in 19-year-old subjects born very preterm. DESIGN AND METHODS Subjects born before 32 weeks of gestation in The Netherlands participating in the Project on Preterm and Small for Gestational Age Infants (POPS) were investigated at 19 years of age. Serum cortisol, DHEA sulfate (DHEAS), and androstenedione (Adione) concentrations were measured in 393 out of 676 eligible subjects, compared with controls, and associated with perinatal growth and pre- and postnatal corticosteroids administration using multiple linear regression analyses. RESULTS Serum DHEAS and Adione in men and women were higher than in controls. In the multiple regression analyses, birth weight SDS showed a statistically significant negative association with serum DHEAS concentrations in women (β: -0.865, 95% confidence interval (CI): -1.254 to -0.476) and in men (β: -0.758, 95% CI: -1.247 to -0.268) and with serum Adione concentrations in women (β: -0.337, 95% CI: -0.593 to -0.082). Early postnatal weight gain showed no association with any of measured adrenal markers. In women, serum Adione was associated with postnatal dexamethasone exposure (β: 0.932, 95% CI: 0.022 - 1.843). CONCLUSIONS Young adults born very preterm show elevated adrenal androgens, particularly when born small for gestational age. Postnatal corticosteroid administration is positively associated with serum Adione in young women.

Sex hormone-binding globulin: an adequate surrogate marker for venous thromboembolism in women using new hormonal contraceptives

This letter to the editor centers on sex hormone-binding globulin (SHBG) as a marker for the thrombotic risk of oral contraceptives. It calls for more studies on markers to reveal the pathphysiological pathway of the thrombotic effect of hormonal contraceptives.

Induction of labour at term with oral misoprostol versus a foley catheter (PROBAAT-II) : A multicentre randomised controlled non-inferiority trial

When pregnancy complications pose a threat to the mother or fetus or both, induction of labor is often required. Induction of labor is accomplished through a variety of methods; in pregnant women having an unfavourable cervix, cervical ripening of the cervix is accomplished through various mechanical and pharmacological means. Oral misoprostol and Foley catheter are believed to be equally effective in women with an unfavorable cervix in accomplishing vaginal birth. The current open-label randomized noninferiority trial was conducted in pregnant women with a singleton gestation in 29 hospitals in the Netherlands (2012 to 2013) to directly compare oral misoprostol with Foley catheter. Women with a viable singleton pregnancy in cephalic presentation, intact membranes, gestational age of 37 weeks or more, and an unfavorable cervix were included in the trial. The women were then randomly allocated (1:1) to oral misoprostol (n = 932) or Foley catheter (n = 927). Oral misoprostol dosage given was 50 µg orally once every 4 hours with a maximum of 3 times a day. Placement of a 30-mL Foley catheter in the cervix was done either digitally or using a vaginal speculum. The results of the study showed that the primary outcome (asphyxia or postpartum hemorrhage) occurred in 12.2% women in the misoprostol group and in 11.5% women in the Foley catheter group (adjusted relative risk [RR], 1.06; 90% confidence interval [CI], 0.86–1.31). Cesarean delivery resulted in 16.8% of labors in the misoprostol group and in 20.1% of the time in the Foley catheter group (no significant difference between groups [RR, 0.84; 95% CI, 0.69–1.01]). When the indication for cesarean delivery was examined, fewer cesarean deliveries for failure to progress in the first stage occurred after induction in the misoprostol group than in the Foley catheter group (6.2% vs 10.6%; RR, 0.58; 95% CI, 0.42–0.79). In addition, operative vaginal delivery occurred more frequently in the misoprostol group. Among the misoprostol group spontaneous membrane rupture was more common and labor augmentation with oxytocin was less likely. The study leads to a conclusion that in terms of safety and effectiveness, induction of labour using oral misoprostol is as safe as mechanical induction using Foley catheter.