Frans M. Helmerhorst

Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) Study Oral Contraceptives and the Risk of Ischemic Stroke

Background and Purpose— Epidemiological studies have shown an increased risk of venous thrombosis in women taking third-generation oral contraceptives, ie, those containing the progestogens desogestrel or gestodene. This study assesses the risk of ischemic stroke with several types of oral contraceptives. Methods— A multicenter, population-based, case-control study was performed in 9 Dutch centers in women aged 18 to 49 years. Women with a first ischemic stroke were compared with control women without vascular diseases. The control subjects were recruited by random-digit dialing and were stratified by age, area of residence, and year of stroke. All patients and control subjects filled in a questionnaire about the use of oral contraceptives and risk factors for ischemic stroke. Odds ratios were adjusted for the stratification factors. Results— Two hundred three women with an ischemic stroke and 925 control women were included. The risk of stroke in women using any type of oral contraceptives versus none was 2.3 (95% CI 1.6 to 3.3). Current users of first-generation oral contraceptives had an odds ratio of 1.7 (95% CI 0.7 to 4.4). Low-dose second-generation oral contraceptives increased the risk of stroke 2.4 times (95% CI 1.6 to 3.7), and third-generation oral contraceptives increased the risk of stroke 2.0 times (95% CI 1.2 to 3.5). The risk of stroke in women using third-generation oral contraceptives was not different from that in women using second-generation oral contraceptives (odds ratio 1.0, 95% CI 0.6 to 1.8). Conclusions— Third-generation oral contraceptives (containing desogestrel or gestodene) confer the same risk of first ischemic stroke as second-generation oral contraceptives (containing levonorgestrel).

The RATIO study: oral contraceptives and the risk of peripheral arterial disease in young women

Summary.  With regard to oral contraceptives, much research has concentrated on venous thrombosis and on the coronary and cerebral forms of atherosclerotic disease, while peripheral arterial disease (PAD) has received little attention. In this case‐control study, we assessed oral contraceptive use and the risk of PAD in young women using a population‐based case‐control study. The women were 18–49 years of age, and had been admitted to a collaborating hospital between January 1990 and October 1995, and had a diagnosis of PAD. Participants were patients with PAD (n = 152), and control women (n = 925), identified by random digit dialing. The diagnosis of PAD was based almost exclusively on intra‐arterial angiography. Patients and control subjects filled out the same structured questionnaire, which included questions on medical history, cardiovascular risk factors, and contraceptive use. The adjusted odds ratio for PAD in women using any type of oral contraceptives vs. no use, was 3.8 (95% CI 2.4–5.8). When first generation oral contraceptive use was compared with no use, the odds ratio was 8.7 (95% CI 3.6–21.3). For second and third generation oral contraceptives, the adjusted odds ratios (compared with non‐users) were 2.6 (95% CI 1.4–4.9) and 3.0 (95% CI 1.4–6.6), respectively. This is the first study on oral contraceptive use and PAD in humans. All types of oral contraceptives were associated with an increased risk of PAD.

The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial

BackgroundCosts of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime.Methods/DesignMulticentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT.DiscussionThe results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines.Trial registrationNTR2657

Cognitive Coping, Goal Adjustment, and Depressive and Anxiety Symptoms in People Undergoing Infertility Treatment A Prospective Study

The relationships between cognitive coping strategies, goal adjustment, and symptoms of depression and anxiety were studied in people with fertility problems. Both cross-sectional and prospective relationships were studied in a sample of 313 patients attending an infertility clinic. Self-report questionnaires were filled out at home. Positive refocusing, rumination and catastrophizing, and goal reengagement were related to symptoms of depression and anxiety. When looking at the long-term effects, rumination and catastrophizing were also related to emotional problems nine months later. These findings suggest that intervention programs should focus on cognitive coping strategies and goal-based processes.

Pericellular-acting proteases in human first trimester decidua

Proteolysis is essential for decidual development during embryonic implantation, but little is known regarding the expression and functions of membrane-type matrix metalloproteinases (MT-MMPs) and urokinase-type plasminogen activator (uPA) and its receptor uPAR in decidua. Therefore, their protein and mRNA levels were analysed in three first trimester decidual tissues, decidual secretory endometrium (DSE), decidua parietalis (DP) and basalis (DB). Decidua was obtained during first trimester pregnancy termination. uPA, uPAR, and MT1/2/3/5-MMP expression were studied by RT-PCR and immunohistochemistry, and CD56-positive uNK cells and CD68-positive macrophages were quantified in serial sections. The mRNAs and antigens of all proteases and uPAR were detectable in the decidual tissues and extravillous trophoblasts (EVT). mRNA levels of all proteases and uPAR, except MT5-MMP, were elevated in both DB and DP compared to DSE, being significant for MT1-MMP and uPAR in DP. MT2- and MT3-MMP mRNAs in DB were 24- and 10-fold higher than in DSE, and 19- and 7-fold increased compared to DP. At the protein level uPA and uPAR were particularly elevated in DB, while pro-angiogenic MT1- and MT3-MMPs were elevated in both DB and DP compared to DSE. MT2-MMP was prominently present in all conditions. The number of uNK cells was increased in DB and DP versus DSE, while a comparable increase in macrophages did not reach statistical significance. These data are consistent with a differential regulation of pericellular proteases in decidua by pregnancy-induced hormones, immune cells and EVT.

European postcoital tests : opinions and practice

Objective To assess differences in opinion and practice with regard to the postcoital test in Europe.

Melanoma risk after ovarian stimulation for in vitro fertilization

STUDY QUESTION Do women treated with ovarian stimulation for IVF have an increased risk of melanoma? SUMMARY ANSWER Ovarian stimulation for IVF does not increase risk of melanoma, even after a prolonged follow-up. WHAT IS KNOWN ALREADY Although exposure to ultraviolet radiation is the major risk factor for melanoma, associations between female sex steroids and melanoma risk have also been suggested. The results of available studies on fertility drugs and melanoma risk are inconclusive since most studies had several methodological limitations such as short follow-up, a small number of cases and no subfertile comparison group. STUDY DESIGN, SIZE, DURATION In 1996, a nationwide historic cohort study (the OMEGA-cohort) was established to examine the risk of cancer after ovarian stimulation for IVF. After a median follow-up of 17 years, cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Melanoma risk in the cohort was compared with that in the general population and between the IVF group and non-IVF group using multivariable Cox regression analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS The cohort comprises 19 158 women who received IVF between 1983 and 1995 and a comparison group of 5950 women who underwent subfertility treatments other than IVF. Detailed IVF-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Dutch Municipal Personal Records Database. MAIN RESULTS AND THE ROLE OF CHANCE In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles was associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; ≥7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21). LIMITATIONS, REASONS FOR CAUTION Despite our large cohort, the number of melanoma cases was rather small, especially in our comparison group, which hampered subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS Our results are reassuring for women who underwent IVF or are contemplating to start IVF. Since our cohort study is one of the largest published so far, with long-term follow-up, a subfertile comparison group, and detailed IVF-treatment data, our results add important information to the available evidence. STUDY FUNDING/COMPETING INTEREST This study was supported by grants from the Dutch Cancer Society (NKI 2006-3631), the Health Research and Development Counsel (28-2540) and the Dutch Ministry of Health.

Effect of the postcoital test on the sexual relationship of infertile couples: a randomized controlled trial *

OBJECTIVE To investigate the impact of the postcoital test (PCT) on the sexual relationship and functioning of infertile couples. DESIGN Randomized controlled study. SETTING University hospital. PATIENTS New infertility patients were randomized to an infertility work-up with (PCT group) or without (non-PCT group) postcoital test as integral part of the investigation. INTERVENTION Performance of the PCT. MAIN OUTCOME MEASURE Both partners completed a questionnaire on their sexual relationship and functioning at the initial visit and after 3 months. RESULTS Of 500 consecutive new couples, 304 fulfilled inclusion criteria and 290 consented to participate (PCT group: 152; non-PCT group: 138). Answers to both the first and second questionnaire were obtained from 84 couples (PCT: 43; non-PCT: 41). After 3 months, couples in the PCT group were at least as satisfied with their sexual relationship as couples in the non-PCT group with little difference having occurred in the 3 months of investigation. CONCLUSION Overall, the influence of the PCT on the sexual relationship of infertile couples is more positive than negative.

Follow-up of 30 pregnancies after embryo cryopreservation

OBJECTIVE In an observational follow-up study, the pregnancy outcome of the first 30 women who conceived after transfer of cryopreserved embryos was evaluated. STUDY DESIGN The main outcome measures were duration and complications of pregnancy, mode of delivery, complications during and after childbirth, birthweight, Apgar score, and congenital anomalies. RESULTS Twenty-six pregnancies ended in birth of one (n = 22) or more (n = 4) infants with a cesarean section rate of 23%. Of the singleton pregnancies 77% were uncomplicated, but there was a high incidence of breech presentation (14%). Infant birthweight tended to be above average with 45% of singletons weighing more than the 75th centile of weight for gestation. There were no major congenital deformations. CONCLUSION The results of our embryo cryopreservation program are encouraging, but sustained follow-up of such pregnancies and infants is needed.

The influence of indomethacin on the hatching of mouse blastocysts

In order to investigate the effect of indomethacin for inhibition of the cyclooxygenase pathway on the hatching process of mouse blastocysts, 508 mouse blastocysts were cultured in modified HAM F10 medium containing 0, 8, 79 or 788 microM indomethacin, added after 24 h of incubation. Hatching was scored after 72 h of incubation. In another series of experiments, indomethacin was added only after blastulation had occurred. Indomethacin in doses of 8 microM and 79 microM, added after 24 h of incubation or after blastulation had occurred, did not influence successful hatching. A dose of 788 microM indomethacin interfered with hatching, but this dose appeared to be toxic for the embryo.