Cancer in pregnancy increases the risk of venous thromboembolism: a nationwide cohort study.

OBJECTIVE: To investigate if cancer in pregnancy causes a higher risk of venous thromboembolism (VTE) during pregnancy and postpartum compared with pregnant women without cancer. DESIGN: A historical prospective cohort study using data from nationwide registries. SETTING AND POPULATION: We assessed all pregnancies in Denmark between 1 January 1977 and 31 December 2017. METHODS: We linked information concerning cancer diagnosis, pregnancy and VTE diagnosis and potential confounders. Event rates of VTE for women with pre-pregnancy cancer, cancer in pregnancy and without cancer were calculated per 10 000 pregnancies and compared using logistic regression analysis. MAIN OUTCOME MEASURES: Occurrence of VTE during pregnancy or the postpartum period. RESULTS: A total of 3 581 214 pregnancies were included in the study and we found 1330 women with cancer in pregnancy. In pregnant women with cancer, the event rate of VTE was 75.2 per 10 000 pregnancies compared with 10.7 per 10 000 pregnancies in the no cancer group. The findings correspond to an increased adjusted odds ratio of 6.50 (95% CI3.5-12.1) in the cancer in pregnancy group in comparison with the no cancer group. CONCLUSIONS: Women with cancer in pregnancy have a markedly higher risk of pregnancy-associated VTE compared with women without cancer. In pregnancy-related VTE risk assessment, the presence of cancer alone may be sufficient to indicate thromboprophylaxis. TWEETABLE ABSTRACT: Cancer in pregnancy increases the risk of VTE during pregnancy and the postpartum period.

Pattern of mortality after menopausal hormone therapy: long-term follow up in a population-based cohort.

OBJECTIVE: To investigate long-term pattern of mortality in menopausal women according to different modalities of hormone therapy. DESIGN: Population-based prospective cohort study. SETTING: Denmark 1993-2013. POPULATION: A total of 29 243 women aged 50-64 years at entry into the Diet, Cancer and Health Cohort, enrolled 1993-97 and followed through 31 December 2013. METHODS: Cox' proportional hazards models for increasingly longer periods of follow-up time were used to estimate mortality pattern according to baseline hormone use adjusted for relevant potential confounders. MAIN OUTCOME(S): All-cause and cause-specific mortality. Outcome information was obtained from the Danish Register of Causes of Death (linkage 99.6%). RESULTS: A total of 4098 women died during a median follow up of 17.6 years. After adjustment for relevant lifestyle risk factors, hormone use had no impact on all-cause mortality, regardless of modality. Among baseline users, lower cardiovascluar disease mortality was only evident after 5 years [hazard ratio (HR) 0.54; 95% CI 0.32-0.92], but dissipated with additional follow up. Conversely, lower colorectal cancer mortality (HR 0.64; 95% CI 0.46-0.89) and higher breast cancer mortality (HR 1.34; 95% CI 1.05-1.72) only became evident after 15 years of follow up. There were no significant associations for mortality from other types of cancer or from stroke. CONCLUSIONS: In this long-term follow-up study, taking hormones during menopause was not associated with overall mortality among middle-aged women. Investigating cause-specific mortality revealed significant, albeit weak, differential associations according to both causes of death and over time, underlining the importance of carefully considering individual risks and duration of treatment when making decisions on hormone therapy. TWEETABLE ABSTRACT: Long-term follow-up study confirms no association between menopausal hormone therapy and overall mortality.

Perinatal outcomes following an earlier post-term labour induction policy: a historical cohort study.

OBJECTIVE: To assess the changes in perinatal outcomes in children born from 37 weeks of gestation after implementation of a more proactive labour induction practice from 2009. DESIGN: Register-based cohort study. SETTING: Denmark, 2000-12. POPULATION: Newborns from 37 weeks of gestation. METHODS: Perinatal outcomes were estimated using a logistic regression analysis with adjustment for gestational age, maternal age, parity, plurality, smoking and body mass index. MAIN OUTCOME MEASURES: Perinatal outcomes. RESULTS: A total of 770 926 infants were included. Labour induction from 37 weeks increased from 9.7% in 2000-02 to 22.5% in 2011-12. From 2003-05 to 2011-12, the risk of umbilical cord pH < 7.0 decreased by 23%; odds ratio (OR) 0.77 (95% confidence interval 0.67-0.89), and the adjusted OR of Apgar score < 7 at 5 minutes was unchanged. The risk of admission to neonatal intensive care units increased by 56%; OR 1.56 (1.47-1.66), whereas the risk of neonatal deaths decreased by 44%; OR 0.56 (0.45-0.70). The risk of cerebral palsy was from 2000-02 to 2009-10 reduced by 26%; OR 0.74 (0.60-0.90). The proportion of infants born with fetal weight ≥ 4500 g decreased by one-third; OR 0.68 (0.65-0.71). However, the risk of shoulder dystocia increased by 32%; OR 1.32 (1.21-1.44), whereas the risk of peripheral nerve injuries was reduced by 43%; OR 0.57 (0.45-0.73). CONCLUSION: The results suggest an overall improvement in perinatal outcomes as a result of a more proactive post-term labour induction practice.

Follicle pool, ovarian surgery and the risk for a subsequent trisomic pregnancy.

STUDY QUESTION: Is there an association between trisomic pregnancy, a marker for decreased oocyte quality, and the reduced oocyte quantity that follows ovarian surgery? SUMMARY ANSWER: Previous ovarian surgery is not associated with an increased risk for a subsequent trisomic pregnancy. WHAT IS KNOWN ALREADY: Ovarian surgery diminishes the number of oocytes. The risk for a trisomic pregnancy is suggested to be higher in women with fewer oocytes, independent of their chronological age. STUDY DESIGN, SIZE, DURATION: This is a matched case-control study. Cases are women with a confirmed trisomic pregnancy occurring between 1 January 2000 and 31 December 2010 regardless of pregnancy outcome and controls are women that had a live born child without a trisomy. In total, there were 8573 participants in the study; 1723 cases and 6850 controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were obtained from Danish medical registries. Matching criteria were maternal age and year of conception. Number of controls matched per case ranged from one to four. Among cases and controls with a trisomic pregnancy, 2.7% (46/1723) versus 2.5% (172/6850) had undergone ovarian surgery before pregnancy. MAIN RESULTS AND ROLE OF CHANCE: History of ovarian surgery is not associated with a higher risk for a subsequent trisomic pregnancy (odds ratio = 1.00, 95% confidence interval 0.99-1.01). Subgroup analyses by indication of surgery and interval between ovarian surgery and pregnancy do not show an effect on trisomic pregnancy risk. LIMITATIONS, REASONS FOR CAUTION: The medical registries used to select cases and controls did not contain information on surgical technique nor volume of ovarian tissue resected, previous trisomic pregnancy prior to the ovarian surgery or long-term use of oral contraceptives. Therefore, correction for these factors was not performed. WIDER IMPLICATIONS OF THE FINDINGS: We did not confirm the hypothesis that ovarian surgery, a marker for decreased oocyte quantity, is related to trisomic pregnancy, a marker for decreased oocyte quality. This suggests that ovarian surgery, which has a direct reductive effect on the size of the follicle pool, may affect oocyte quality differently when compared with the reduction in follicle pool size due to ageing. STUDY FUNDING/COMPETING INTERESTS: The study was supported by grants from the Gratama Stichting, University of Groningen and the University Medical Center Groningen, The Netherlands. Ø.L. has within the last 3 years received honoraria for speeches in pharmacoepidemiological issues, not related to this study. The Department of Obstetrics and Gynaecology receives unrestricted educational grants from Ferring Pharmaceuticals. A.H. received a grant from ZonMW (i.e. National Dutch Scientific funding) for a RCT not related to this publication. Dr A.H. received speakers fee from MSD for an educational presentation. All other authors have no conflict of interest.

Trends in perinatal health after assisted reproduction: a Nordic study from the CoNARTaS group.

STUDY QUESTIONS: Has the perinatal outcome of children conceived after assisted reproductive technology (ART) improved over time? SUMMARY ANSWER: The perinatal outcomes in children born after ART have improved over the last 20 years, mainly due to the reduction of multiple births. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: A Swedish study has shown a reduction in unwanted outcomes over time in children conceived after ART. Our analyses based on data from more than 92 000 ART children born in four Nordic countries confirm these findings. STUDY DESIGN: Nordic population-based matched cohort study with ART outcome and health data from Denmark, Finland, Norway and Sweden. PARTICIPANTS, SETTING AND METHODS: We analysed the perinatal outcome of 62 379 ART singletons and 29 758 ART twins, born from 1988 to 2007 in four Nordic countries. The ART singletons were compared with a control group of 362 215 spontaneously conceived singletons. Twins conceived after ART were compared with all spontaneously conceived twins (n = 122 763) born in the Nordic countries during the study period. The rates of several adverse perinatal outcomes were stratified into the time periods: 1988-1992; 1993-1997; 1998-2002 and 2003-2007 and presented according to multiplicity. MAIN RESULTS AND ROLE OF CHANCE: For singletons conceived after ART, a remarkable decline in the risk of being born preterm and very preterm was observed. The proportion of ART singletons born with a low and very low birthweight also decreased. Finally, the stillbirth and infant death rates have declined among both ART singletons and twins. Throughout the 20 year period, fewer ART twins were stillborn or died during the first year of life compared with spontaneously conceived twins, presumably due to the lower proportion of monozygotic twins among the ART twins. LIMITATIONS, REASONS FOR CAUTION: We were not able to adjust for some potential confounders such as BMI, smoking, length or cause of infertility. The Nordic ART populations have changed over time, and in recent years, both less as well as severely reproductive ill couples are being treated. This may have affected the observed trends. WIDER IMPLICATIONS OF THE FINDINGS: It is assuring that data from four countries confirm an overall improvement over time in the perinatal outcomes of children conceived after ART. Furthermore, data show the beneficial effect of single embryo transfer, not only in regard to lowering the rate of multiples but also concerning the health of singletons. STUDY FUNDING/COMPETING INTERESTS: The European Society for Human Reproduction and Embryology (ESHRE), the University of Copenhagen and the Danish Agency for Science, Technology and Innovation has supported the project. The CoNARTaS group has received travel and meeting funding from the Nordic Federation of Obstetrics and Gynecology (NFOG). None of the authors has any competing interests to declare.

Risk of stillbirth and infant deaths after assisted reproductive technology: a Nordic study from the CoNARTaS group.

STUDY QUESTION: Is the risk of stillbirth and perinatal deaths increased after assisted reproductive technology (ART) compared with pregnancies established by spontaneous conception (SC)? SUMMARY ANSWER: A significantly increased risk of stillbirth in ART singletons was only observed before 28 + 0 gestational weeks. WHAT IS KNOWN ALREADY: The current literature indicates that children born after ART have an increased risk of perinatal death. The knowledge on stillbirth in ART pregnancies is limited. STUDY DESIGN, SIZE, DURATION: A population based case-control study. PARTICIPANTS/MATERIALS, SETTING AND METHODS: A total of 62 485 singletons and 29 793 twins born after ART in Denmark, Finland, Norway and Sweden, from 1982 to 2007, were compared with 362 798 spontaneously conceived (SC) singletons and 132 181 twins. MAIN RESULTS AND THE ROLE OF CHANCE: The adjusted rate ratio for stillbirth at gestational weeks 22 + 0 to 27 + 6 was 2.08 [95% confidence interval (CI) 1.55-2.78] for ART versus SC singletons. After 28 + 0 gestational weeks there was no significant difference in the risk of stillbirth between ART and SC singletons. ART twins had a lower risk of stillbirth compared with SC twins, but when restricting the analysis to opposite-sex twins and excluding all monozygotic twins, there was no significant difference between the groups. Singletons conceived by ART had an overall increased risk of early neonatal death (adjusted odds ratio 1.54, 95% CI 1.28-1.85) and death within the first year after birth (1.45, 1.26-1.68). No difference regarding these two parameters was found when further adjusting for the gestational age [(0.97, 0.80-1.18) and (0.99, 0.85-1.16), respectively]. ART twins had a lower risk of early neonatal and infant deaths than SC twins, but no difference was found when restricting the analyses to opposite-sex twins. LIMITATIONS, REASON FOR CAUTION: We were not able to adjust for potential confounders, such as a prior history of stillbirth, induction of labour, body mass index or smoking. WIDER IMPLICATIONS OF THE FINDINGS: The risk of stillbirth in ART versus SC singletons was only increased for very early gestational ages (before 28 weeks). This might indicate that the current clinical management of ART pregnancies is sufficient regarding prevention of stillbirth during the third trimester. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest was reported. The European Society for Human Reproduction and Embryology (ESHRE), the University of Copenhagen, Denmark, the Danish Agency for Science, Technology and Innovation and Sahlgrenska University Hospital, Gothenburg, Sweden supported the project. The CoNARTaS group has received travel and meeting funding from the Nordic Society of Obstetrics and Gynecology (NFOG).

Ovarian reserve parameters: a comparison between users and non-users of hormonal contraception.

It remains controversial whether anti-Müllerian hormone (AMH) concentration is influenced by hormonal contraception. This study quantified the effect of hormonal contraception on both endocrine and sonographic ovarian reserve markers in 228 users and 504 non-users of hormonal contraception. On day 2-5 of the menstrual cycle or during withdrawal bleeding, blood sampling and transvaginal sonography was performed. After adjusting for age, ovarian reserve parameters were lower among users than among non-users of hormonal contraception: serum AMH concentration by 29.8% (95% CI 19.9 to 38.5%), antral follicle count (AFC) by 30.4% (95% CI 23.6 to 36.7%) and ovarian volume by 42.2% (95% CI 37.8 to 46.3%). AFC in all follicle size categories (small, 2-4 mm; intermediate, 5-7 mm; large, 8-10 mm) was lower in users than in non-users of hormonal contraception. A negatively linear association was observed between duration of hormonal-contraception use and ovarian reserve parameters. No dose-response relation was found between the dose of ethinyloestradiol and AMH or AFC. This study indicates that ovarian reserve markers are lower in women using sex steroids for contraception. Thus, AMH concentration and AFC may not retain their accuracy as predictors of ovarian reserve in women using hormonal contraception. Serum anti-Müllerian hormone (AMH) concentration is an indirect marker of the number of small follicles in the ovary and thereby the ovarian reserve. The AMH concentration is now widely used as one of the markers of the ovarian reserve in ovarian hormonal stimulation regimens. Hence the AMH concentration in a patient is used to decide the dose of the ovarian hormonal stimulation prior to IVF treatment. In some infertile patients, hormonal contraception is used prior to ovarian hormonal stimulation and therefore it is important to clarify whether serum AMH concentration is influenced by the use of sex steroids. The aim of this study was to quantify the potential effect of hormonal contraception on the ovarian function by hormonal analyses and ovarian ultrasound examination. Examinations were performed in the early phase of the menstrual cycle or the hormone-free interval of hormonal contraception. We compared the AMH concentration, the antral follicle count (AFC) and the ovarian volume in 228 users versus 504 non-users of hormonal contraception. Users of hormonal contraception had 29.8% lower AMH concentration, 30.4% lower AFC and 42.2% lower ovarian volume than non-users. These findings were more pronounced with increasing duration of hormonal contraception. No dose-response relation was found between the dose of ethinylestradiol and the impact on serum AMH and AFC. The study indicates that ovarian reserve markers are lower in women using sex steroids for contraception. Thus, serum AMH concentration and AFC may not retain their accuracy as predictors of the ovarian reserve in women using hormonal contraception.

Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study.

OBJECTIVE: To assess the fetal loss rate following amniocentesis and chorionic villus sampling (CVS). METHODS: This was a national registry-based cohort study, including all singleton pregnant women who had an amniocentesis (n = 32 852) or CVS (n = 31 355) in Denmark between 1996 and 2006. Personal registration numbers of women having had an amniocentesis or a CVS were retrieved from the Danish Central Cytogenetic Registry, and cross-linked with the National Registry of Patients to determine the outcome of each pregnancy. Postprocedural fetal loss rate was defined as miscarriage or intrauterine demise before 24 weeks of gestation. RESULTS: The miscarriage rates were 1.4% (95% CI, 1.3-1.5) after amniocentesis and 1.9% (95% CI, 1.7-2.0) after CVS. The postprocedural loss rate for both procedures did not change during the 11-year study period, and was not correlated with maternal age. The number of procedures a department performed had a significant effect on the risk of miscarriage. In departments performing fewer than 500 amniocenteses, the odds ratio for fetal loss was 2.2 (95% CI, 1.6-3.1) when compared to departments performing more than 1500 procedures during the 11-year period. For CVS the risk of miscarriage was 40% greater in departments performing 500-1000 and 1001-1500 as compared to those performing more than 1500 procedures. CONCLUSIONS: The miscarriage rates (i.e. spontaneous loss and procedure-related loss) after amniocentesis and CVS were 1.4% and 1.9%, respectively. This difference may be explained by the difference in gestational age at the time of the procedures. The miscarriage rate was inversely correlated with the number of procedures performed in a department.

Occlusive vascular diseases in oral contraceptive users. Epidemiology, pathology and mechanisms.

Despite being an unprecedented departure from normal physiology, the combined oral contraceptive is not only highly effective, but it also has a remarkably good safety record. Concerns over safety persist, though, particularly with regard to venous thromboembolism (VTE), stroke and myocardial infarction (MI). Epidemiological studies consistently show an increase in risk of VTE, but the results are more contentious with regard to arterial diseases. Despite 40 years of research, the mechanisms behind these adverse effects are not understood. In this review, we integrate information from published studies of the epidemiology and pathology of the occlusive vascular diseases and their risk factors to identify likely explanations for pathogenesis in oral contraceptive users. Oral contraceptives induce both prothrombotic and fibrinolytic changes in haemostatic factors and an imbalance in haemostasis is likely to be important in oral contraceptive-induced VTE. The complexity of the changes involved and the difficulty of ascribing clinical significance has meant that uncertainty persists. A seriously under-researched area concerns vascular changes in oral contraceptive users. Histologically, endothelial and intimal proliferation have been identified in women exposed to high plasma estrogen concentrations and these lesions are associated with thrombotic occlusion. Other structural changes may result in increased vascular permeability, loss of vascular tone and venous stasis. With regard to arterial disease risk, epidemiological information relating to dose effects and joint effects with other risk factors, and studies of pathology and changes in risk factors, suggests that oral contraceptive use per se does not cause arterial disease. It can, nevertheless, synergise very powerfully with subclinical endothelial damage to promote arterial occlusion. Accordingly, the prothrombotic effects of the oral contraceptive estrogen intervene in a cycle of endothelial damage and repair which would otherwise remain clinically silent or would ultimately progress - in, for example, the presence of cigarette smoking or hypertension - to atherosclerosis. Future work in this area should focus on modification of the effects of established risk factors by oral contraceptive use rather than modification of the supposed risk of oral contraceptive use by established risk factors. Attempts to understand vascular occlusion in oral contraceptive users in terms of the general features of VTE or with reference to atherosclerosis may be limiting, and future work needs to acknowledge that such occlusions may have unique features. Unequivocal identification of the mechanisms involved would contribute considerably to the alleviation of fears over vascular disease and to the development of even safer formulations.

[Severe male infertility. Genetic investigation and counseling prior to intracytoplasmic sperm injections]. / Mandlig infertilitet i svaer grad. Genetisk udredning og rådgivning før intracytoplasmatisk saedcelleinjektion.

Intracytoplasmatic sperm injection (ICSI) has improved the success rate in treating severe male infertility. The method may now be used with sperm from the epididymis and testis. This article summarizes our knowledge on genetic factors affecting male gamete formation or function. Infertile men with severe impairment of spermatogenesis showed a higher than normal incidence of chromosomal abnormalities and 10-20% had microdeletion, in the Y-chromosome. About 75% of males with congenital bilateral absence of vas deferens (CBAVD) have mutations in the cystic fibrosis trans-membrane conductance regulator (CFTR) gene. In conclusion, we recommend genetic counselling to all couples with a diagnosis of male infertility prior to ICSI. Men with severe oligozoospermia or non-obstructive azoospermia should have karyotype analysis performed and with establishment of diagnostic tools to reveal Y-chromosome deletions, this should be offered to the same group of men. Men with obstructive azoospermia and congenital albilateral absence of vas deferens as well as their wives should be screened for cystic fibrosis mutations.

Risk factors among young women with endometrial cancer: a Danish case-control study.

OBJECTIVE: This study was undertaken to identify and quantify risk factors for endometrial cancer among young women. STUDY DESIGN: This case-control study included all Danish women <50 years old who had endometrial cancer diagnosed during the period 1987 to 1994. A total of 237 case patients and 538 population control subjects matched with the case patients for age and residence were included in the analysis. RESULTS: Women with a family history of endometrial cancer had an odds ratio for endometrial cancer of 2.1 (95% confidence interval, 1.1-3.8)). Completion of 1 term pregnancy implied an odds ratio of 0.6 (95% confidence interval, 0.3-1.1). The risk of endometrial cancer decreased significantly with increasing age at first birth and with the number of induced abortions. Use of oral contraceptives for 1 to 5 years decreased the risk of endometrial cancer (odds ratio, 0.2; 95% confidence interval, 0.1-0.3). The odds ratio for endometrial cancer among women who received hormone replacement therapy for 1 to 5 years was 3.1 (95% confidence interval, 1.4-7.0). Body mass index was not demonstrated to be an independent risk factor in this study. The protective impacts of the different exposures (risk factors) can be expressed as etiologic fractions, which indicate how much each exposure reduces the occurrence of endometrial cancer compared with a situation without the existence of that particular exposure. These fractions were as follows: oral contraceptive use for > or =1 year, -45%; 2 term pregnancies, -88%; age > or =30 y when giving birth for the first time, -38%; and a history of incomplete pregnancy, -16%. CONCLUSION: A number of risk factors for endometrial cancer are common to premenopausal and postmenopausal women: family history, reproductive history, hormone replacement therapy, and the use of oral contraceptives. Among young women reproductive variables imply the greatest prophylactic potential.

Smoking and use of oral contraceptives: impact on thrombotic diseases.

OBJECTIVES: The study was intended to evaluate the effects of oral contraceptives and smoking on the risks of arterial and venous thromboembolic diseases among young women. STUDY DESIGN: The study included a survey of data from published epidemiologic studies and evaluation of registry records of all Danish women discharged from the hospital from 1980 through 1993 after a first thromboembolic event. Questionnaires returned by survivors of such events and by control women during the period from 1994 through 1995 were analyzed. RESULTS: In the 1980-1993 data the absolute risk of thrombotic diseases was seen to increase rapidly with age-exponentially for acute myocardial infarction or cerebral thromboembolic attack, linearly for venous thromboembolism-with risks of arterial diseases exceeding those of venous diseases. In the 1994-1995 data the relative risk of thrombotic diseases was seen to increase among users of oral contraceptives irrespective of age. Risk of venous thromboembolism (but not of acute myocardial infarction or cerebral thromboembolic attack) declined as duration of current oral contraceptive use lengthened, risk of acute myocardial infarction or cerebral thromboembolic attack was significantly decreased as ethinyl estradiol doses were reduced, and the relative risk (compared with nonusers of oral contraceptives) for arterial thromboembolic disease among users of desogestrel or gestodene (in conjunction with midrange or low doses of ethinyl estradiol) was lower than the relative risk among users of second-generation progestogens (in conjunction with midrange doses of ethinyl estradiol). The combination of smoking with oral contraceptive use may have a synergistic effect on risks of acute myocardial infarction and cerebral thromboembolic attack (but not of venous thromboembolism), particularly among users of high-dose (50 micrograms) ethinyl estradiol preparations. CONCLUSION: Among the formulations currently marketed in Denmark, where only the progestins desogestrel and gestodene are available with low-dose (20 micrograms) ethinyl estradiol (and only desogestrel was available in that form at the time of our studies), we prefer these third-generation oral contraceptives for smokers. We might also consider such oral contraceptives for women >35 years old as long as they had no other risk factors for thrombotic arterial diseases.

PIP: This study assesses the effects of cigarette smoking and oral contraceptive (OC) use on the risks of arterial and venous thromboembolic diseases among women in their reproductive years. A survey of published epidemiologic studies is included together with an evaluation of registry records of Danish women discharged from hospitals from 1980 through 1993 after a first thromboembolic event. Analysis was made of questionnaires sent to survivors of such an event and to control women during the period from 1994 through 1995. The study also includes an evaluation of thrombotic disease prevalence, determination of OC influence on the risk of the disease, and comparison of disease prevalence among smoking and nonsmoking users of OC. Results showed that the risk of acute myocardial infarction among OC users was significantly higher than among non-OC users. OC use had less of an effect on acute myocardial infarction risk than on the risk of cerebral thromboembolic attack. The risk of venous thromboembolism among users of OC was influenced by the duration of OC use; the shorter the use, the higher the risk, while smoking had little effect. Epidemiologic studies suggest that arterial disease risk in young (men/women) decreases within 5-10 years of smoking cessation. Smoking, with a low dose of OC, acted as an independent risk factor for myocardial infarction and cerebral attack. The absolute risk for older nonusers and nonsmokers was higher by 10-fold than the risk for younger counterparts. Thus, among the formulations available in Denmark, preference is given to third-generation OCs for young female smokers and for smoking women over age 35, provided they have no other risk factor for thrombotic arterial disease.

Oral contraceptives and thrombosis. From risk estimates to health impact.

OBJECTIVE: The scientific debate on oral contraceptives (OCs) and thrombotic diseases continues unabated. The aim of this survey was to evaluate available scientific data on OCs and thrombotic diseases and to make tentative prescription recommendations of OCs to women with and without various thrombotic risk factors. CONSENSUS: In women 15-29 years old, venous thromboembolism is about twice as common as arterial complications. In women between 30 and 44 years, the number of arterial complications exceeds venous diseases by about 50%. The mortality from arterial diseases is 3.5 times higher than the number of deaths from venous diseases in women below 30 years, and 8.5 times higher in women 30-44 years old. A significant disability is more frequent in women suffering and surviving an arterial complication than in women with venous thromboembolism. Although many important scientific issues still have to be addressed, the available scientific data suggests a differential influence of OCs with second and third generation progestagens on the risk of venous and arterial diseases. OCs with second generation progestagens seem to confer a smaller increase in the risk of venous diseases and a higher increase in risk of arterial complications, compared with OCs containing third generation progestagens. The possible difference on the venous side seems to be smaller than primarily anticipated. RESULTS: Young women without any known risk factor for thrombotic diseases may use any low-dose OC. If OCs are prescribed to women with known risk factors for arterial thrombotic disease; e.g. smoking, diabetes, controlled hypertension, migraine without aura, family disposition of acute myocardial infarction (AMI) or thrombotic stroke, a low-dose pill with a third generation progestagen may have an advantage. If OCs are considered for women with risk factors for venous disease such as severe obesity, varicose veins, family history of VTE or with factor V Leiden mutation, a low-dose combined pill with a second generation progestagen may be preferable. In women above 30 years, OCs with third generation progestagens generally seem to confer less overall thrombotic morbidity, mortality and disability than OCs with second generation progestagens. These women should reconsider, however, the indication of combined OCs in the presence of significant risk factors of thrombotic diseases.

PIP: This article discusses available scientific data on oral contraceptives (OCs) and thrombotic diseases and provides tentative prescription recommendations of OCs to women, with and without various thrombotic risk factors. Several studies concerning OCs and venous thromboembolism (VTE), including the original studies serving as scientific databases, were presented. VTE was twice as common as arterial complications in women 15-29 years old, while arterial complications were 50% higher than VTE in women between 30 and 44 years of age. The mortality of arterial disease was 3.5 times higher than the number of deaths from venous disease in women below 30 years, and 8.5 times higher in women aged 30-44 years. The available scientific data suggests a differential influence of OCs with second and third generation progestagens on the risk of venous and arterial diseases. From this consensus, a low-dose OC was prescribed for young women without any known risk factor for thrombotic diseases. Women with a known risk factor for arterial thrombotic disease, a low-dose pill with a third generation progestogen, may have an advantage while a low-dose pill combined with a second generation progestogen was preferable for women with risk factors for venous disease. In women above 30 years, OCs with third generation progestagens generally seem to confer less overall thrombotic morbidity, mortality, and disability than OCs with second generation progestagens. These women should reconsider, however, the indication of combined OCs in the presence of significant risk factors of thrombotic diseases.

[Estrogen replacement in women treated for breast cancer]. / Ostrogensubstitution til kvinder behandlet for mammacancer.

Oestrogen replacement therapy in women with a history of breast cancer has long been considered contraindicated. However, the literature does not indicate an increased risk of recurrent breast cancer in postmenopausal women receiving oestrogen replacement therapy. We advocate that women with a history of breast cancer without nodal involvement could be offered oestrogen replacement therapy and thereby benefit from prevention of cardiovascular disease and osteoporosis. But the patients must accept a potentially increased risk of recurrence. We emphasize the need for randomized prospective studies.

Ovarian stimulation and borderline ovarian tumors: a case-control study.

OBJECTIVE: To assess the risk of borderline ovarian cancer among infertile women treated with fertility drugs. DESIGN: Case-control study. SETTING: Nationwide data obtained from public registers and postal questionnaires. PATIENT(S): All Danish women <60 years old with borderline ovarian cancer during the period 1989-1994 and randomly selected population controls. The analysis included 231 cases and 1,721 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Influence of parity, infertility, and fertility drugs on the risk of borderline ovarian cancer after multivariate confounder control. RESULT(S): The odds ratio (OR) for borderline ovarian cancer among infertile untreated nulliparous women compared with fertile nulliparous women was 1.9. The OR for borderline ovarian cancer among treated nulliparous women compared with untreated infertile nulliparous women was 1.5, and the OR among treated parous women compared with untreated infertile parous women was 1.5. CONCLUSION(S): Among fertile women, the difference in the risk of borderline ovarian cancer between nulliparous women and parous women was not statistically significant. Nulliparous women who were infertile and who did not receive medical treatment had a twofold higher risk of borderline ovarian cancer than fertile nulliparous women. There was no statistically significant increase in the risk of borderline ovarian cancer among nulliparous women who were treated with fertility drugs compared with nulliparous untreated infertile women or among parous women who were treated with fertility drugs compared with parous untreated infertile women.

Oral contraceptives and venous thromboembolism. A case-control study.

To assess the influence of oral contraceptives (OC) on the risk for venous thromboembolism (VTE) in young women, a 5-year case-control study including all women 15-44 years old suffering a first deep venous thrombosis or a first pulmonary embolism from all Danish hospitals, along with 1200 control subjects during the period 1994-1995, was conducted. Of 586 patient and 1200 control subject questionnaires sent out, 523 patient (89.2%) and 1074 control (89.5%) questionnaires were returned with an agreement to participate. After exclusion of women with nonvalid diagnoses, women who were pregnant, and women with previous VTE or acute myocardial infarction (AMI), 375 patients and 1041 control subjects were available for analysis. Potential tested confounders included: body mass index, length of OC use, family history of VTE, AMI, or stroke, smoking habits, coagulopathies, diabetes, years of schooling, certainty of diagnosis, previous births, and treated hypertension during any pregnancy. A multivariate analysis was performed. Estrogen dose had no influence on the risk for VTE. The risk for VTE among current users of OC was primarily influenced by duration of use, with significantly decreasing odds ratios (OR) over time: < 1 year; 5.1 (3.1-8.5); 1-5 years; 2.5 (1.6-4.1); and > 5 years; 2.1 (1.5-3.1), all compared with those for nonusers of OC. This trend was still significant after adjustment for progestin types. Without adjustment for duration of use, current users of OC with second generation (levonorgestrel or norgestimate) and third generation (desogestrel or gestodene) progestins had OR of 1.8 (1.1-2.9) and 3.2 (2.3-4.4), respectively. After correction for duration of use, however, no significant differences were found between users of OC with different types of progestins. In conclusion, OC increase the risk for VTE significantly. The risk among current users of OC is primarily influenced by duration of use. No difference in risk was found according to estrogen dose, and the difference in risk between different types of progestins was not statistically significant after adjustment for duration of use.

Cerebral thrombosis and oral contraceptives. A case-control study.

To assess the influence of oral contraceptives (OC) on the risk of cerebral thrombosis and transient cerebral ischemic attacks, a 5-year case-control study including all Danish hospitals was conducted. All women 15-44 years old who suffered a cerebral thromboembolic attack (CTA) during the period 1994-95 and 1200 age matched control subjects were included. Of 309 patients and 1200 control subjects questionnaires sent out, 271 patients (87.7%) and 1074 control subjects (89.5%) responded and agreed to participate. After exclusion of women with nonvalid diagnoses, previous thromboembolic diseases, or current pregnancy, 219 patients and 1041 control subjects were available for analysis. After confounder control and with nonusers as reference, current users of first generation OC (50 micrograms of ethinyl estradiol [EE] or estrans) had an odds ratio (OR) of CTA of 1.86 (95% confidence interval [CI] 0.88-3.92); users of second generation OC (levonorgestrel or norgestimate) had an OR of 2.37 (1.35-4.16); and users of third generation OC (desogestrel or gestodene) had an OR of 1.32 (0.78-2.22). Users of OC with 50, 30-40, or 20 micrograms EE had OR of 2.65 (1.11-6.34), 1.60 (1.05-2.43), and 1.59 (0.57-4.58), respectively. Odds ratios for specific progestin types were as follows: estrans 1.37 (0.60-3.13), levonorgestrel 2.43 (1.40-4.21), norgestimate 7.09 (1.87-26.8), desogestrel 1.62 (0.72-3.63), and gestodene 1.24 (0.67-2.30). Duration of use was without significant influence on the risk and the OR were constant across the age bands. Compared with women who had never used OC, former users had an OR of CTA of 0.95 (0.66-1.51). In conclusion, use of OC with 50 micrograms of EE and OC with second generation progestins increased the risk of CTA significantly. OC with third generation progestins did not have any significant influence on the risk of CTA. The risk of CTA among former users of OC was not increased.

Incidence of ovarian cancer after hysterectomy: a nationwide controlled follow up.

OBJECTIVE: To estimate the risk of developing ovarian cancer after abdominal (total or subtotal) hysterectomy on benign indication. DESIGN: Prospective historical cohort study with 12.5 years of follow up. SETTING: Denmark, nationwide. POPULATION: All Danish women (aged 0 to 99 years) having undergone hysterectomy with conservation of at least one ovary for a benign indication from 1977 to 1981 (n = 22,135). Follow up was conducted from 1977 to 1991. The reference group included all Danish women who had not undergone hysterectomy, age-standardised according to the hysterectomy group (n = 2,554,872). METHODS: Registry data derived from the Danish National Register of Patients (diagnoses and operation codes) and the Civil Registration System (information about general population, including time of death). MAIN OUTCOME MEASURES: Incidence rate of ovarian cancer, lifetime risk of ovarian cancer, relative risk of ovarian cancer. RESULTS: Seventy-one women developed ovarian cancer on average 7.0 years after hysterectomy and 10,659 women in the reference group had ovarian cancer diagnosed after on average 6.4 years. The incidence rate of ovarian cancer was 0.27 per 1000 person-years in the group that had undergone hysterectomy and 0.34 per 1000 person-years in the general population (age-standardised). The extrapolated lifetime risk of developing ovarian cancer was 2.1% after hysterectomy and 2.7% in the general population (RR 0.78; 95% CI 0.60-0.96). CONCLUSIONS: The risk of ovarian cancer is lower among women who have undergone hysterectomy compared with those who have not. The protection seems to decrease with time.

Infertility, fertility drugs, and invasive ovarian cancer: a case-control study.

OBJECTIVE: To assess the risk of invasive ovarian cancer among infertile women treated with fertility drugs. DESIGN: A case-control study. SETTING: Nationwide data based on public registers. PATIENT(S): All Danish women (below the age of 60 years) with ovarian cancer during the period from 1989 to 1994 and twice the number of age-matched population controls. Included in the analysis were 684 cases and 1,721 controls. MAIN OUTCOME MEASURE(S): Influence of parity, infertility, and fertility drugs on the risk of ovarian cancer after multivariate confounder control. Risk measure(s): odds ratios (OR) with 95% confidence intervals. RESULT(S): Nulliparous women had an increased risk of ovarian cancer compared with parous women: OR 1.5 to 2.0. Infertile, nontreated nulliparous women had an OR of 2.7 (1.3 to 5.5) compared with noninfertile nulliparous women. The OR of ovarian cancer among treated nulliparous women was 0.8 (0.4 to 2.0) and among treated parous 0.6 (0.2 to 1.3), compared with nontreated nulliparous and parous infertile women, respectively. CONCLUSION(S): Nulliparity implies a 1.5- to 2-fold increased risk of ovarian cancer. Infertility without medical treatment among these women increased the risk further. Among parous as well as nulliparous women, treatment with fertility drugs did not increase the ovarian cancer risk compared with nontreated infertile women.

The influence of thrombotic risk factors when oral contraceptives are prescribed. A control-only study.

OBJECTIVES: The aim of this study was to assess preferential prescribing of OC according to different thrombotic risk factors. MATERIAL AND METHODS: The control group in an ongoing Danish case-control study on stroke and OCs collected in 1994 and 1995 underwent a control-only analysis concerning the occurrence of thrombotic risk factors among users of different types of OC. Specific attention was given to differences between OCs with second and third generation progestagens. The association between specific risk factors and the pill types was assessed crude and after multivariate analysis with confounder control for age and other risk factors, in order to identify risk factors, which after these corrections still had a significant confounding influence on the prescribing of OC. RESULTS: Users of OCs with third generation progestagens had a significantly higher proportion of familial thrombotic disposition (23.1%) than users of OCs with second generation progestagens (7.1%) (p = 0.01). After correction for age and other risk factors this difference was still highly significant (p = 0.002). Among users of third generation pills the proportion of short time users (< 1 year) (22.4%) was significantly higher than the per cent among users of OCs with second generation progestagens (5.5%) (p < 0.001). This difference was still significant after correction for age and other risk factors (p < 0.001). Smoking, years of schooling, migraine, and body mass index did not differ significantly between the two pill groups. CONCLUSION: In Denmark, women with familial thrombotic disposition are four times more likely being prescribed OCs with third versus second generation progestagens compared with women without such a disposition. At the same time users of OCs with third generation progestagens include significantly more short time users than users of OCs with second generation progestagens. For thrombotic diseases where familial disposition or duration of use of OCs play a role for the pill-associated risk, these differences may significantly influence the thrombotic risk measures in case-control studies and non-randomized cohort studies unless confounder control is conducted for this selection.

PIP: An analysis of the occurrence of thrombotic risk factors among users of different types of combined oral contraceptives (OCs) revealed the existence of differential prescribing patterns based on these risk factors. The 206 study participants were among the 1200 controls in a 1994-95 Danish case-control study on stroke and OCs. The 118 users of third-generation OCs containing the progestins desogestrel or gestodene had a significantly higher rate of familial thrombotic disposition (23.1%) than the 56 users of second-generation OCs containing levonorgestrel, norgestrel, and norgestimate (7.1%). Even after adjustment for age and other risk factors, this trend remained significant (p = 0.002). This finding suggests that general practitioners are asking women about thrombotic familial disposition before prescribing OCs and basing the OC type on this information. In addition, there were significantly more short-time users (under 1 year) among users of third-generation OCs (22.4%) than of second-generation OCs (5.5%). This difference also remained significant after adjustment for age and other risk factors (p 0.001). There were no differences between the OC groups in terms of smoking, educational attainment, migraine, and body mass index. Since both thrombotic disposition and duration of OC use may influence the risk of thrombotic diseases, these potential confounders should be controlled in epidemiologic analyses of OC-related thromboembolic risks.