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Study question Is the treatment outcome compromised after superovulation for fresh IVF/ICSI in comparison to frozen cycle with spontaneous ovulation and luteal support with progesterone? Summary answer Live birth rate (LBR) is dependent on embryo quality both in the fresh and frozen cycles with no sign of harmful effect of the superovulation. What is known already Freeze-all strategy has been advocated in recent years based on the assumption that luteal phase after superovulation is not optimal for embryo implantation. The effects of variable hormonal treatments, given in association with ART, on the endometrium, are still largely unknown. Therefore, more data is needed in order to optimize the treatment policies. Study design, size, duration This is an observational retrospective single-center cohort study. Data were collected from Oulu University Hospital’s ART-database including a total of 5647 single embryo transfer cycles from years 1995–2020. Patients stimulated with long agonist protocol for IVF/ICSI and day 2–3 transfer were included. Frozen embryo transfer was performed in a natural cycle with an ovulation test used for timing of transfer. Luteal support with progesterone was given for two weeks in all cycles. Participants/materials, setting, methods There were 3053 IVF/ICSI fresh cycles (2237 top and 816 N-top) and 2594 frozen cycles (806 top and 1788 N-top). The main outcome measure was LBR compared between fresh and frozen cycles when either a top or a N-top embryo was transferred. As a secondary outcome, clinical pregnancy rate was investigated. Data on the age and body mass index (BMI) of the patients was available. Student’s T-test was used to compare continuous variables. Main results and the role of chance The groups did not differ regarding the age and BMI of the patients. After the transfer of a top quality embryo the clinical pregnancy rate (35.4 vs. 30.8%; p Limitations, reasons for caution This study only represents cleavage stage embryo transfers, and all FETs were performed in a natural cycle. In a retrospective study there may also be residual confounding that could not be excluded. Wider implications of the findings: This study provides further evidence that treatment outcome regarding LBR is not affected by superovulation therapy. Hence, the use of freeze-all strategy is warranted only in cases with a risk of ovarian hyperstimulation syndrome. Trial registration number Not applicable

Research question Is the growth of term singletons born after frozen embryo transfer (FET) comparable to those born after fresh embryo transfer and natural conception up to 5 years of age? Design Observational cohort study in an academic medical centre and municipal child health clinics with repeated measurements carried out by medical professionals. Term singletons born after FET (n = 110) and fresh embryo transfer (n = 181) and their matched natural conception controls (n = 543) born in Oulu, Northern Finland, were included. Mean weights, lengths, heights and head circumferences at the ages of 4, 8 and 18 months and 3 and 5 years were compared. At 3 and 5 years, body mass indices were compared. Results Childhood growth did not differ between term singletons born after FET, fresh embryo transfer and natural conception, correcting for exact age at measurement and adjusting for maternal body mass index and paternal height. Conclusions Similar growth between children born after FET, fresh embryo transfer and natural conception offers reassurance of the safety and feasibility of the steadily increasing use of embryo cryopreservation in assisted reproduction.

Are there differences in estrogen and progesterone secretion in singleton pregnancies, up to Week 11, between spontaneous pregnancies, after controlled ovarian hyperstimulation and fresh embryo transfer (COH + ET) and after frozen embryo transfer in a spontaneous cycle (FET)?Serum progesterone and estradiol (E2) concentrations after COH + ET were higher in early pregnancy, lasting up to Week 7-8, than FET and spontaneous pregnancies, while hormone levels after FET did not differ from spontaneous pregnancies.The risk of adverse perinatal outcomes after COH + ET seems to be increased when compared with spontaneous pregnancies. One of the reasons suggested for this is related to ovarian hyperstimulation.This was a prospective cohort study consisting of three different groups of pregnant women which were followed-up weekly until Week 11 of their pregnancies. The spontaneous pregnancy group consisted of 41 women, the COH + ET group consisted of 39 and the FET group consisted of 30 women.Women in the control group with spontaneous conception were recruited from local prenatal clinics. Women in the COH + ET and FET groups were recruited from the Reproductive Unit of Oulu University Hospital. At each visit, a three-dimensional ultrasonography was performed to examine the ovarian volumes and vascularization. A blood sample was drawn to analyse progesterone and E2 levels. The pregnancy outcome was included in the analysis.At pregnancy Week 5, the serum progesterone levels were higher after the COH + ET (median 312, inter-quartile range 183-480 nmol/l), when compared with the spontaneous (63, 52-80 nmol/l; P0.001) and FET (74, 48-96 nmol/l; P0.001) pregnancies. At Week 11, the P (189, 124-260 nmol/l) was still higher in the COH + ET group (FET 101, 78-120 nmol/l, P0.001; spontaneous 115, 80-139 nmol/l, P0.01) than the other two groups. The E2 levels at Week 5 were also significantly higher after COH + ET (4.1, 2.2-6.6 nmol/l) than in the spontaneous pregnancies (1.1, 0.7-1.6 nmol/l, P0.001) or after FET (0.7, 0.6-0.9 nmol/l, P0.001). The volume of the ovaries and the intraovarian vasculature in the COH + ET group were significantly higher when compared with the other two groups (P0.001). The birthweight was negatively correlated with the serum P (R -0.340, P0.01) and E2 (R= -0.275, P0.05) in pregnancy Weeks 5-8. In the multivariate analysis evaluating the factors affecting birthweight of the newborn, the significant factors were the length of gestation, maternal height and progesterone or E2 secretion during Weeks 5-8.Because of the low number of patients in this study, larger cohort studies are required to confirm the findings.The findings here indicate that COH-induced increased luteal activity should be evaluated by measuring steroid levels or the ovarian size or vascularity, rather than number of oocytes retrieved. If unphysiologically high steroid activity during pregnancy after COH contributes to the risk of adverse perinatal outcomes after fresh embryo transfer, milder stimulation protocols or even freezing of all of the embryos should be considered.This study was supported by a research grant from the Academy of Finland. The authors declare no conflicts of interest.

ObjectiveReduced sex hormone-binding globulin (SHBG) concentration predicts insulin resistance and type 2 diabetes, but its association with cardiovascular disease (CVD) risk is unclear. We examined the association between SHBG and cardiovascular risk factors, independently of total testosterone (TT), in young men.DesignObservational, cross-sectional study.SettingGeneral community.ParticipantsThe study included 2716 men aged 31 years in the Northern Finland Birth Cohort in 1996 with clinical examination data and fasting blood samples.Outcome variablesBlood pressure (BP), lipids and C-reactive protein (CRP) as biological CVD risk markers.ResultsSHBG concentration was significantly and inversely related to systolic and diastolic BP, triglycerides and CRP, but positively to HDL cholesterol after adjusting for insulin, BMI, waist circumference, smoking, education and physical activity (allPPPConclusionsIn this cohort of young adult men, higher SHBG concentration was associated with a more favourable CVD risk profile, independently of TT. SHBG concentration modified the associations of TT with CVD risk factors.

Is there a different risk for major congenital anomalies (CAs) in children born after frozen-thawed embryo transfer (FET) compared with children born after fresh embryo transfer (ET)?Children born after FET have a similar risk of developing major CAs as children born after fresh ET.The perinatal outcome in children born after FET is as good as that after fresh ET. Children born as a result of assisted reproductive technology (ART) have an increased risk for CAs when compared with spontaneously conceived children, but the knowledge on the risk for CAs in specific organ systems of children born after FET is limited.This register-based cohort study includes women who have undergone ART treatments with ET leading to singleton births (n = 4772) between the years 1995 and 2006. The women were identified from the registers of the infertility clinics, and the corresponding births were matched with data from the Finnish Medical Birth Register (FMBR). The 10% random sample of women with spontaneous pregnancies from the FMBR served as the reference group (n = 31,243). The study data were linked with the Register of Congenital Malformations using the mothers' and children's personal identification numbers to get information on CAs. Furthermore, the personal identification numbers of the ART women were linked with the Register of Induced Abortions to find their selective terminations of pregnancy for severe foetal anomalies.The study was focused on singleton births and included 1830 children born after FET, 2942 children born after fresh ET and 31 243 children born after spontaneous pregnancies. Only major CAs were analysed in keeping with European Concerted Action on Congenital Anomalies and Twins. The risk estimates for CAs were adjusted for the children's year of birth and maternal age, parity and socioeconomic status. The total prevalence of major CAs was counted, including both births and selective terminations of pregnancy for major fetal anomalies (n = 33).Among singletons at least one major CA was reported in 77 cases (4.2%) in the FET group, 132 cases (4.5%) in the fresh ET group and 994 cases (3.2%) in the reference group. The risk for at least one major CA of the children born after FET was not increased compared with the children born after fresh ET [adjusted odd ratio (aOR) 0.95; 0.71-1.27]. Furthermore, no increased risks according to the organ system affected were found between these two ART groups. When comparing the children born after ART (FET and fresh ET) with the reference group children, the risk of having at least one major CA was moderately increased in the ART group (aOR 1.24; 1.05-1.47).Because of the study design we were neither able to examine the aetiology of infertility nor could we compare the data with a group of subfertile women to account for the effect of infertility per se on CAs.Perinatal outcomes of FET children, including the risks for CAs, are good and comparable with outcomes of other ART children indicating that slow freezing is a safe method to use during ART treatments.University Hospital of Oulu and Helsinki, Finland. THL covered the data linkages and the work of Annukka Ritvanen and Mika Gissler. There are no competing interests to be reported.

OBJECTIVE: To study the association between body size from birth to adulthood and self-reported symptoms of polycystic ovary syndrome (PCOS), particularly hirsutism and menstrual disturbances. DESIGN: Longitudinal, population-based study of a cohort of women born in 1966 in northern Finland. The study population included 2007 women who were not pregnant and did not use hormonal contraception. Of these 528 (26%) had self-reported symptoms of PCOS. RESULTS: Weight at birth, gestational age, being small for gestational age or growth retardation at birth were not associated with PCOS symptoms at 31 y. An increased risk of PCOS symptoms was observed among women with abdominal obesity (waist/hip ratio >85th percentile) at 31 y who had normal weight in adolescence and were overweight (body mass index (BMI) 25.0-29.9 kg/m(2)) or obese (BMI>30.0 kg/m(2)) at 31 y (relative risk (RR) (95% CI) 1.44(1.10-1.89)), and among women with abdominal obesity who were overweight or obese at both 14 and 31 y (1.71 (1.30-2.24)). A total of 30% and 41% of the women with PCOS symptoms in these groups could be attributed, respectively, to overweight, obesity and abdominal obesity at 31 y. CONCLUSIONS: These results suggest that obesity in adolescence and in adulthood, and also weight gain after adolescence, particularly in the presence of abdominal obesity, are associated with self-reported PCOS symptoms in adulthood. Thus, based on the results from intervention studies treating PCOS and the results of this study, the prevention of obesity and abdominal obesity is important among young women.

OBJECTIVE: We compared the metabolic and cardiovascular parameters of a reference group of women with those of women who used 2 contraceptive regimes that are used worldwide: the levonorgestrel-releasing intrauterine device and oral contraceptives. STUDY DESIGN: We investigated a cohort of 2814 women at age 31 years from the general population-based Northern Finland Birth Cohort who were born in 1966. Women were classified as oral contraceptive users (n = 687 women), levonorgestrel-releasing intrauterine device users (n = 168 women), or no use of hormonal contraception (reference group; n = 1959 women). The analyses were adjusted for body mass index, current alcohol use, household income, and area of residence. RESULTS: Compared with the reference group, oral contraceptive users had higher systolic and diastolic blood pressure, raised levels of inflammatory indices (C-reactive protein), and impaired insulin sensitivity. Levonorgestrel-releasing intrauterine device users displayed a lower high-density lipoprotein and total cholesterol, but a similar cholesterol/ high-density lipoprotein ratio, and higher leukocyte count compared with the reference group. Oral contraception users were insulin-resistant compared with levonorgestrel-releasing intrauterine device users with higher blood pressure, raised lipid levels (such as total cholesterol and triglycerides) and insulin levels, and lower homeostasis model assessment and insulin sensitivity, despite smaller waist and lower waist-hip ratio. CONCLUSION: Oral contraception usage was associated with adverse findings in several metabolic, cardiovascular, and inflammatory parameters, which is consistent with an increased future risk of cardiovascular and metabolic disease. These findings should invite more criticism of recent trends that encourage the prescription of oral contraceptives for years during reproductive life and especially in premenopausal women. In contrast, levonorgestrel-releasing intrauterine device or progestin-only pills may offer long-term health benefits over oral contraceptives and should be preferred to oral contraceptives for women in their forties and/or with metabolic risk factors for cardiovascular diseases and type 2 diabetes mellitus.

OBJECTIVE: To investigate the occurrence of oligo-amenorrhoea and hirsutism, infertility and metabolic morbidity among first-degree relatives of women with and without self-reported oligo-amenorrhoea and hirsutism. DESIGN: Nested case-control study. SETTING, POPULATION AND METHODS: A postal questionnaire about symptoms of oligo-amenorrhoea and hirsutism was sent to all women of the Northern Finland Birth Cohort 1966 (n = 5889). From this population were randomly selected 98 women with both symptoms and 163 without symptoms. A further questionnaire on the occurrence of oligo-amenorrhoea, hirsutism, infertility, early balding and metabolic morbidity in their relatives was sent to this subpopulation. MAIN FINDINGS: We obtained data on 183 relatives of 43 women with symptoms and 412 relatives of 86 symptomless women. Compared with relatives of symptomless women, mothers of women with symptoms suffered significantly more often from hirsutism and menstrual disorders, and sisters more often from hirsutism and infertility, and had fewer children and were more often childless. There was an increased prevalence of diabetes in the sisters and of hypertension in the fathers of women with symptoms. CONCLUSIONS: These results strengthen earlier findings of significantly increased metabolic and reproductive morbidity in the relatives of women with symptoms of PCOS.

AIMS/HYPOTHESIS: Common variants of the gene encoding transcription factor 7-like 2 (TCF7L2) have a powerful effect on individual risk of type 2 diabetes (per allele odds ratio approximately 1.35). Polycystic ovary syndrome (PCOS) and type 2 diabetes are familial conditions sharing common features. Based on this, the aim of the present study was to establish whether variation in TCF7L2 also influences the development of PCOS. METHODS: We conducted a genetic association study of variants of TCF7L2 (rs7903146 and rs12255372) using both case-control and quantitative trait approaches. Case-control analyses were conducted in (1) 369 PCOS cases and 2574 controls of UK British/Irish origin, and (2) 540 women with PCOS symptoms and 1083 controls from the Northern Finland Birth Cohort of 1966. Quantitative trait analyses (androgen levels) were also performed (1249 individuals). RESULTS: There was no association between rs7903146 and PCOS in the UK case-control study (Cochran-Armitage test, p = 0.51); nor with symptomatic status in the Finnish cohort (p = 0.36). In addition, there were no relationships between the TCF7L2 single nucleotide polymorphism rs7903146 and androgen levels (UK cases, p = 0.99; Finnish controls, p = 0.57; Finnish symptomatic cases, p = 0.80). Results at rs12255372 were similar, reflecting strong linkage disequilibrium with rs7903146. CONCLUSIONS/INTERPRETATION: Our study was powered to detect an effect on PCOS susceptibility similar to that previously reported for these variants on type 2 diabetes. Failure to detect any evident association with PCOS provides the strongest evidence yet that the genetic architecture of these related conditions is qualitatively distinct.

Is an elective single-embryo transfer (eSET) policy feasible for women aged 40 or older?For older women (aged 40-44 years) with a good prognosis, an eSET policy can be applied with acceptable cumulative clinical pregnancy rates and live birth rates.Various studies have shown the effectiveness of eSET in women aged35 years with high cumulative pregnancy rates and low rates of multiple births.This retrospective cohort study included 628 women treated between 2000 and 2009.Women aged 40-44 years underwent a fresh cycle of IVF or ICSI treatment with eSET (n = 264) or double-embryo transfer (DET) (n = 364). In the subsequent frozen-thawed embryo transfer cycles, SET/DET was performed in both groups according to the number of embryos available and the opinion of the couple. The study was performed at the Family Federation of Finland Helsinki Fertility Clinic.In the fresh cycles, the clinical pregnancy rates were 23.5 and 19.5% in the eSET and DET groups, respectively, and live birth rates were 13.6 and 11.0%, respectively. In the fresh cycles with eSET, there were no twin pregnancies, but in the DET group, there were three sets of twins (7.5%). The cumulative clinical pregnancy rates per oocyte retrieval were 37.1 and 24.2% in the eSET and DET groups, respectively (P0.001), and the cumulative live birth rates were 22.7 and 13.2%, respectively (P = 0.002). Cumulative twin rates were 6.7% (n = 4) in the eSET group and 8.3% (n = 4) in the DET group (P = 0.726). All of the twin pregnancies in the eSET group resulted from frozen and thawed DET embryo transfer cycles.The characteristics of the two patients groups are not comparable because the suitability of eSET was individually assessed by a clinician based on both clinical prognostic factors and the outcome of IVF or ICSI, i.e. the number and quality of embryos.This study may be generalized to IVF units having experience in eSET and cryopreservation.

STUDY QUESTION Are self-reported menstrual disorders associated with hyperandrogenaemia and metabolic disturbances as early as in adolescence? SUMMARY ANSWER Menstrual disorders at the age 16 are a good marker of hyperandrogenaemia, and an adverse lipid profile was associated with higher androgen levels. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Hyperandrogenism per se has been suggested to be a significant metabolic risk factor in women and a cause of physical and psychological morbidity in adolescent girls. A weak positive correlation has been described between hyperandrogenaemia and obesity in adolescent girls, but the clinical consequences are still poorly understood. Hyperandrogenism and insulin resistance are also key features of polycystic ovary syndrome (PCOS), and women with PCOS are consequently at an increased risk of developing type 2 diabetes mellitus and/or metabolic syndrome, and may have increased cardiovascular morbidity. Our findings confirm that the association between menstrual disorders, hyperandrogenism, obesity and metabolic risks is already evident in adolescence. STUDY DESIGN This population-based, cross-sectional study used postal questionnaires to targeting 15-16-year-old girls in the Northern Finland Birth Cohort 1986 (n= 4567). PARTICIPANTS AND SETTING There were 3669 girls who answered the postal questionnaire and out of 3373 girls who also underwent clinical examinations and blood tests, 2448 were included in the analyses. The questionnaire included one question about the regularity and length of the menstrual cycle: 'Is your menstrual cycle (the interval from the beginning of one menstrual period to the beginning of the next period) often (more than twice a year) longer than 35 days?' The girls who answered 'yes' to this question were considered to be suffering from menstrual disorders and were classified as 'symptomatic'. The girls who answered 'no' were defined as 'non-symptomatic'. MAIN RESULTS AND THE ROLE OF CHANCE There were 709 (29%) girls who reported menstrual disorders (symptomatic girls) and 1739 who had regular periods (non-symptomatic girls). In the whole population and in both study groups, there were significant correlations between body mass index (BMI) (and waist-to-hip ratio), hyperandrogenaemia and metabolic parameters. Symptomatic girls exhibited significantly higher serum concentrations of testosterone (P= 0.010), lower levels of sex hormone-binding globulin (P =0.042) and higher free androgen indices [FAIs; geometric mean 3.38 (interquartile range (IQR): 2.27, 5.18) versus 3.08 (IQR: 2.15, 4.74), P= 0.002]. The two groups had comparable BMI and insulin sensitivity, and serum levels of glucose, insulin and lipids. There was a significant linear trend towards higher FAI values in the higher BMI quartiles in both symptomatic and non-symptomatic girls. In the whole population, there was a statistically significant linear decrease in high-density lipoprotein concentrations (P < 0.001) and higher triglyceride concentrations (P =0.004) in the upper FAI quartile. IMPLICATIONS Information regarding menstrual disorders in adolescence is a good marker of hyperandrogenaemia and may be an early risk factor for the development of PCOS in adulthood. The association between obesity, hyperandrogenism and metabolic risks is already evident in adolescence, which strengthens the importance of noting menstrual disorders at an early stage. BIAS, LIMITATIONS, GENERALIZABILITY: The cross-sectional nature of the study does not allow us to draw conclusions concerning the metabolic risks of this population in later life. The diagnosis of menstrual disorders was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. This study was not designed to diagnose PCOS, as ultrasonography was not available and there was no clinical evaluation of hyperandrogenism (i.e. hirsutism). However, we were able to take into account potential confounding factors in the analyses. STUDY FUNDING/COMPETING INTERESTS This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 104781, 120315, 129269, 1114194, SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643) and the Medical Research Council, UK (PrevMetSyn/SALVE). None of the authors have any conflict of interest to declare.

BACKGROUND: The number of children born after frozen embryo transfer (FET) is steadily rising. However, studies on obstetric and perinatal outcomes are limited. Our primary aim was to compare the perinatal health of children born after FET and fresh embryo transfer, and to use data from children born after spontaneous conception as a reference. METHODS: In a register-based cohort study we evaluated the obstetric and perinatal outcomes of children born after FET (n = 2293), fresh embryo transfer (n = 4151) and those born after spontaneous pregnancy (reference group; n = 31 946). Data were collected from the registers of two infertility outpatient clinics, two university hospitals and the Finnish Medical Birth Register (1995-2006). RESULTS: After adjusting for confounding factors the FET group showed decreased risks of preterm birth [adjusted odd ratio (AOR) 0.83, 95% confidence interval (CI) 0.71-0.97], low birthweight (AOR 0.74; 0.62-0.88) and being small for gestational age (AOR 0.63; 0.49-0.83) compared with the fresh embryo transfer group. Mean birthweight was 134 g higher in the FET singletons versus the fresh embryo transfer singletons (P < 0.0001). When FET singletons were compared with the reference group, increased risks of preterm birth (AOR 1.45; 1.25-1.68) and low birthweight (AOR 1.22; 1.03-1.45) and a decreased risk of being small for gestational age (AOR 0.71; 0.54-0.92) were found. No excess of perinatal and infant mortality occurred between the groups. CONCLUSIONS: Embryo freezing does not adversely affect perinatal outcome in terms of prematurity, low birthweight and being small for gestational age versus the fresh embryo transfer and the outcome is similar or even better, particularly regarding fetal growth. Our study, which is one of the largest on FET pregnancies, provides further evidence on the safety of FET.

Background Increased uterine artery (UtA) vascular impedance at the time of embryo transfer can decrease implantation and pregnancy rates in women undergoing IVF/ICSI. We hypothesized that low-dose aspirin decreases UtA vascular impedance on the day of embryo transfer in unselected IVF/ICSI patients when medication is started concomitantly with controlled ovarian stimulation. In addition, as secondary outcome measures, we investigated whether low-dose aspirin decreases the incidence of non-optimal (bilateral UtA PI > or = 3.0) uterine haemodynamics and whether it affects arcuate, radial and spiral artery vascular impedances and endometrial thickness. Methods A total of 122 women who underwent IVF/ICSI were randomized to receive 100 mg aspirin (n = 61) or placebo (n = 61) daily, starting on the first day of gonadotrophin stimulation. Doppler ultrasonography was performed on the day of embryo transfer. Results Embryo transfer took place in 57 women in the aspirin group and in 56 women in the placebo group. UtA mean PI values did not differ significantly between the groups. The incidence of non-optimal uterine haemodynamics was lower in the aspirin group than in the placebo group (P = 0.03). Other secondary outcome measures did not differ between the groups. Conclusions In unselected IVF/ICSI women, low-dose aspirin therapy, when started concomitantly with controlled ovarian stimulation, did not affect UtA vascular impedance on the day of embryo transfer. However, the incidence of non-optimal uterine haemodynamics was significantly lower in the aspirin group than in the placebo group. ClinicalTrials.gov: NCT00683202.

Objective To determine whether low-dose aspirin improves uteroplacental hemodynamics in unselected in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) subjects when medication is started concomitantly with controlled ovarian hyperstimulation. Methods Thirty-seven pregnant women who had undergone IVF/ICSI and had been randomized to receive 100 mg aspirin (n = 17) or placebo (n = 20) daily, started concomitantly with controlled ovarian hyperstimulation, were included in this study. Doppler ultrasound examination was performed at 6, 10, 13 and 18 weeks' gestation. Uterine artery (UtA) pulsatility index (PI) was calculated and bilateral UtA notching was noted. Subplacental arcuate artery PI was obtained at 6 and 10 weeks' gestation. Umbilical artery (UA) PI and mean velocity were calculated at 10, 13 and 18 weeks' gestation. In the aspirin group there was one early pregnancy miscarriage, and one patient discontinued the study medication owing to early pregnancy bleeding. A total of 15 women in the aspirin group and 20 women in the placebo group underwent the complete ultrasound protocol. Results At 6 weeks' gestation, arcuate artery PI and at 18 weeks' gestation, UtA PI were lower (P < 0.05) in the aspirin group than in the placebo group. At 18 weeks' gestation, bilateral UtA notching tended to be more common in the placebo group (40%) than in the aspirin group (13%) (P = 0.06). UA PI and mean velocity did not differ significantly between the groups. Conclusion Low-dose aspirin reduces uteroplacental vascular impedance in early and mid pregnancy in unselected IVF/ICSI subjects when medication is started concomitantly with controlled ovarian hyperstimulation. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

STUDY QUESTION: Are uterine fibroids associated with increased cardiovascular risk? SUMMARY ANSWER: This study reports an association between increased serum lipids and metabolic syndrome with an increased risk of uterine fibroids. WHAT IS KNOWN ALREADY: Recent studies suggest similarities in biological disease mechanisms and risk factors for fibroids and atherosclerosis: obesity, hypertension and abnormal serum lipids. These findings are awaiting confirmation that a population-based follow-up study could offer with extensive health examination data collection linked with a national hospital discharge register. STUDY DESIGN, SIZE, DURATION: The Northern Finland Birth Cohort (NFBC1966) is a population-based long-term follow-up study including all children with estimated date of delivery in 1966 in the Northern Finland area. The data were collected from national registries, postal questionnaires and clinical health examinations. The study population for this study comprised all females included in the NFBC1966 that underwent an extensive clinical health examination at age 46 years (n = 3635). PARTICIPANTS/MATERIALS, SETTING, METHODS: All females included in the NFBC1966 who were alive and traceable (n = 5118) were invited for the 46-year follow-up study; 3268 (63.9%) responded, returned the postal questionnaire and attended the clinical examination. Uterine fibroid cases were identified through the national hospital discharge register that has data on disease diagnoses based on WHO ICD-codes. Uterine fibroid codes, ICD-9: 218 and ICD-10: D25 were used for case identification. Self-reported fibroid cases were identified through the postal questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 729 fibroid cases were identified, including 293 based on hospital discharge registries. With adjustment for BMI, parity, education and current use of exogenous hormones the risk of prevalent fibroids rose significantly for every 1 mmol/l increase in LDL (OR = 1.13, 95% CI: 1.02-1.26 for all cases) and triglycerides (OR = 1.27, 95% CI: 1.09-1.49 for all cases). Metabolic syndrome associated with hospital discharge-based fibroid diagnosis (OR = 1.48, 95% CI: 1.09-2.01). Additionally every 1 unit increase in waist-hip ratio associated with fibroids (OR = 1.32, 95% CI: 1.10-1.57). LIMITATIONS, REASONS FOR CAUTION: The case ascertainment may present some limitations. There was likely an under-identification of cases and misclassification of some cases as controls; this would have diluted the effects of reported associations. The data analysed were cross-sectional and therefore cause and effect for the associations observed cannot be distinguished. WIDER IMPLICATIONS OF THE FINDINGS: Increased serum lipids and metabolic syndrome are associated with increased risk of uterine fibroids. Along with central obesity these findings add to an increased risk for cardiovascular disease among women with fibroids. These observations may suggest that there are shared predisposing factors underlying both uterine fibroids and adverse metabolic and cardiac disease risk, or that metabolic factors have a role in biological mechanisms underlying fibroid development. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Academy of Finland, University Hospital Oulu, University of Oulu, Finland, Northern Finland Health Care Foundation, Duodecim Foundation, ERDF European Regional Development Fund-Well-being and health: Research in the Northern Finland Birth Cohort 1966. The authors declare no conflict of interest.

Objective: The study was aimed to evaluate which factors affect the cumulative live birth rate after elective single embryo transfer in women younger than 36 years. Additionally, number of children in women with more than one delivery per ovum pick-up after fresh elective single embryo transfer and subsequent frozen embryo transfers was assessed. Study design: Retrospective cohort study analysing data of a university hospital's infertility clinic in 2001-2010. A total of 739 IVF/ICSI cycles with elective single embryo transfer were included. Analyses were made per ovum pick-up including fresh and subsequent frozen embryo transfers. Factors affecting cumulative live birth rates were examined in uni- and multivariate analyses. A secondary endpoint was the number of children born after all treatments. Results: In the fresh cycles, the live birth rate was 29.2% and the cumulative live birth rate was 51.3%, with a twin rate of 3.4%. In the multivariate analysis, having two (odds ratio (OR) 1.73; 95% confidence interval (CI) 1.12-2.67) or >= 3 top embryos (OR 2.66; 95% CI 1.79-3.95) was associated with higher odds for live birth after fresh and frozen embryo cycles. Age, body mass index, duration of infertility, diagnosis or total gonadotropin dose were not associated with the cumulative live birth rate. In cycles with one top embryo, the cumulative live birth rate was 40.2%, whereas it was 64.1% in those with at least three top embryos. Of women who had a live birth in the fresh cycle, 20.4% had more than one child after all frozen embryo transfers. Among women with three or more top embryos after ovum pick-up, 16.1% gave birth to more than one child. Conclusion: The cumulative live birth rate in this age group varies from 40% to 64% and is dependent on the quality of embryos. Women with three or more top embryos have good chance of having more than one child per ovum pick-up without elevated risk of multiple pregnancies. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

STUDY QUESTION Are there differences in the physical health of singleton children born after frozen embryo transfer (FET) compared with children born after fresh embryo transfer (fresh ET)? SUMMARY ANSWER Register-based health indicators were similar among FET and fresh ET singletons during a 3-year follow-up. WHAT IS KNOWN ALREADY Large cohort studies have shown that perinatal outcomes are similar or even better in FET than fresh ET children. The early childhood morbidity among FET and fresh ET children has been shown to be quite similar, but so far these studies have been small. The short-term health outcomes of assisted reproductive technology (ART) children have been shown to be slightly worse compared with spontaneously conceived children. STUDY DESIGN, SIZE, DURATION This register-based study includes women who had undergone ART treatments leading to singleton live births (n = 4758 children) in 1995-2006. A 10% random sample of women with spontaneous pregnancies from the Finnish Medical Birth Register (FMBR) served as the reference group (n = 31 137 children). The children were identified through the FMBR by using the mother's personal identification (ID) number. Children's ID numbers were linked with two nationwide registries; the Finnish Hospital Discharge Register and the Cause-of-Death Register at Statistics Finland. Information on all visits was received until 2009 using ICD-10 codes. PARTICIPANTS/MATERIALS, SETTING, METHODS The study includes 1825 children born after FET, 2933 children born after fresh ET and 31 137 children born after spontaneous pregnancies. The risk estimates for diseases were adjusted for the child's year of birth and maternal age, parity, socio-economic status and prematurity. The study focused on the differences between FET and fresh ET children. MAIN RESULTS AND THE ROLE OF CHANCE Most health indicators were similar among FET and fresh ET children during the 3-year follow-up. The most common discharge diagnoses, including gastroenteritis and colitis, otitis, upper and lower respiratory diseases, asthma and allergies were similar between the ART groups. A large proportion of FET children (70.1%) and fresh ET children (69.9%) had visited a hospital at least once (P = 0.877). The risk of hospital admission did not differ between the two groups after adjusting for premature births [adjusted odds ratio (aOR) 1.01; 0.88-1.17]. Comparing with children born after spontaneously conceived pregnancies, the risk of hospital admission was slightly increased in the ART group, even after adjusting for premature births (aOR 1.10; 1.02-1.19). LIMITATIONS, REASONS FOR CAUTION Due to the study design, we were not able to control for some parental background factors, such as the cause and length of infertility. Furthermore, the health registries do not include data on the growth of the children. Our findings are generalizable only to the slow-freezing method. WIDER IMPLICATIONS OF THE FINDINGS Our study provides further evidence of the safety of embryo cryopreservation. The early physical health of FET children is similar to that of children born after fresh ET. STUDY FUNDING/COMPETING INTERESTS This study was funded by the University Hospital of Oulu and Helsinki, Finland. The National Institute for Health and Welfare (THL) covered the data linkages and the work of Mika Gissler. There are no competing interests to be reported.

CONTEXT: Variation at the insulin gene VNTR (variable number tandem repeat) minisatellite has been reported to be associated with polycystic ovary syndrome (PCOS), but findings have been inconsistent and all studies have featured small sample sizes. OBJECTIVE: To gain a robust understanding of the role of the INS-VNTR in PCOS susceptibility. DESIGN: Case-control, family-based association and quantitative trait analyses. SETTING AND PARTICIPANTS: A UK population comprising 255 parent-offspring trios, 185 additional cases, and 1062 control subjects (cases and controls all British/Irish) as well as 1599 women from a northern Finland population-based birth cohort characterized for PCO symptomatology and testosterone levels. VNTR class was inferred from genotyping of the -23HphI variant. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): INS-VNTR genotype frequencies between subject groups, body mass index, and testosterone levels by genotype. RESULTS: Case-control analyses in both UK and Finnish samples failed to confirm previously reported class III allele associations with PCOS (UK, P = 0.43, Finnish, P = 0.31; Kruskal-Wallis chi2). Transmission analysis in trios showed no excess transmission of either allele (P = 0.62), regardless of parent of origin (maternal: P = 0.73; paternal: P = 0.66). No association between genotype and testosterone levels was seen in any sample (UK PCOS subjects, P = 0.95; Finnish symptomatic cases, P = 0.38; Finnish control women, P = 0.58). CONCLUSIONS: Despite the strong biological candidacy and supportive data from previous studies, we conclude that variation at the INS-VNTR has no major role in the development of PCOS.

Background The zona pellucida (ZP) has multiple roles in reproductive processes, including oocyte maturation, fertilization and implantation. We used, for the first time, a genetic approach to study whether human ZP genes possess structural alterations in women with unsuccessful IVF trials. In theory, this may result in gradual reduction of sperm-zona interaction and eventually in total fertilization failure (TFF). Methods Eighteen infertile women (TFFs) whose IVF did not result in any fertilized oocytes, whereas fertilization by ICSI was successful, were screened for mutations in ZP genes by means of conformation-sensitive gel electrophoresis. Twenty-three fertilizers in IVF (FIVFs) and 68 women with proven fertility (WPFs) constituted the two control groups. Results Altogether, 20 sequence variations were found in the ZP genes. Two variations in ZP3, one in the regulatory region (c. 1-87 T --> G) and one in exon 6 [c. 894 G --> A (p. K298)] existed more frequently in TFFs than in FIVF and WPF groups (P-values 0.027 and 0.008, respectively). Conclusions Our study on ZP genes of infertile women revealed a high degree of sequence variations. This may reflect gradual reduction of fertility among TFFs, but the putative roles and influences of single variations can only be hypothesized.

AIMS/HYPOTHESIS: Although the variable number tandem repeat (VNTR) minisatellite 5' to the insulin gene is among the most studied polymorphisms in diabetes, the relationships between VNTR variation, diabetes-related traits and predisposition to type 2 diabetes remain unclear. Since inadequate sample size is likely to have been an obstacle to reliable inference, we examined the relationship between VNTR variation and a range of diabetes-related traits in a cohort of 5,753 Finnish adults. MATERIALS AND METHODS: VNTR genotypes were derived, by typing at the -23HphI variant site, for 5,646 individuals from the Northern Finland Birth Cohort 1966. Associations were sought between these genotypes and a range of anthropometric (BMI, WHR), physiological (blood pressure) and biochemical (fasting glucose, insulin, lipids, indices of insulin sensitivity and beta cell function) measures obtained at clinical examination at 31 years. RESULTS: We found no evidence that VNTR genotype was significantly associated with measures of insulin secretion, insulin sensitivity, glycaemia, adiposity or blood pressure. CONCLUSIONS/INTERPRETATION: Despite evidence from several relatively small studies suggesting that INS-VNTR genotypes are associated with predisposition to type 2 diabetes, reduced beta cell function and measures of adiposity, the present study failed to detect any association with a range of diabetes-related traits. Taken with other recent studies in large population-based cohorts, these data suggest that previous studies have, at the very least, overestimated the influence of the INS-VNTR on type 2 diabetes-related traits. The effects of INS-VNTR variation on insulin transcription observed in vitro appear not to translate into detectable differences in basal insulin secretion in humans.

BACKGROUND: Poor ovarian and endometrial responses to gonadotrophin stimulation in assisted reproduction techniques lead to decreased pregnancy rates. The aim of the present study was to test the hypothesis that low-dose aspirin started prior to controlled ovarian stimulation improves ovarian responsiveness, pregnancy rate (PR) and pregnancy outcome. METHODS: A total of 374 women who were to undergo IVF/ICSI were randomized to receive 100 mg of aspirin (n = 186) or placebo (n = 188) daily. Treatment was started on the first day of controlled ovarian stimulation. It was continued until menstruation or a negative pregnancy test. Pregnant women continued the medication until delivery. The main outcome measures were the number of oocytes, number and quality of embryos, the clinical PR and pregnancy outcome. RESULTS: The mean (± SD) number of oocytes (12.0 ± 7.0 versus 12.7 ± 7.2), the total mean number of embryos (5.82 ± 4.35 versus 5.99 ± 4.66), the mean number of top quality embryos (0.99 ± 1.39 versus 1.18 ± 1.51) and the number of embryos transferred (1.64 ± 0.64 versus 1.63 ± 0.71) did not differ in the aspirin and placebo groups. Between the aspirin and placebo group, there was no statistically significant difference in clinical PR per embryo transfer (25.3%, n = 44 out of 174 versus 27.4%, n = 48 out of 175) or clinical PR per cycle initiated (23.7% versus 25.5%). Birth rate per embryo transfer did not differ significantly between the aspirin (18.4%) and placebo (21.1%) groups. The incidence of poor responders [12 (6.5%) versus 13 (6.9%)] was similar in both groups. CONCLUSIONS: The present results indicate that low-dose aspirin treatment does not have any beneficial effect on ovarian responsiveness, PR and pregnancy outcome in unselected women undergoing IVF/ICSI.

Variation at the insulin gene (INS-)VNTR (variable number of tandem repeats) minisatellite polymorphism has been reported to be associated with both early growth and adult metabolic phenotypes. However, the samples studied have been small and the relationship between INS-VNTR variation and parameters of early growth inconsistent, with four previous studies producing conflicting results. We have studied the relationship between INS-VNTR class (measured by genotyping the nearby −23HphI variant with which it is in tight linkage disequilibrium) and early growth in 5,646 members of the Northern Finnish Birth Cohort of 1966. Comparing class III homozygotes with other genotypes using multivariate linear regression analysis, we found no significant associations with any early growth measure (birth weight, birth length, ponderal index, and head circumference at 1 year), even after stratifying subjects by growth trajectory during infancy and/or birth order. For example, among infants with limited postnatal growth realignment (n = 2,470), class III/III infants were no heavier at birth (difference [±SE] in the means [fully adjusted], 58 ± 51 g; P = 0.26) than class I/− infants. No significant associations were detected following reanalysis with an additive model (for example, for birth weight, β = 20 g [95% CI −3 to 44], P = 0.09). Studies of this large population-based cohort have failed to generate convincing evidence that INS-VNTR variation influences early growth.

The metabolic cardiovascular disease (CVD) risk factors of women with self-reported oligomenorrhea and/or hirsutism, which are symptoms of polycystic ovary syndrome (PCOS), were investigated in a general population-based Northern Finland Birth Cohort 1966 Study to determine whether women with PCOS symptoms at 31 yr would be distinguishable from asymptomatic controls in terms of CVD risk factors. A total of 518 cases with oligomenorrhea and/or hirsutism and 1036 randomly selected controls were analyzed. C-Reactive protein (CRP; median, 0.70 vs. 0.60 mg/liter; P = 0.026), triglycerides (mean, 0.97 vs. 0.91 mmol/liter; P = 0.039), body mass index (BMI; mean, 25.1 vs. 24.2 kg/m(2); P < 0.001), and waist/hip ratio (mean, 0.82 vs. 0.81; P = 0.001) were significantly higher, and high-density lipoprotein cholesterol levels were lower (mean, 1.60 vs. 1.66 mmol/liter; P = 0.002) in the cases compared with the controls. Total cholesterol, low-density lipoprotein cholesterol, and blood pressure showed no statistically significant differences between the cases and the controls. In terms of metabolic CVD risk factors, women reporting hirsutism alone were indistinguishable from the control group, and those who reported both oligomenorrhea and hirsutism had the most severe changes in risk factor profiles. Because obesity is strongly related to PCOS symptoms, the analyses were stratified by BMI. After stratification into normal weight (BMI, or=30 kg/m(2)) groups, the waist/hip ratio was significantly higher among the overweight cases (mean, 0.84 vs. 0.83; P = 0.04). Among the obese women, high-density lipoprotein cholesterol was significantly lower (mean, 1.32 vs. 1.48 mmol/liter; P = 0.002) among the cases, and triglycerides tended to be higher (mean, 1.43 vs. 1.27 mmol/liter; P = 0.068) than in controls. In conclusion, these results indicate that self-reported symptoms of oligomenorrhea and/or hirsutism, particularly in the presence of both symptoms, may be helpful to identify women with metabolic cardiovascular risk factor accumulation associated with PCOS.

Insulin resistance and hyperinsulinemia are characteristic of polycystic ovary syndrome (PCOS), especially in obese women. Insulin-sensitizing drugs such as metformin have improved ovulation and lowered serum testosteronelevels in nonobese women with PCOS-even those with normal insulin sensitivity. This trial randomized 17 nonobese women (body mass index [BMI] less than 25 kg/m 2 ) with PCOS to receive either 500 mg metformin twice a day for 3 months, followed by 1 gm twice daily for 3 months longer, or oral contraceptive pills containing 35 μg ethinyl estradiol and 2 mg cyproterone acetate (EE-CA). Contraceptive pills were given for 3 weeks each month. Polycystic ovaries were demonstrated by vaginal ultrasonography in all patients. BMI declined significantly at 3 months and slightly at 6 months in metformin-treated women, as did the waist-to-hip ratio (WHR). BMI increased in the EE-CA group, with no change in the WHR. Hirsutism decreased slightly at 6 months on EE-CA but did not change during metformin therapy. Mean ovarian volume decreased significantly with EE-CA, but did not change substantially during metformin therapy. In neither group did the area under the curve for glucose change significantly after 6 months of treatment. Fasting insulin levels decreased significantly in metformin-treated women, as did early-phase insulin secretion. Early-phase C-peptide secretion tended to increase in these women. Hepatic insulin extraction in the fasting state rose significantly, but did not change in the EE-CA group. Fasting energy expenditure decreased with metformin therapy but increased significantly in the EE-CA group. Insulin-stimulated serum-free fatty acid levels tended to decrease after 6 months of metformin therapy but increased significantly with EE-CA treatment. Women in both groups had significantly decreased levels of serum testosterone, androstenedione, and dehydroepiandrosterone. The free-androgen index also declined significantly. In the EE-CA group. the LDL/HDL ratio decreased while serum triglycerides increased. Metformin therapy reduced hyperinsulinemia and hyperandrogenism in these nonobese women with PCOS. Menstrual cycles were improved in some instances. EE-CA treatment also improved hyperandrogenism and did not significantly worsen insulin sensitivity. Metformin offers an effective approach to treating such women for anovulation.

The reason for the elevated levels of HCG in assisted reproduction pregnancies remains unknown. Our hypothesis was that this increase is caused by the ovarian superovulation therapy.We compared the beta-HCG and alpha-fetoprotein (AFP) multiples of the median (MoM) in singleton pregnancies after IVF or ICSI with those achieved by frozen embryo transfer (FET) in spontaneous cycles.The HCG and AFP MoMs (plus minus SEMs) of 59 FET pregnancies were compared with 144 IVF (including 48 ICSI) pregnancies. The maternal HCG of pregnancies following ovarian stimulation was 1.31 plus minus 0.08 MoM compared with 1.35 plus minus 0.12 MoM in the unstimulated ones. The values for AFP were 1.06 plus minus 0.05 versus 1.11 plus minus 0.05 respectively. No significant differences could be observed between pregnancies following stimulated IVF/ICSI and unstimulated FET cycles.Our results show that second trimester maternal serum HCG is also elevated in singleton pregnancies following spontaneous FET cycles. The increased maternal serum HCG in IVF pregnancies is thus not related to superovulation therapy. Because of the elevated maternal serum HCG levels, serum screening cannot be performed reliably in pregnancies following assisted reproduction technology. Ultrasonographic detection of the nuchal translucency is unaffected and should be used for this group of women undergoing assisted reproduction.

Background The aim of the present study was to investigate the steroidogenic response pattern to HCG in obese women with polycystic ovary syndrome (PCOS) and the possible effects of metformin treatment on it. Methods A single injection of human chorionic gonadotrophin (HCG, 5000 IU) was given to 12 obese [body mass index (BMI) > or = 27 kg/m2] women with PCOS and to 27 control women. Blood samples for assays of 17alpha-hydroxyprogesterone (17-OHP), androstenedione, testosterone and oestradiol were collected at baseline and 1, 2 and 4 days after the injection. Responses to HCG were also assessed in the PCOS women after 2-month treatment with metformin (500 mg x 3 daily). Results Serum 17-OHP and oestradiol concentrations peaked at 24 h in the PCOS women and preceded the maximum testosterone concentration, which was seen at 48 h. In the control women the maximum concentrations of all these steroids were reached 96 h after HCG. After metformin treatment, the basal serum testosterone concentration and the areas under the androstenedione (AUC(A)) and testosterone (AUC(T)) response curves after HCG decreased significantly. Conclusions The results demonstrate that obese PCOS women have a male-type steroidogenic response pattern to a single injection of HCG and a higher androgen secretory capacity than control women, which may be explained by the increased thecal cell activity in the polycystic ovary. The slight alleviation of hyperandrogenism brought about by metformin therapy appears to be due to its effect on ovarian steroidogenesis possibly mediated by decreased insulin action.

Background The main reason for adverse treatment outcome in assisted reproduction is the high rate of multiple pregnancies. The only strategy to avoid dizygotic twins is to transfer one embryo at a time. Methods A total of 144 women, who had had at least four good quality embryos available after IVF/intracytoplasmic sperm injection (ICSI) and who had no more than one previous failed treatment cycle, were randomized to have either one or two embryos transferred. The treatment outcomes including those after frozen embryo transfer were compared between these groups. Results The clinical pregnancy rate per transfer was 32.4% in the one embryo transfer group and 47.1% in the two embryo transfer group, the difference being not significant. Eleven twin deliveries (n = 39) occurred in the two embryo transfer group and there was one pair of monozygotic twins in the one embryo transfer group. The cumulative pregnancy rate per patient after transfer of fresh and frozen embryos was 47.3% in the one embryo transfer group and 58.6% in the two embryo transfer group. Conclusions Our results indicate that among women who have good quality embryos in their first IVF/ICSI, good treatment results can be achieved. They support the idea of changing embryo transfer policy towards one embryo transfer without any remarkable decrease in the success rate, while dizygotic twins can be avoided.

Metformin, a biguanide antihyperglycemic drug, has been shown to improve ovarian function and glucose metabolism in women with polycystic ovary syndrome (PCOS), but results concerning its effects on insulin sensitivity are controversial. Oral contraceptive pills are commonly used in the treatment of PCOS; but, like metformin, their influence on insulin sensitivity is not well known. We randomized 32 obese (body mass index > 27 kg/m2) women with PCOS, either to metformin (500 mg x 2 daily for 3 months, then 1,000 mg x 2 daily for 3 months) or to ethinyl estradiol (35 microg)-cyproterone acetate (2 mg) oral contraceptive pills (Diane Nova) for 6 months. Metformin significantly decreased the waist-to-hip ratio, serum testosterone, fasting free fatty acid, and insulin concentrations and improved oxidative glucose utilization and menstrual cyclicity, with slight (but nonsignificant) improvements in insulin hepatic extraction and insulin sensitivity. Diane Nova significantly decreased serum testosterone and increased serum sex hormone-binding globulin concentrations and glucose area under the curve during oral glucose tolerance test. It is concluded that metformin, probably by way of its effect on adipose tissue, leads to reduction of hyperinsulinemia and concomitant improvement in the menstrual pattern; and therefore, it offers a useful alternative treatment for obese, anovulatory women with PCOS. Despite slight worsening of glucose tolerance, Diane Nova is an efficient treatment for women with hyperandrogenism and hirsutism.

Objective To evaluate the feasibility of endometrial assessment after endometrial thermal ablation. Study design Prospective observational study. A total of 57 women (age 47–52 years), who had undergone endometrial thermal ablation as a treatment for heavy menstrual bleeding (HMB) 3–10 years (mean 6 years) earlier, were examined with transvaginal ultrasound and saline sonohysterography. Endometrial samples were collected with a Pipelle device. Visualisation of endometrium, access to uterine cavity, change in cavity length, success in outpatient endometrial sampling and success in sonohysterography were evaluated. Results Endometrial thickness was 4.5 mm in amenorrhoeic women ( n = 17), 5.6 mm in eumenorrhoeic women ( n = 37) and 6.6 mm in hypermenorrhoeic women ( n = 3). An endometrial sample was successfully taken in 44 (77%) women, and in 13 (23%) women endometrial sample taking failed. The length of the uterine cavity compared to the length measured before endometrial thermal ablation was 0.5–5 cm (mean 2 cm) shorter in 34 women, unchanged in four women and longer in five women. The uterine cavity distended regularly in only nine (16%) women. In 14 (25%) women the cavity distended irregularly or only partly, and in 24 (42%) women the uterine cavity did not distend at all, but appeared as a narrow tube. In 10 (18%) women the sonohysterography catheter did not enter the uterine cavity at all. Conclusion Endometrial assessment is compromised after previous endometrial thermal ablation. Both endometrial sampling and sonohysterography fail quite often, causing problems in diagnosis of abnormal bleeding. Intrauterine adhesions may also decrease the reliability of the endometrial sampling.

Objective The aim of this study was to evaluate the role of transvaginal salpingosonography in the assessment of tubal patency among women previously treated conservatively for pelvic inflammatory disease and surgically for a benign ovarian tumor. Design Twenty-two women were recruited for this study at the University Hospital of Oulu. Transvaginal salpingosonography was scheduled to be performed twice within a 3-month interval. X-ray hysterosalpingography was chosen as a reference method and was performed within 2 days of the second salpingosonography examination during the same menstrual cycle. Altogether, 31 Fallopian tubes were assessed with the second salpingosonography examination and X-ray hysterosalpingography. Results Twenty-nine Fallopian tubes were observed by both methods to be patent (i.e. 29 tubes by each method, but not necessarily the same tubes). An occlusion was diagnosed by each method in two tubes only, of which one appeared occluded by both methods, while one tube from each method appearing to be occluded was demonstrated to be patent using the other method. The agreement of transvaginal salpingosonography compared with X-ray hysterosalpingography was 94%, the sensitivity 50%, the specificity 97%, the positive predictive value 50% and the negative predictive value 97%. Two successive transvaginal salpingosonography examinations were performed in 18 patients with 27 Fallopian tubes. Disagreement was observed for only one tube. The agreement between these two examinations was 96%, the sensitivity 100%, the specificity 96%, the positive predictive value 67% and the negative predictive value 100%. The kappa coefficient was 0.78 (95% confidence interval 0.75–0.81). Conclusions In conclusion, transvaginal salpingosonography can be used in patients with previous pelvic inflammatory disease and adnexal surgery due to its ease of use, reliability and low costs on an out-patient basis. Among these patients, tubal patency was a common finding. Copyright © 1999 International Society of Ultrasound in Obstetrics and Gynecology

This paper presents a benchmark study on the use of simulation models to represent the powder compaction process. A two level part that represents a synchroniser hub is used as detailed experimental information for this part is documented in the literature. The models used incorporate different representations of friction and material yielding behaviour together with different fill densities. The study shows that computer modelling is capable of predicting density distributions and tool set force levels for the powder compaction process. It has highlighted the sensitivity of the output with respect to friction, fill density, and material yield models. It has also shown that models that incorporate material behaviour using different material models yield surprisingly reasonable results. Based on best performance, it is now possible to predict density to within 0·05 g cm-3 and tool set force within 10%for an iron powder. The computational requirements indicate a simulation time of typically 1 h for a two level component. This makes simulation a practical tool for this industry sector.

A total of 811 intrauterine insemination (IUI) cycles in which clomiphene citrate/human menopausal gonadotrophin (HMG) was used for ovarian stimulation were analysed retrospectively to identify prognostic factors regarding treatment outcome. The overall pregnancy rate was 12.6% per cycle, the multiple pregnancy rate 13.7%, and the miscarriage rate 23.5%. Logistic regression analysis revealed five predictive variables as regards pregnancy: number of the treatment cycle (P = 0.009), duration of infertility (P = 0.017), age (P = 0.028), number of follicles (P = 0.031) and infertility aetiology (P = 0.045). The odds ratios for age < 40 years, unexplained infertility aetiology (versus endometriosis) and duration of infertility < or = 6 years were 3.24, 2.79 and 2.33, respectively. A multifollicular ovarian response to clomiphene citrate/HMG resulted in better treatment success than a monofollicular response, and 97% of the pregnancies were obtained in the first four treatment cycles. The results indicate that clomiphene citrate/HMG/IUI is a useful and cost-effective treatment option in women < 40 years of age with infertility duration < or = 6 years, who do not suffer from endometriosis.

(1999). The prevalence of polycystic ovaries in healthy women. Acta Obstetricia et Gynecologica Scandinavica: Vol. 78, No. 2, pp. 137-141.

Objective: This prospective study was undertaken to examine the usefulness of a long gonadotrophin releasing hormone agonist (GnRH-a)/human menopausal gonadotrophin (hMG) protocol in intrauterine insemination (IUI) treatment. The results were compared to those of clomiphene citrate (CC)/hMG/IUI. Study Design: Seventy-five patients were recruited to a GnRH-a/hMG group (group 1) while 88 patients underwent CC/hMG stimulation and served as controls (group 2). The study subjects were stimulated with a long GnRH-a/hMG regimen. IUI was performed 36 h after the administration of human chorionic gonadotrophin. Results: The number of preovulatory follicles, the thickness of endometrium and sperm parameters were similar in both groups. The hMG requirements were significantly higher in group 1 than in group 2 (21.2±5.1 vs. 8.1±3.1 ampoules). The pregnancy rate was 20% in group 1 and 12.5% in group 2, the difference being not significant. Conclusion: The pregnancy rates were not significantly different between the GnRH-a/hMG/IUI and CC/hMG/IUI groups. In addition, GnRH-a/hMG stimulation is notably more expensive than CC/hMG, and for these reasons, GnRH-a/hMG stimulation is not cost-effective in routine IUI therapy.

Objective: To compare the efficacy of fallopian tube sperm perfusion utilizing a Foley catheter technique with standard IUI. Design: Randomized controlled study. Setting: The infertility units of the University Central Hospital and the Family Federation of Finland, Oulu, Finland. Patient(s): One hundred infertile women with unexplained factor, minimal to mild endometriosis, mild male factor, or ovarian dysfunction, undergoing 50 IUI and 50 fallopian tube sperm perfusion cycles stimulated by clomiphene citrate and hMG. Intervention(s): Thirty-six hours after hCG administration, patients were randomized to either the IUI group (group 1, 50 patients and cycles) or the fallopian tube sperm perfusion group (group 2, 50 patients and cycles). Intrauterine insemination was performed using a standard method and fallopian tube sperm perfusion with a pediatric Foley catheter, which prevents the reflux of sperm suspension. Main Outcome Measure(s): Number of clinical pregnancies. Result(s): The fallopian tube sperm perfusion method using a Foley catheter technique was easy to perform and convenient for the patients. The overall pregnancy rate per cycle was 8% for fallopian tube sperm perfusion and 20% for IUI, a difference that was not significant. Conclusion(s): The fallopian tube sperm perfusion method using a Foley catheter offers no advantage in comparison with the conventional IUI technique.

Which clinical and laboratory factors affect live birth rate (LBR) after frozen-thawed embryo transfer (FET)?Top quality embryo characteristics, endometrial preparation protocol, number of embryos transferred and BMI affected independently the LBR in FET.FET is an important part of present-day IVF/ICSI treatment. There is limited understanding of the factors affecting success rates after FET.This is a two-centre retrospective cohort study. Analysis was carried out on 1972 consecutive FET cycles in 1998-2007, with embryos frozen on Day 2. The primary outcome was LBR per cycle.We assessed the independent effect on LBR of the following variables: female age, female age at embryo freezing, BMI, diagnosis, primary versus secondary infertility, fertilization by IVF versus ICSI, pregnancy in the fresh cycle, type (spontaneous, spontaneous with luteal progesterone and estrogen/progesterone substitution) and rank of the FET cycle, as well as number and presence (yes versus no) of top quality embryo(s) at freezing, thawing and transfer, damaged thawed embryos and overnight culture.In 78% of the cycles with top quality embryos frozen (n = 1319), at least one embryo still had high-quality morphology after thawing. Top quality embryo morphology observed at any stage of culture improved the outcome even if high-quality characteristics disappeared before transfer. LBRs after the transfer of a top quality embryo were similar in the FET (24.9%) and fresh cycles of the same period (21.9%). The chance of live birth increased significantly if ≥1 top quality embryo was present at freezing (odds ratio (OR) 1.85, 95% confidence interval (CI) 1.10-3.14), at thawing (OR 1.93, CI 1.20-3.11) or at transfer (OR 3.41, CI 2.12-5.48). Compared with spontaneous cycles with luteal support, purely spontaneous cycles (OR 0.58, CI 0.40-0.84) and hormonally substituted FET (OR 0.47, CI 0.32-0.69) diminished the odds of pregnancy. BMI (OR 0.96, CI 0.92-0.99) and transfer of two embryos versus one (OR 1.45, CI 1.08-1.94) were other factors that improved LBR after FET.The sample sizes available in some subanalyses were small, limiting the power of the study.The presence of ≥1 top quality embryo at any step of the freezing and thawing process increases the chance of pregnancy. The data do not support the freezing of all embryos for transfer in order to improve the outcome. A top quality embryo transferred in FET may even have the same potential as in a fresh cycle. On the contrary, LBR in the group with no top quality embryos frozen was quite low (10.4%), raising the question of whether a re-evaluation of freezing criteria is necessary to avoid costly treatments with a low success rate.

The role of transvaginal pulsed colour Doppler ultrasound in the prediction of the outcome of in-vitro fertilization (IVF) therapy was assessed longitudinally in 30 patients during stimulated cycles. The pulsatility index (PI) of the uterine arteries did not change significantly until the mid-luteal phase. Within 6 days after the beginning of stimulation the maximum peak systolic velocity of the uterine blood flow had increased significantly from 27.6 +/- 8.9 to 36 +/- 12.8 cm/s. No difference was found in uterine PI between pregnant and non-pregnant women. The PI of intra-ovarian flow was also similar in both groups. However, there was an insignificant increase in uterine receptivity when the PI of the uterine artery was between 2.0 and 2.99 on the day of embryo transfer. Nevertheless, the appraisal of the prognostic outcome of the treatment could not be made with Doppler.

Objective To evaluate the cost difference between a daycase endometrial thermal ablation performed under general anaesthesia and an outpatient endometrial ablation using local anaesthetic. Study design Calculations using real reported resource use in 20 daycase procedures and 16 outpatient procedures. Results The costs were 1865 euros for daycase procedure versus 1065 euros for outpatient procedure. Conclusion The cost of endometrial thermal ablation can be considerably minimised by taking the procedure out of the theatre and performing it under local anaesthetic instead of general anaesthesia. This setting makes endometrial thermal ablation cost-effective.

One-hundred women undergoing ovarian stimulation with gonadotrophin-releasing hormone agonist (GnRH-a) and a human menopausal gonadotrophin (HMG) for in-vitro fertilization (IVF) participated in this randomized comparative study. The effectiveness of long-acting s.c. goserelin (Zoladex depot; 49 patients) and intranasally (i.n.) administered buserelin acetate (Suprefact; 51 patients) for pituitary down-regulation was compared. Treatment with s.c. goserelin (3.6 mg) or i.n. buserelin acetate (200 micrograms; 6 times/day) was started on day 21-23 of the cycle. Stimulation with 150 IU of HMG/day was started after at least 11 days of GnRH-a treatment. There were no differences in the time required for follicular development nor in the clinical outcome between groups treated with either goserelin or buserelin. The number of oocytes recovered in the goserelin group was 6.7 +/- 5.0 versus 6.3 +/- 4.9 in the buserelin group. There were 11 pregnancies after the use of goserelin (22.4%) and 12 pregnancies in those given buserelin (24.0%). The number of HMG ampoules needed for follicular maturation was higher in the goserelin group (27.9 +/- 7.8) than in the buserelin group (24.6 +/- 7.8, P < 0.05). The patients given buserelin suffered significantly more from tiredness, depression, headache and abdominal pain than those receiving goserelin, whereas there were no differences between the groups in experiencing mental irritability, nausea and swelling. Subcutaneous goserelin depot injection offers a useful alternative for pituitary down-regulation in IVF stimulation.

Objective To compare the effectiveness of elective single embryo transfer versus double embryo transfer on the outcomes of live birth, multiple live birth, miscarriage, preterm birth, term singleton birth, and low birth weight after fresh embryo transfer, and on the outcomes of cumulative live birth and multiple live birth after fresh and frozen embryo transfers. Design One stage meta-analysis of individual patient data. Data sources A systematic review of English and non-English articles from Medline, Embase, and the Cochrane Central Register of Controlled Trials (up to 2008). Additional studies were identified by contact with clinical experts and searches of bibliographies of all relevant primary articles. Search terms included embryo transfer, randomised controlled trial, controlled clinical trial, single embryo transfer, and double embryo transfer. Review methods Comparisons of the clinical effectiveness of cleavage stage (day 2 or 3) elective single versus double embryo transfer after fresh or frozen in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included. Trials were included if the intervention differed only in terms of the intended number of embryos to be transferred. Trials that involved only blastocyst (day five) transfers were excluded. Results Individual patient data were received for every patient recruited to all eight eligible trials (n=1367). A total of 683 and 684 women randomised to the single and double embryo transfer arms, respectively, were included in the analysis. Baseline characteristics in the two groups were comparable. The overall live birth rate in a fresh IVF cycle was lower after single (181/683, 27%) than double embryo transfer (285/683, 42%) (adjusted odds ratio 0.50, 95% confidence interval 0.39 to 0.63), as was the multiple birth rate (3/181 (2%) v 84/285 (29%)) (0.04, 0.01 to 0.12). An additional frozen single embryo transfer, however, resulted in a cumulative live birth rate not significantly lower than the rate after one fresh double embryo transfer (132/350 (38%) v 149/353 (42%) (0.85, 0.62 to 1.15), with a minimal cumulative risk of multiple birth (1/132 (1%) v 47/149 (32%)). The odds of a term singleton birth (that is, over 37 weeks) after elective single embryo transfer was almost five times higher than the odds after double embryo transfer (4.93, 2.98 to 8.18). Conclusions Elective single embryo transfer results in a higher chance of delivering a term singleton live birth compared with double embryo transfer. Although this strategy yields a lower pregnancy rate than a double embryo transfer in a fresh IVF cycle, this difference is almost completely overcome by an additional frozen single embryo transfer cycle. The multiple pregnancy rate after elective single embryo transfer is comparable with that observed in spontaneous pregnancies.

background: Low-dose aspirin therapy could improve remodelling of maternal spiral arteries during early placentation and prevent subsequent pregnancy-related hypertensive disorders. We investigated whether low-dose aspirin therapy reduces the incidence of hypertensive pregnancy complications in unselected IVF and ICSI patients when medication was started prior to pregnancy. methods: A total of 487 patients who underwent IVF/ICSI were randomized to receive 100 mg aspirin (n ¼ 242) or placebo (n ¼ 245) daily, starting on the first day of gonadotrophin stimulation. Pregnant women continued the medication until delivery. A total of 107 patients (52 with aspirin and 55 with placebo) experienced live birth and were included in this follow-up study. The main outcome measure was the incidence of hypertensive pregnancy complications. results: Embryo transfer took place in 227 (94%) women in the aspirin group and in 229 (93%) women in the placebo group. The live birth rate between the aspirin (22.9%) and placebo (24.0%) groups did not differ significantly (P ¼ 0.78). The overall incidence of hypertensive pregnancy complications was 15.4% (8/52) in the aspirin group and 18.2% (10/55) in the placebo group (P ¼ 0.70, 95% confidence interval for the difference of proportions 217 to 11%). There were two cases of severe pre-eclampsia in the aspirin group and three cases in the placebo group. conclusions: In the present study, the incidence of hypertensive pregnancy complications did not differ statistically significantly between low-dose aspirin and placebo groups in unselected IVF/ICSI patients, when medication was started concomitantly with gonadotrophin stimulation and continued until delivery. The study was registered at clinicaltrials.gov. NCT00683202.

To study the effect of growth hormone (GH) in combination with an ultrashort-term gonadotropin-releasing hormone analogue/human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) regimen in ovarian hyperstimulation for in vitro fertilization (IVF).Prospective randomized placebo-controlled study.University-based IVF program.Fifty-four normally cycling women (27 control and 27 GH-treated) participated in this study.Human recombinant GH (24 IU)/placebo was given intramuscularly on alternate days starting on cycle day 4 until the day of last hMG injection.Serum estradiol (E2) and progesterone (P) concentrations were slightly lower in the GH group than in the placebo group on the day of hCG injection and 1 day thereafter (P0.01 to 0.001). Serum luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone (T), and sex hormone-binding globulin did not differ between the groups. The follicular fluid (FF) concentration of T was higher in the GH group than in the placebo group (15.9 +/- 6.0 nmol/L versus 10.2 +/- 4.9 nmol/L, P0.005), and no differences were observed in the FF concentrations of E2, P, and insulin-like growth factor I between the groups. In granulosa cells isolated from patients who received GH treatment, the levels of 3 beta-hydroxysteroid dehydrogenase and aromatase messenger ribonucleic acid were significantly higher than in the patients receiving placebo. The number of hMG ampules needed for follicular development and the number of follicles and oocytes recovered were similar in both groups.These results indicate that GH administration modifies ovarian steroidogenic response to gonadotropins in IVF patients, suggesting a role for GH in the regulation of human ovarian function.

Five patients with advanced ovarian granulosa cell malignancies resistant to cytotoxic chemotherapy were treated with monthly subcutaneous injections of long-acting gonadotropin releasing hormone (GnRH) agonist analog. One partial response and one stabilization of the disease were observed. In three patients, the tumor continued to progress. Treatment response was monitored with serum inhibin assay. Four patients had high serum inhibin concentrations at the beginning of GnRH analog treatment, while one patient had an inhibin-negative tumor. In three of four patients, serum inhibin remained relatively constant, or decreased during the first 3 months of therapy. It subsequently increased, in parallel with clinical deterioration. Further clinical trials with GnRH analogs are warranted in this malignancy in which serum inhibin appeared to be a clinically valuable tumor marker.

The aim of the study was to evaluate a possible lateral difference in ovarian activity and its effect on cycle fecundity. A database was analysed retrospectively which covered 477 cycles in which frozen/thawed embryo transfer had been carried out. The cycles were spontaneous, with no hormonal treatment. Women with ovulation problems as a reason for infertility treatment were excluded. Factors investigated were the side of ovulation, endometrial thickness on cycle days 10-12 and on the day of embryo transfer, and pregnancy rate per embryo transfer. Ovulation was right-sided in 273 of the 477 cycles (57.2%) and left-sided in 204 of the cycles (42. 8%) (95% CI 38.3-47.2, P = 0.002). In the age category of 30-37 years, covering 288 cycles, the incidence of left-sided ovulation was 126 (43.7%, 95% CI 38.0-49.5, P = 0.034). In this category, the endometrial thickness (+/-SD) was significantly greater on the day of embryo transfer (i.e. at time of implantation) when there had been left-sided ovulation compared with right-sided [9.6 mm (2.0) versus 9.1 mm (1.8), P = 0.037]. In addition, the pregnancy rate per embryo transfer was higher when ovulation had been on the left side [32/126 (25.2%) versus right side 24/162 (14.8%), P = 0.035, 95% CI 0.0122-0.199]. In conclusion, right-sided ovulation was more frequent than left-sided in the whole group. This is the first study to report that the side of ovulation has a clinical impact. These data support the hypothesis that the side of ovulation is significant in terms of embryo implantation.

BACKGROUND: Although elective single embryo transfer (eSET) minimizes the multiple birth rate after in vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI), there remain concerns in many countries that it is less effective and more expensive than conventional double embryo transfer (DET). METHODS: We compared the clinical outcome achieved in the years 1995-1999, in which eSET was rarely used (4.2% of women, DET period) with that of the years 2000-2004, in which eSET was more widely used (46.2%, eSET period). In the DET period, 826 women had 1359 fresh embryo cycles followed by 589 frozen-thawed embryo transfer (FET) cycles. In the eSET period, 684 women had 1027 fresh and 683 FET cycles. The cumulative term live birth rate/woman was the primary clinical outcome measure. An incremental cost-effectiveness ratio of a term live birth was also calculated based on hospital charges and medication prices of IVF/ICSI treatment. RESULTS: The cumulative pregnancy rate/oocytes pickup (38.2 versus 33.1%, P = 0.01), cumulative live birth rate/oocytes pickup (28.0 versus 22.5%, P = 0.002) and cumulative live birth rate/woman (41.7 versus 36.6%, P = 0.04) were all higher in the eSET period than in the DET period. The cumulative multiple birth rate was significantly lower in the eSET period than in the DET period (8.9 versus 19.6%, P < 0.0001). A term live birth in the eSET period was 19 889 euros less expensive than in the DET period. CONCLUSIONS: This study shows that eSET with cryopreservation is more effective and less expensive than DET and should be adopted as a treatment of choice.