Sinikka Nuojua-Huttunen

Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995–2006

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.

Factors affecting the outcome of frozen–thawed embryo transfer

STUDY QUESTION Which clinical and laboratory factors affect live birth rate (LBR) after frozen-thawed embryo transfer (FET)? SUMMARY ANSWER Top quality embryo characteristics, endometrial preparation protocol, number of embryos transferred and BMI affected independently the LBR in FET. WHAT IS KNOWN ALREADY FET is an important part of present-day IVF/ICSI treatment. There is limited understanding of the factors affecting success rates after FET. STUDY DESIGN, SIZE, DURATION 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. PARTICIPANTS/MATERIALS, SETTING, METHODS 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. MAIN RESULTS AND THE ROLE OF CHANCE 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. LIMITATIONS, REASONS FOR CAUTION The sample sizes available in some subanalyses were small, limiting the power of the study. WIDER IMPLICATIONS OF THE FINDINGS 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.

Adrenal steroidogenesis is related to insulin in hyperandrogenic women

OBJECTIVE To evaluate ovarian and adrenal steroid secretion in women with severe hyperandrogenism. DESIGN A prospective study. SETTING The Gynecological Endocrine Research Unit of the University Central Hospital, Oulu, Finland. PATIENTS Thirteen obese, hirsute women with severe hyperandrogenism. INTERVENTIONS Adrenocorticotropin hormone stimulation and dexamethasone suppression tests and selective catheterizations of the left ovarian and adrenal veins were performed. MAIN OUTCOME MEASURES The concentrations of insulin, P, 17-hydroxyprogesterone (17-OHP), androstenedione (A), T, DHEA, DHEAS, and cortisol were measured. RESULTS The secretory gradients of T and its precursors, P, 17-OHP, A, and DHEA in the selective catheterizations showed the adrenal to be the main source of excessive steroid production in these patients. The concentrations of P (r = 0.82), 17-OHP (r = 0.89), A (r = 0.84), T (r = 0.86), and cortisol (r = 0.87) in the adrenal vein showed a strong correlation with insulin measured from the same samples. CONCLUSIONS Excessive androgens were secreted mainly by the adrenals in these obese hyperinsulinemic women. Correlation analyses suggested that insulin stimulates adrenal androgen and cortisol secretion, which may constitute an important component of the pathogenetic mechanisms of hyperandrogenism and the polycystic ovary syndrome.

Low-dose aspirin therapy and hypertensive pregnancy complications in unselected IVF and ICSI patients: a randomized, placebo-controlled, double-blind study

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 = 242) or placebo (n = 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 = 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 = 0.70, 95% confidence interval for the difference of proportions -17 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.

Sequence variations in human ZP genes as potential modifiers of zona pellucida architecture

To examine putative associations between zona pellucida (ZP) anomalies and sequence variations in genes expressing structural ZP glycoprotein components, sequence data of 31 volunteers participating in IVF treatments were obtained and analyzed together with morphologic data of the respective oocytes. Our results suggest that some of the most frequent zona anomalies may be at least partly explained by sequence variations in genes expressing the four human ZP proteins, especially those in ZP2 and ZP3.

Long gonadotrophin releasing hormone agonist/human menopausal gonadotrophin protocol for ovarian stimulation in intrauterine insemination treatment

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.

Short- and long-term health consequences and current satisfaction levels for altruistic anonymous, identity-release and known oocyte donors

STUDY QUESTION What are the short- and long-term health consequences and current satisfaction of altruistic oocyte donors? SUMMARY ANSWER Donating oocytes in the majority (>90%) of donation cycles is not associated with harmful long-term general or reproductive health effects. WHAT IS KNOWN ALREADY Knowledge of long-term health effects of oocyte donation on donors is sparse and follow-up studies have usually been carried out on commercial donors. Thus far, no major long-term harmful effects have been demonstrated. Most studies have reported a high level of donor satisfaction, but also less favorable experiences have been published. STUDY DESIGN, SIZE AND DURATION A retrospective cross-sectional survey of all women who had donated oocytes between 1990 and 2012 at three fertility clinics was carried out in spring 2013. A self-administered questionnaire was sent out to a total of 569 former oocyte donors. PARTICIPANTS, SETTING, METHODS In all, 428 past donors answered the questionnaire assessing donors demographic characteristics, short- and long-term medical and psychological experiences and satisfaction related to donations. Of the donors, 87% (371/428) were unknown and 13% (57/428) were known to the recipient. The mean follow-up time after the donation was 11.2 years (range from 0.5 to 23 years) and the mean age of the respondents was 42 years at the time of the study. To learn whether the demographic profile of donors was affected by the Finnish Assisted Reproduction Technology (ART) Act of 2007, we divided the 428 respondents into two groups: (i) women whose first donation took place between 1990 and 2007 (79% of the respondents) and (ii) women whose first donation took place between 2008 and 2012 (21% of the respondents). Before 2008, donors were non-identifiable (anonymous) but after 2008 persons born as a result of gamete donation could, from the age of 18, receive on request information identifying the donor. MAIN RESULTS AND THE ROLE OF CHANCE The response rate was 75% (428/569). The mean age of the donors did not differ between the two time periods, but there was a higher proportion of donors in the youngest age group (20-24 years) and more childless donors (P < 0.05) after 2008 than between 1990 and 2007. Immediate complications occurred in 7.2% (42/582) of the donation cycles and the most common complication was ovarian hyperstimulation syndrome (OHSS) in 5.0% (29/582) of the treatments. There were no reports of ovarian or uterine cancer and only one case of breast cancer. After the donation, 11.5% of the donors experienced unsuccessful attempts to become pregnant. Almost all donors (99%) were satisfied or very satisfied with their decision to donate and 95% would warmly recommend it to other women. There were no differences between the known and unknown donors in this respect, or between the two time periods (before or after the ART Act in 2008). Four donors (1%) had regretted donation, and 7% would have wanted to have more support before and 14% after the donation. LIMITATIONS, REASON FOR CAUTION Although the response rate was high, 25% of all former donors in the three participating clinics could not be included due to lack of response. The results are based on self-reported assessment of the experiences of former donors, and it is not possible to estimate the influence of recall bias. WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this is the largest study of health consequences and satisfaction levels on oocyte donors. Data from this study can be used to inform donor candidates about the medical aspects involved in the treatment and it provides information on how to support these women during and after the donation. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from the Medical Society Life and Health, and from the Otto A. Malm Foundation. There are no competing interests to report.