Daimin Wei

Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome

BACKGROUND The transfer of fresh embryos is generally preferred over the transfer of frozen embryos for in vitro fertilization (IVF), but some evidence suggests that frozen-embryo transfer may improve the live-birth rate and lower the rates of the ovarian hyperstimulation syndrome and pregnancy complications in women with the polycystic ovary syndrome. METHODS In this multicenter trial, we randomly assigned 1508 infertile women with the polycystic ovary syndrome who were undergoing their first IVF cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. After 3 days of embryo development, women underwent the transfer of up to two fresh or frozen embryos. The primary outcome was a live birth after the first embryo transfer. RESULTS Frozen-embryo transfer resulted in a higher frequency of live birth after the first transfer than did fresh-embryo transfer (49.3% vs. 42.0%), for a rate ratio of 1.17 (95% confidence interval [CI], 1.05 to 1.31; P=0.004). Women who underwent frozen-embryo transfer also had a lower frequency of pregnancy loss (22.0% vs. 32.7%), for a rate ratio of 0.67 (95% CI, 0.54 to 0.83; P<0.001), and of the ovarian hyperstimulation syndrome (1.3% vs. 7.1%), for a rate ratio of 0.19 (95% CI, 0.10 to 0.37; P<0.001), but a higher frequency of preeclampsia (4.4% vs. 1.4%), for a rate ratio of 3.12 (95% CI, 1.26 to 7.73; P=0.009). There were no significant between-group differences in rates of other pregnancy and neonatal complications. There were five neonatal deaths in the frozen-embryo group and none in the fresh-embryo group (P=0.06). CONCLUSIONS Among infertile women with the polycystic ovary syndrome, frozen-embryo transfer was associated with a higher rate of live birth, a lower risk of the ovarian hyperstimulation syndrome, and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer. (Funded by the National Basic Research Program of China and others; ClinicalTrials.gov number, NCT01841528.).

Transfer of Fresh versus Frozen Embryos in Ovulatory Women

Background Elective frozen‐embryo transfer has been shown to result in a higher live‐birth rate than fresh‐embryo transfer among anovulatory women with the polycystic ovary syndrome. It is uncertain whether frozen‐embryo transfer increases live‐birth rates among ovulatory women with infertility. Methods In this multicenter, randomized trial, we randomly assigned 2157 women who were undergoing their first in vitro fertilization cycle to undergo either fresh‐embryo transfer or embryo cryopreservation followed by frozen‐embryo transfer. Up to two cleavage‐stage embryos were transferred in each participant. The primary outcome was a live birth after the first embryo transfer. Results The live‐birth rate did not differ significantly between the frozen‐embryo group and the fresh‐embryo group (48.7% and 50.2%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.89 to 1.06; P=0.50). There were also no significant between‐group differences in the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy. Frozen‐embryo transfer resulted in a significantly lower risk of the ovarian hyperstimulation syndrome than fresh‐embryo transfer (0.6% vs. 2.0%; relative risk, 0.32; 95% CI, 0.14 to 0.74; P=0.005). The risks of obstetrical and neonatal complications and other adverse outcomes did not differ significantly between the two groups. Conclusions The live‐birth rate did not differ significantly between fresh‐embryo transfer and frozen‐embryo transfer among ovulatory women with infertility, but frozen‐embryo transfer resulted in a lower risk of the ovarian hyperstimulation syndrome. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China; Chinese Clinical Trial Registry number, ChiCTR‐IOR‐14005406.)

Polycystic ovary syndrome susceptibility single nucleotide polymorphisms in women with a single PCOS clinical feature

STUDY QUESTION What is the direct genetic contribution of the polycystic ovary syndrome (PCOS) susceptibility single nucleotide polymorphisms (SNPs), identified by previous genome-wide association studies (GWAS) to the definitive clinical features of the syndrome? SUMMARY ANSWER Each single PCOS clinical feature had a specific genetic association, and rs4385527 in the chromosome 9 open reading frame 3 (C9orf3) conferred a particular risk to the three defined PCOS clinical features in this study, which suggested its fundamental role in the etiology of PCOS. WHAT IS KNOWN ALREADY PCOS is a heterogeneous disorder characterized by anovulation (OA), hyperandrogenism (HA) and polycystic ovary morphology (PCOM). Two previous GWAS in China have identified 15 independent susceptibility SNPs related to PCOS (PCOS-SNPs). However, little is known about the candidate gene of each clinical feature. STUDY DESIGN, SIZE, DURATION Case-control study. Three independent groups of women were recruited from 2010 to 2012: 746 subjects with OA only, 278 subjects with HA only and 536 subjects with PCOM only. A total of 1790 healthy women with none of the above pathological characteristics were also enrolled as control subjects during the same time period. PARTICIPANTS/MATERIALS, SETTING, METHODS All participants were women of reproductive age. Genotype and allelic frequencies of 15 PCOS-SNPs were determined in all subjects using direct sequencing and Sequenom Arrays. The allelic frequencies of each case group were compared with the controls. MAIN RESULTS AND THE ROLE OF CHANCE After adjustment for age and BMI, variants in luteinizing hormone/choriogonadotropin receptor (LHCGR) (rs13405728), C9orf3 (rs4385527) and insulin receptor gene (INSR) (rs2059807) were strongly associated with OA (Padjust < 0.01, <0.001 and <0.05, respectively); rs4385527 in C9orf3 was strongly associated with HA (Padjust< 0.001); variants in the thyroid adenoma associated gene (THADA) (rs13429458 and rs12478601), DENN/MADD domain containing 1A (DENND1A)(rs10818854), and C9orf3 (rs4385527) were significantly associated with PCOM (Padjust < 0.01, <0.001, <0.05 and <0.001, respectively). LIMITATIONS, REASONS FOR CAUTION The sample size of some case groups was relatively small, which therefore limited the statistical power of the analysis to a certain extent. WIDER IMPLICATIONS OF THE FINDINGS The present study indicates a potential common genetic basis of three PCOS clinical features. Other specific associated genes may play a synergistic role, leading to heterogeneous pathophysiological changes. Additionally, the increased frequency of PCOS-risk alleles in women with single PCOS clinical features suggests that these subjects have an elevated risk of developing the syndrome, although they cannot be currently diagnosed. STUDY FUNDING/COMPETING INTERESTS This research was supported by the National Basic Research Program of China (973 Program) (2012CB944700, 2011CB944502), the National Key Technology Research and Development Program(2011BAI17B00), the National Natural Science Foundation of China (81430029, 81201441, 81490743, 31371453), the Scientific Research Foundation of Shandong Province of Outstanding Young Scientist (2012BSE27089) and the Fundamental Research Funds of Shandong University(2014GN025). There were no competing interests.

Live birth after fresh embryo transfer vs elective embryo cryopreservation/frozen embryo transfer in women with polycystic ovary syndrome undergoing IVF (FreFro-PCOS): study protocol for a multicenter, prospective, randomized controlled clinical trial

BackgroundPolycystic ovary syndrome (PCOS) patients are at increased risk of pregnancy complications, which may impair pregnancy outcome. Transfer of fresh embryos after superovulation may lead to abnormal implantation and placentation and further increase risk for pregnancy loss and complications. Some preliminary data suggest that elective embryo cryopreservation followed by frozen–thawed embryo transfer into a hormonally primed endometrium could result in a higher clinical pregnancy rate than that achieved by fresh embryo transfer.Methods/DesignThis study is a multicenter, prospective, randomized controlled clinical trial (1:1 treatment ratio of fresh vs. elective frozen embryo transfers).. A total of 1,180 infertile PCOS patients undergoing the first cycle of in vitro fertilization (IVF) or intracytoplasmic sperm injection will be enrolled and randomized into two parallel groups. Participants in group A will undergo fresh embryo transfer on day 3 after oocyte retrieval, and participants in group B will undergo elective embryo cryopreservation after oocyte retrieval and frozen–thawed embryo transfer in programmed cycles. The primary outcome is the live birth rate. Our study is powered at 80 to detect an absolute difference of 10 at the significance level of 0.01 based on a two-sided test.DiscussionWe hypothesize that elective embryo cryopreservation and frozen–thawed embryo transfer will reduce the incidence of pregnancy complications and increase the live birth rate in PCOS patients who need IVF to achieve pregnancy.Trial registrationClinicalTrials.gov Identifier: NCT01841528

Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome.

STUDY QUESTION Do oral contraceptives (OCs) and progestins impact live birth rate of IVF when used for cycle scheduling in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER OCs used for scheduling IVF cycle were associated with lowered rates of pregnancy and live birth after fresh embryo transfer, whereas progestins used for this purpose yield higher rates of pregnancy and live birth than OCs. WHAT IS KNOWN ALREADY Due to oligo-menorrhea in PCOS, OCs and progestin are extensively used to schedule the start of an IVF cycle in women with PCOS. Little is known about the effect of such pretreatments on outcomes, especially, the rate of live birth. STUDY DESIGN, SIZE, DURATION This was a nested cohort study and secondary analysis of a multicenter randomized trial, which was designed to compare live birth rate after fresh embryo transfer vs frozen embryo transfer (FET) in women with PCOS (Frefro-PCOS). A total of 1508 women were enrolled from 14 centers between June 2013 and May 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS At the discretion of local investigators, subjects were instructed to wait for spontaneous menses (Control group, n = 323), or were prescribed progestins (P group, n = 283) or OCs (OCs group, n = 902) to induce menstruation prior to the start of ovarian stimulation. GnRH antagonist protocol was initiated at Day 2 or 3 of induced or spontaneous menses cycle. The rates of pregnancy, pregnancy loss and live birth after either fresh embryo transfer or FET were compared among these three groups. MAIN RESULTS AND THE ROLE OF CHANCE With fresh embryo transfer, women with OC-induced menses had lower rates of clinical pregnancy (48.8% vs 63.6%, relative rate (RR): 0.77, 95% CI: 0.66–0.89) and live birth (36.1% vs 48.1%, RR: 0.75, 95% CI: 0.61–0.92) than women with spontaneous menses. With freeze-all and deferred FET, women with OC-induced menses had a similar pregnancy rate but a higher pregnancy loss rate (27.7% vs 13.0%, RR: 2.13, 95% CI: 1.28–3.52) after FET than women with spontaneous menses. The live birth rate after FET in women with OC-induced menses, progestin-induced menses and spontaneous menses was 49.4%, 50.7% and 60.2%, respectively (P = 0.06). Progestin-induced menses was associated with similar rates of pregnancy, pregnancy loss and live birth after transfer of either fresh or frozen embryos compared with spontaneous menses. Multivariate logistic regression analysis showed that OCs used for menses induction was associated with lower rate of live birth. LIMITATIONS, REASONS FOR CAUTION The methods for menses induction were not assigned randomly, thus selection bias was highly likely because of the study design and significant differences that were observed in the baseline characteristics of the women in the different groups. The mean BMI in this study population was relatively normal; the applicability of this result to obese PCOS women needs to be evaluated in further study. WIDER IMPLICATIONS OF THE FINDINGS Our results suggest that either waiting for a spontaneous menses or using progestin is a better option than using OCs to induce menses in women with PCOS prior to ovarian stimulation using GnRH antagonist protocol for IVF. Further randomized controlled studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by National Basic Research Program of China (973 Program) (2012CB944700), the State Key Program of National Natural Science Foundation of China (81430029), National Natural Science Foundation of China (81471428) and Thousand Talents Program (Drs Legro and Zhang H). Dr Legro reports receiving consulting fees from Euroscreen, Kindex, Bayer and Millendo Pharmaceuticals and research funding from Ferring. Others report no disclosures. TRIAL REGISTRATION NUMBER Frefro-PCOS was registered at Clinicaltrials.gov: NCT01841528.

Family-based analysis of adiponectin gene polymorphisms in Chinese Han polycystic ovary syndrome

OBJECTIVE To study the association between two single-nucleotide polymorphisms (SNPs) variants (rs2241766 and rs1501299) of the adiponectin gene (ADIPOQ) and polycystic ovary syndrome (PCOS) in PCOS family trios. DESIGN Family-based study. SETTING University hospital. PATIENT(S) A total of 224 unrelated PCOS probands, their biologic parents, and 204 control subjects. INTERVENTION(S) Anthropometric, hormonal, and metabolic assessment; genotype detection. MAIN OUTCOME MEASURE(S) Basic endocrine, serum fasting glucose (FG), fasting insulin (FINS), total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels were measured. The transmission disequilibrium test (TDT) was used to analyze the association between two SNPs of ADIPOQ and PCOS. RESULT(S) A significant positive association was detected between SNP rs1501299 and PCOS. Compared with AA genotype, AC and CC genotypes had increased risk for PCOS, and the difference remained significant after adjustment for age, body mass index, and testosterone (T). The levels of T, TG, HDL cholesterol, and FINS were significantly higher in obese PCOS patients. However, we failed to find significant overtransmission of the other SNP, rs2241766, from parents to PCOS offspring. The genotype frequencies of rs2241766 and rs1501299 were not different in obese and lean PCOS patients and their parents. CONCLUSION(S) TDT confirms that SNP rs1501299 in the ADIPOQ is significantly associated with the risk of PCOS in the Chinese Han population. The present data may provide a basis for further studies of the role of the ADIPOQ in the etiology of PCOS.

Obstetric complications after frozen versus fresh embryo transfer in women with polycystic ovary syndrome: results from a randomized trial

OBJECTIVE To evaluate the effect of frozen embryo transfer on maternal and neonatal complications of singleton and twin pregnancies compared with fresh embryo transfer in women with polycystic ovary syndrome (PCOS). DESIGN A secondary analysis of a multicenter, randomized, controlled trial comparing live birth after frozen vs. fresh embryo transfer (FreFro-PCOS). SETTING Reproductive medicine centers. PATIENT(S) A total of 1,508 patients with a diagnosis of PCOS who were undergoing IVF were enrolled. INTERVENTION(S) On day of oocyte retrieval, eligible patients were randomized to the fresh or frozen embryo transfer groups. Up to two embryos were transferred in both groups. All pregnancies were followed up until delivery. MAIN OUTCOME MEASURE(S) Gestational diabetes mellitus, pre-eclampsia, preterm birth, small for gestational age, and large for gestational age. RESULT(S) The risks of gestational diabetes mellitus, preterm birth, and small for gestational age were comparable between the frozen and fresh embryo transfer groups in both singleton and twin births. However, singleton infants born after frozen embryo transfer were more likely to be large for gestational age (25.2% vs. 17.5%; relative risk 1.44, 95% confidence interval 1.01-2.07, P=.044) than those born after fresh embryo transfer. Twin pregnancy after frozen embryo transfer had a higher risk of pre-eclampsia (12.0% vs. 2.8%; relative risk 4.31, 95% confidence interval 1.27-14.58, P=.009) than those after fresh embryo transfer. CONCLUSION(S) In women with PCOS, frozen embryo transfer resulted in an increased risk of large for gestational age in singleton pregnancy and a higher risk of pre-eclampsia in twin pregnancy. CLINICAL TRIAL REGISTRATION NUMBER NCT01841528.

Younger poor ovarian response women achieved better pregnancy results in the first three IVF cycles

This retrospective cohort study observed the live birth rates as well as cumulative live birth rates in women with poor ovarian response (POR) undergoing IVF-embryo transfer treatment, stratified for age and cycle number. Four hundred and one patients with POR diagnosed according to the Bologna criteria were enrolled and 700 IVF-ET cycles were analysed. The overall live-birth rate per cycle was 18.3%. From cycle 1 up to cycle 3, the live-birth rates decreased significantly from 22.2% to 11.1%. The live-birth rate fell to 2.4% in cycles 4 and over. When age advanced, the live birth rates decreased obviously (P < 0.01): 30.0% for women < 35 years old, 17.0% for those 35-40 years old, and 9.0% for women older than 40 years. Similarly, the cumulative live birth rates dropped from 48.0% (< 35 years) to 16.9% (≥ 40 years) accordingly. Younger patients (< 35 years old) with POR achieved better pregnancy results compared with patients of advanced age. Extremely low live-birth rates could be anticipated after three unsuccessful cycles; therefore it may not be appropriate to suggest more IVF cycles in POR women.

Effect of Preconception Impaired Glucose Tolerance on Pregnancy Outcomes in Women With Polycystic Ovary Syndrome

Context Women with polycystic ovary syndrome (PCOS) commonly have intrinsic insulin resistance and are recommended to undergo an oral glucose tolerance test (OGTT) for diabetes screening. However, the effect of preconception impaired glucose tolerance (IGT) on pregnancy is still unclear. Objective To prospectively assess the effect of preconception IGT on pregnancy outcomes. Design, Setting, Patients, Interventions, and Main Outcome Measures This was a secondary analysis of a multicenter randomized trial in 1508 women with PCOS comparing live birth and obstetric complications between fresh and frozen embryo transfer. At baseline, fasting and 2-hour glucose and insulin levels after 75-g OGTT were measured. Results Women with preconception IGT had higher risks of gestational diabetes in both singleton pregnancy [9.5% vs 3.2%; odds ratio (OR) 3.13; 95% confidence interval (CI) 1.23to 7.69] and twin pregnancy (20.0% vs 3.2%; OR 7.69; 95% CI 2.78 to 20.00) than women with normoglycemia. Preconception IGT was associated with a higher risk of large for gestational age in singleton newborns compared with normoglycemia (34.7% vs 19.8%; OR 2.13; 95% CI 1.19 to 3.85) or isolated impaired fasting glucose (i-IFG) (34.7% vs 15.4%; OR 2.94; 95% CI 1.33 to 6.25). Women with preconception IGT had a higher singleton pregnancy loss rate than women with i-IFG (31.4% vs 17.5%; OR 2.17; 95% CI 1.11 to 4.17). After adjusting for age, body mass index, duration of infertility, total testosterone level, and treatment groups (frozen vs fresh embryo transfer), these associations remained. Conclusions Preconception IGT, independent from BMI, was associated with adverse pregnancy outcome compared with i-IFG and normoglycemia.

Live birth after fresh versus frozen single blastocyst transfer (Frefro-blastocyst): study protocol for a randomized controlled trial

BackgroundMultiple pregnancies are one of the major safety concerns of in vitro fertilization (IVF) due to the increased risk of maternal and neonatal complications. Single embryo transfer is the most effective way to reduce the risk of multiple pregnancies. Selection of the embryo and optimization of the implantation environment are crucial to retain the success rate when the number of transferred embryos is diminished. Fresh embryo transfer with supra-physiological levels of hormones has been suggested to have an adverse effect on implantation. Elective frozen embryo transfer has been suggested to result in a higher rate of live birth than fresh embryo transfer. However, there is still a lack of evidence from randomized clinical trials comparing the efficacy and safety between frozen and fresh single blastocyst transfers.Methods/designWe are conducting a randomized controlled trial in women aged 20–35 undergoing their first cycle of IVF with or without intracytoplasmic sperm injection. After ovarian stimulation with a gonadotropin-releasing hormone antagonist protocol, women who obtain four or more embryos on day 3 of the embryo culture are randomized into two parallel groups: a single fresh blastocyst transfer group and a single frozen blastocyst transfer group (all blastocysts vitrified and a deferred frozen blastocyst transfer). The primary outcome is singleton live birth.DiscussionThe results of this study will provide evidence for the efficacy and safety of the strategy of elective frozen single blastocyst transfer in women with a good prognosis.Trial registrationChinese Clinical Trial Registry, ChiCTR-IOR-14005405. Registered on 30 Oct 2014.