Yi-Min Zhu

Overweight and obesity negatively affect the outcomes of ovarian stimulation and in vitro fertilisation: a cohort study of 2628 Chinese women

Objective. To explore the effects of overweight and obesity on the outcomes of in vitro fertilisation (IVF) in Chinese infertile patients. Study design. A retrospective cohort study was carried out in 2222 normal weight (18.5 ≤ BMI < 25), 379 overweight (25 ≤ BMI < 30) and 27 obese (BMI ≥ 30) women who underwent their first IVF cycles between 2002 and 2008. Cycle characteristics and IVF outcomes were analysed. Results. Obese women required significantly higher dose of rFSH (3272 IU vs. 2587 IU, p < 0.001) and days of stimulation (11.89 ± 4.57 vs. 10.42 ± 2.03, p < 0.001), but exhibited less oocytes retrieved and significantly lower fertilisation rate (54.1% vs. 61.1%, p < 0.001) than normal weight women. Compared with normal weight women, overweight women displayed significantly less oocytes retrieved (12.98 ± 6.91 vs. 14.49 ± 7.96, p < 0.001), lower fertilisation rate (60.8 ± 23.3 vs. 61.1 ± 23.0, p < 0.001), less cleavaged embryos (7.55 ± 4.86 vs. 8.67 ± 5.90, p < 0.001), less high-grade embryos (4.65 ± 3.96 vs. 5.59 ± 4.81, p < 0.001) and cryopreserved embryos (4.44 ± 4.55 vs. 5.49 ± 5.55, p < 0.001). All parameters of pregnancy outcomes, including pregnancy rate, miscarriage rate and live birth rate, were comparable among three groups. Conclusions. Overweight and obesity are related with impared ovarian response, and negatively affect the outcomes of IVF.

High Maternal Serum Estradiol Environment in the First Trimester Is Associated With the Increased Risk of Small-for-Gestational-Age Birth

CONTEXT There are increasing concerns that a disrupted endocrine environment may disturb the growth of the fetus. Assisted reproductive technology (ART) situates gamete/embryo in a supraphysiological estradiol (E2) environment and, thus, provides an ideal model to investigate this problem. OBJECTIVE Our objective was to investigate whether the maternal high-E2 environment in the first trimester increases the risks of low birth weight (LBW) and small-for-gestational-age (SGA) birth. METHODS In total, 8869 singletons born after fresh embryo transfer (ET) (n = 2610), frozen ET (n = 1039), and natural conception (NC) (n = 5220) and their mothers were included. Birth weight, LBW, SGA, and maternal serum E2 levels were investigated. RESULTS The mean serum E2 levels of women undergoing fresh ET at 4 and 8 weeks of gestation were significantly higher than those of the women undergoing frozen ET and the women with NC (P < .01). Serum E2 levels of women undergoing fresh ET at 4 and 8 weeks of gestation were positively correlated to those on the day of human chorionic gonadotropin (hCG) administration (r = 0.5 and r = 0.4, respectively; P < 0.01). The birth weight after fresh ET was significantly lower than that after frozen ET and NC (P < 0.01), with increased incidence of LBW and SGA (P < .05). Furthermore, in the fresh ET group, singletons of mothers with high E2 levels (≥10460 pmol/L on the day of hCG administration) had higher risks of LBW (P < .01) and SGA (P < .01) than those with low E2 levels, and maternal serum E2 level on the day of hCG administration negatively correlated with the birth weight (P < .01). CONCLUSIONS The maternal high-E2 environment in the first trimester is correlated with increased risks of LBW and SGA. Evaluation of serum E2 before ET should be adopted to reduce the possibility of high E2 exposure to gamete/embryo.

Endoplasmic reticulum stress induced by oxidative stress in decidual cells: a possible mechanism of early pregnancy loss

Early pregnancy loss (EPL) is one of the most common complications of human reproduction. Combined with our previous proteomic studies on villous and decidual tissues of EPL, we found that alterations of the proteins involved in oxidative stress (OS), unfolded protein response (UPR) and proteolysis presented a complex and dynamic interaction at the maternal-fetal interface. In the present study, we developed a cell model of OS using normal decidual cells to examine cell viability and expression levels of proteins related to endoplasmic reticulum stress (ER stress) and UPR. We found that glucose regulated protein 78 (GRP 78) and ubiquitinated proteins were significantly up-regulated in hydrogen peroxide (H2O2) treated decidual cells in a dose-dependent manner. Excessive OS could influence proper function of UPR by decreasing VCP in decidual cells, thereby leading to cell damage as well as inhibition of cell growth and activation of apoptosis. Furthermore, when pretreated with MG 132, a pharmacological inhibition of the proteasome, the H2O2 treated decidual cells became less viable and could not up-regulate the expression level of GRP 78 to resolve the protein-folding defects, which indicating that malfunction of UPR in decidual cells might aggravate the inhibitory effect of OS in decidual cells. The present results reveal that abnormal protein profiles associated with OS induced ER stress and malfunction of UPR might be involved in the development of EPL, and OS and ER stress are potential targets for pregnant care and prognosis in normal pregnancy and its disorders.

Comparison of semen quality and outcome of assisted reproductive techniques in Chinese men with and without hepatitis B.

In this study, we aimed to determine the effects of hepatitis B virus (HBV) infection on sperm quality and the outcome of assisted reproductive technology (ART). A total of 916 men (457 HBV-positive and 459 HBV-negative) seeking fertility assistance from January 2008 to December 2009 at the Womens Hospital in the School of Medicine at Zhejiang University were analysed for semen parameters. Couples in which the men were hepatitis B surface antigen (HBsAg)-seropositive were categorized as HBV-positive and included 587 in vitro fertilisation (IVF) and 325 intracytoplasmic sperm injection (ICSI) cycles from January 2004 to December 2009; negative controls were matched for female age, date of ova retrieval, ART approach used (IVF or ICSI) and randomized in a ratio of 1:1 according to the ART treatment cycles (587 for IVF and 325 for ICSI). HBV-infected men exhibited lower semen volume, lower total sperm count as well as poor sperm motility and morphology (P < 0.05) when compared to control individuals. Rates of two-pronuclear (2PN) fertilisation, high-grade embryo acquisition, implantation and clinical pregnancy were also lower among HBV-positive patients compared to those of HBV-negative patients after ICSI and embryo transfer (P < 0.05); IVF outcomes were similar between the two groups (P > 0.05). Logistic regression analysis showed that HBV infection independently contributed to increased rates of asthenozoospermia and oligozoospermia/azoospermia (P < 0.05) as well as decreased rates of implantation and clinical pregnancy in ICSI cycles (P < 0.05). Our results suggest that HBV infection in men is associated with poor sperm quality and worse ICSI and embryo transfer outcomes but does not affect the outcome of IVF and embryo transfer.

The presence and expression of the hepatitis B virus in human oocytes and embryos

BACKGROUND The objective of this study was to explore the potential for vertical transmission of hepatitis B virus (HBV) from parents to offspring via human germ cells. METHODS For study samples, 250 oocytes from hepatitis B surface antigen (HBsAg) seropositive women and 578 embryos from couples with at least one HBsAg seropositive partner were collected. HBV DNA in the nuclei of oocytes and embryos was detected by fluorescence in situ hybridization; HBsAg expression was analysed using immunofluorescence; and serum HBV DNA levels were measured by real-time PCR. The HBV infection duration of the women and the serum HBsAg status of their mothers were also examined. RESULTS HBV DNA was present in 9.6% (24/250) of oocytes and 14.4% (83/578) of embryos. Rates of HBV DNA positive embryos were similar among couples in which the woman, man or both partners were HBsAg seropositive, 13.1% (57/436), 21.3% (16/75) and 14.9% (10/67), respectively. Rates of positivity in oocytes and embryos were significantly higher in a group with high serum levels HBV DNA than in a group with lower serum levels (P= 0.004 and P= 0.002, respectively). Higher rates of oocyte positivity were found for women whose mothers were HBV infected compared with those with uninfected mothers. Expression of HBsAg was observed in 8.7% (2/28) oocytes and 14.1% (10/71) embryos (P= 0.34). CONCLUSIONS The presence of HBV DNA in human oocytes or embryos was related to the womens serum levels of HBV DNA and the infection status of their mothers. The HBV positive embryos were either maternally or paternally dependent. HBV infection may result in vertical transmission to the offspring via germ cells.

Assisted reproductive technologies impair the expression and methylation of insulin-induced gene 1 and sterol regulatory element-binding factor 1 in the fetus and placenta.

OBJECTIVE To evaluate the cholesterol metabolism linked to assisted reproductive technology (ART) by analyzing the expression levels and DNA methylation patterns of the insulin-induced gene (INSIG), sterol regulatory element-binding protein (SREBP), and SREBP cleavage-activating protein in the fetus and placenta. DESIGN Experimental research study. SETTING An IVF center, university-affiliated teaching hospital. PATIENT(S) Four patients groups were recruited: pregnancies after IVF/intracytoplasmic sperm injection (ICSI) (n = 55), natural pregnancies (n = 40), multifetal reduction after IVF/ICSI (n = 56), and multifetal reduction after controlled ovarian hyperstimulation (COH) (n = 42). INTERVENTION(S) Expression and DNA methylation of INSIG-SREBP- SREBP cleavage-activating protein in the fetus and placenta samples were determined. MAIN OUTCOME MEASURE(S) The expression and DNA methylation patterns were tested by real-time quantitative polymerase chain reaction (PCR) and pyrosequencing. RESULT(S) In the ICSI treatment group, significantly higher levels of triglycerides and apolipoprotein-B were observed in cord blood compared with controls. Meanwhile, in ICSI-conceived fetuses, the expression of INSIG1 was significantly higher, and methylation rates were lower, than in the IVF and control groups. Furthermore, in the placenta, the INSIG1 and SREBF1 transcripts were also significantly higher with lower methylation rates in the ICSI group than in the IVF and control groups. CONCLUSION(S) Our results indicated that the dysregulation of INSIG1 and SREBF1 caused by ART were observed not only in the fetus but also in the placenta, primarily in the ICSI group. However, the long-term sequelae of this dysregulation should be closely followed.

Cardiovascular Dysfunction in Offspring of Ovarian-Hyperstimulated Women and Effects of Estradiol and Progesterone: A Retrospective Cohort Study and Proteomics Analysis

CONTEXT The cardiovascular dysfunction in children born with assisted reproductive technologies has been of great concern. However, the association of ovarian hyperstimulation syndrome (OHSS), a complication of assisted reproductive technologies, with worse cardiovascular functions and underlying mechanism remains unknown. OBJECTIVES The objective of the study was to assess the cardiovascular functions of children born to mothers with OHSS and investigate the underlying regulator(s). DESIGN AND SETTING This was a retrospective cohort recruited in a university hospital. PARTICIPANTS AND METHODS We assessed the cardiovascular functions by Doppler echography in 42 children born to OHSS women, 34 children of mothers with non-OHSS in vitro fertilization, and 48 spontaneously conceived (SC) children (mean age ∼ 4.5 y). Groups were matched for gestational age at delivery and birth weight. An isobaric tag for relative and absolute quantitation-labeled proteomics analysis was performed with another set of umbilical arteries from OHSS and SC pregnancies (n = 3 for both groups). RESULTS Children of OHSS mothers showed a significantly decreased mitral ratio of early to late mitral peak velocities, reduced systolic and diastolic diameters of common carotid arteries, and impaired flow-mediated dilation compared with non-OHSS in vitro fertilization and SC children. Intima-media thickness and arterial stiffness indices were similar in the three groups. In the proteomics study, 1640 proteins were identified from OHSS and SC umbilical arteries, and 40 differentially expressed proteins were selected for further analysis. Estradiol and progesterone were identified as activated upstream regulators. CONCLUSIONS Children born to ovarian-hyperstimulated women displayed cardiovascular dysfunctions. The underlying mechanisms may involve the effects of supraphysiological estradiol and progesterone levels.

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.)

Maternal and Live-birth Outcomes of Pregnancies following Assisted Reproductive Technology: A Retrospective Cohort Study

This study was carried out to explore associations between assisted reproductive technology (ART) and maternal and neonatal outcomes compared with similar outcomes following spontaneously conceived births. We conducted a retrospective cohort study of pregnancies conceived by ART (N = 2641) during 2006–2014 compared to naturally conceived pregnancies (N = 5282) after matching for maternal age and birth year. Pregnancy complications, perinatal complications and neonatal outcomes of enrolled subjects were investigated and analysed by multivariate logistic regression. We found that pregnancies conceived by in vitro fertilization (IVF) were associated with a significantly increased incidence of gestational diabetes mellitus, gestational hypertension, preeclampsia, intrahepatic cholestasis of pregnancy, placenta previa, placental abruption, preterm premature rupture of membranes, placental adherence, postpartum haemorrhage, polyhydramnios, preterm labour, low birth weight, and small-for-date infant compared with spontaneously conceived births. Pregnancies conceived by intracytoplasmic sperm injection (ICSI) showed similar elevated complications, except some of the difference narrowed or disappeared. Singleton pregnancies or nulliparous pregnancies following ART still exhibited increased maternal and neonatal complications. Therefore, we conclude that pregnancies conceived following ART are at increased risks of antenatal complications, perinatal complications and poor neonatal outcomes, which may result from not only a higher incidence of multiple pregnancy, but also the manipulation involved in ART processes.

Auricular Acupressure Reduces Anxiety Levels and Improves Outcomes of in Vitro Fertilization: A Prospective, Randomized and Controlled Study

The study was to explore whether auricular acupressure (AA) can relieve anxiety during the period from trans-vaginal oocyte retrieval to the embryo transfer in IVF treatment and whether AA can improve the outcomes of IVF. 305 infertile patients with tubal blockage who were referred for IVF were included. The women were randomized into a control group with 102 cases, a Sham-AA group with 102 cases and an AA group with 101 cases. The anxiety levels were rated with Spielbergers State Trait Anxiety Inventory and the Amsterdam Preoperative Anxiety and Information Scale. Data of clinical pregnancy rate (CPR), implantation rate (IR) and live birth rate (LBR) were obtained. The levels of neuropeptide Y (NPY) and transforming growth factor alpha (TGF-alpha) in the follicular fluids were detected with ELISA. After treatment, in AA group, the levels of state anxiety, preoperative anxiety and need-for-information were significantly lower, whereas CPR, IR, LBR and NPY levels in the follicular fluids were markedly higher than Sham-AA group and control group. We concluded that AA could help to reduce anxiety levels associated with IVF and improves the outcomes of IVF partly through increasing the levels of NPY in the follicular fluids.