Misdiagnosis and Delayed Diagnosis for Ectopic and Heterotopic Pregnancies after In Vitro Fertilization and Embryo Transfer

This study examined the misdiagnosis and delayed diagnosis factors for ectopic pregnancy（EP） and heterotopic pregnancy（HP） after in vitro fertilization and embryo transfer（IVF-ET） in an attempt to reduce the diagnostic error. Clinical data of patients who underwent IVF-ET treatment and had clinical pregnancy from 12463 cycles were retrospectively analyzed. Their findings of serum β-hCG test and transvaginal ultrasonography were also obtained during follow-up. These patients were divided into two groups according to the diagnosis accuracy of EP/HP： early diagnosis and misdiagnosis/delayed diagnosis. The results showed that the incidence of EP and HP was 3.8%（125/3286） and 0.8%（27/3286） respectively for IVF/ICSI-ET cycle, and 3.8%（55/1431） and 0.7%（10/1431） respectively for frozen-thawed embryo transfer（FET） cycle. Ruptured EP occurred in 28 patients due to initial misdiagnosis or delayed diagnosis. Related factors fell in 3 categories：（1） clinician factors： misunderstanding of patients＇ medical history, insufficient training in ultrasonography and unawareness of EP and HP;（2） patient factors： noncompliance with medical orders and lack of communication with clinicians;（3） complicated conditions of EP： atypical symptoms, delayed elevation of serum β-hCG level, early rupture of cornual EP, asymptomatic in early gestation and pregnancy of unknown location. All the factors were interwoven, contributing to the occurrence of EP and HP. It was concluded that complicated conditions are more likely to affect the diagnosis accuracy of EP/HP after IVF-ET. Transvaginal ultrasonography should be performed at 5 weeks of gestation. Intensive follow-up including repeated ultrasonography and serial serum β-hCG tests should be performed in patients with a suspicious diagnosis at admission.

Quick recovery and characterization of cell-free DNA in seminal plasma of normozoospermia and azoospermia： implications for non-invasive genetic utilities

We established a quick and reliable method for recovering cell-free seminal DNA （cfsDNA）, by using the binding-washing-elution procedure on the DNA purification column. Low variations （below 15%） among the triplicate values of cfsDNA quantity verified the reproducibility of our cfsDNA recovery method. Similar cfsDNA yield and size distribution between seminal plasma acquired by filtration and centrifugation confirmed the presence of cfsDNA. To investigate the general characterization of cfsDNA, the quantitation and size distribution of cfsDNA from normozoospermic and azoospermic semen were analyzed by real-time PCR and electrophoresis, respectively. CfsDNA concentration in semen with normozoospermia （n = 11） was 1.34 ± 0.65 μg ·mL^-1, whereas a higher cfsDNA concentration was observed in azoospermia （2.56 ± 1.43 μg ·mL^-1, n = 9）. The continuous distribution of DNA fragments ranging from -1 kb to 15 kb and a spectrum of multiples of 180-bp fragments were observed in each normozoospermic and azoospermic sample. Distinct characteristic DNA ladder fragmentations in some azoospermic samples implicated that cfsDNA originate partly from apoptotic cells. CfsDNAs of 36 selected azoospermic patients with known information of Y chromosome microdeletion were subjected to the same microdeletion analysis by multiplex PCR and PCR amplification of sY114 （1 450 bp）. All multiplex PCR reactions with cfsDNA amplified successfully and provided the same result as leukocyte DNA. PCR amplification of sY114 gave a 1 450-bp amplicon as expected. Our data suggested the potential use of cfsDNA in search of biomarker or diagnostic procedures.

Cumulative Live Birth Rate after Three Ovarian Stimulation IVF Cycles for Poor Ovarian Responders According to the Bologna Criteria

Summary： This study explored the cumulative live birth rate after three ovarian stimulation in vitro fer- tilization （IVF） cycles for poor ovarian responders according to the Bologna criteria. In this retrospec- tive cohort study, 479 poor ovarian responders according to the Bologna criteria in the first ovarian stimulation IVF cycle between July 2006 and January 2012 in our IVF centre were included. The cu- mulative live birth rate was calculated by optimistic and pessimistic methods. The cumulative live birth rate after three ovarian stimulation IVF cycles for poor ovarian responders according to the Bologna criteria was 12.7%-20.5%. The three-cycle cumulative live birth rate was 18.5%--24.5%, 13.2%-27.4% and 8.6%-14.9% for poor responders aged ≤35 years, 36-39 years and 〉40 years, re- spectively. In conclusion, poor responders according to the Bologna criteria can receive an acceptable cumulative live birth, rate after three ovarian stimulation IVF cycles, especially poor responders aged 〈40 years.

A Retrospective Study on the Use of High-Dose Letrozole while Undergoing Ovarian Stimulation for Oocyte and Embryo Cryopreservation in Cancer Patients

Objective: To determine the efficacy of letrozole in suppressing estradiol levels during ovarian stimulation in cancer patients. Methods: A retrospective chart review of cancer patients undergoing ovarian stimulation for fertility preservation between 2014-2019 at a private university-affiliated fertility clinic in Canada was conducted. Ovarian stimulation was completed with no letrozole (Group A, n = 10), and adjuvant daily letrozole use at 5.0 (Group B, n = 34) or 7.5 mg (Group C, n = 61). The primary outcomes were peak estradiol levels and oocyte yield. ANOVA with a post hoc two-tailed t-test assuming equal variance was utilized as a statistical method. Result(s): Patient age and AFC count were not different between groups. The yield of mature eggs was not different at each letrozole dose;9.2 ± 6.0, 13.9 ± 6.5 and 12.7 ± 7.2 for Groups A to C respectively (p = 0.18). Mean estradiol levels(pmol/L) were reduced in a dose-dependent manner;7432 ± 4553 for Group A, 2072 ± 1656 for Group B, and 1445 ±1238 for Group C (A vs. C, p vs. C, p Conclusion(s): The use of letrozole during ovarian stimulation for oocyte and embryo cryopreservation in cancer patients can maintain physiologic estradiol levels, while ensuring satisfactory oocyte and embryo yield. Letrozole can, therefore, minimize the theoretical risk of stimulating residual and metastatic diseases, while still optimizing future fertility outcomes.

Male factor infertility and ART

For years, the management and treatment of male factor infertility has been ‘experience＇ and not ‘evidence＇ based. Although not evidence-based, current clinical practice involves extensive use of assisted reproductive techniques （ART）. Where specific treatments are not indicated or have failed, ART have become popular adjunctive treatments for alleviating male factor infertility. According to the limited evidence available, intrauterine insemination （IUI） may be considered as a first-line treatment in a couple in which the female partner has a normal fertility status and at least 1 × 10^6 progressively motile spermatozoa are recovered after sperm preparation. If no pregnancy is achieved after 3-6 cycles of IUI, optimized in vitro fertilization （IVF） can be proposed. When less than 0.5× 106 progressively motile spermatozoa are obtained after seminal fluid processing or sperm are recovered surgically from the testis or epididymis, intracytoplasmic sperm injection （ICSI） should be performed. Although the outcome of no other ART has ever been scrutinized as much before, no large-scale ‘macroproblems＇ have as yet been observed after ICSI. Yet, ICSI candidates should be rigorously screened before embarking on IVF or ICSI, and thoroughly informed of the limitations of our knowledge on the hereditary aspects of male infertility and the safety aspects of ART.

A Second Dose of GnRHa in Combination with Luteal GnRH Antagonist May Eliminate Ovarian Hyperstimulation Syndrome in Women with≥30 Follicles Measuring≥11 mm in Diameter on Trigger Day and/or Pre-trigger Peak Estradiol Exceeding 10 000 pg/mL

This observational study included 21 patients at remarkably high risk of ovarian hyperstimulation syndrome(OHSS),characterized by more than 30 follicles measuring≥11 mm in diameter on trigger day and/or pre-trigger peak estradiol exceeding 10 000 pg/mL.which was also the feature of women with established severe early OHSS followed by gonadotrophin-releasing hormone agonist(GnRHa)trigger and freeze-all policy that previously have been reported.All patients received a second dose of GnRHa 12 h after the first GnRHa trigger combined with administration of GnRH antagonist at 0.25 mg/day for a period of 3 days from the day of oocyte retrieval onwards.The in vitro fertilization(IVF)outcomes may be preferable compared with a bolus of GnRHa trigger and none of the included patients developed moderate-to-severe OHSS.Moreover,patients'symptoms,reproductive honnone levels and ultrasound findings were improved significantly.This new strategy seems to be efficacious and could be a further supplement of GnRHa trigger with or without applying freeze-all strategy to completely prevent early-onset moderate to severe OHSS,especially for the patients characterized by≥30 follicles measuring≥11 mm in diameter on trigger day and/or pre-trigger peak estradiol exceeding 10 000 pg/mL.Further studies should be performed to compare this regimen with conventional methods of OHSS prevention.

Outcome of Assisted Reproduction Treatment in Women with Extremely Low Antimullerian Hormone (AMH) Levels

Purpose: To evaluate age related ovarian response to controlled ovarian hyperstimulation, clinical pregnancy and ongoing pregnancy rates beyond 20 weeks in women undergoing assisted reproduction treatment (ART) with antimullerian hormone (AMH) levels of <5 pmol/l. Methods: Retrospective analysis of data from 63 women with AMH of In-vitro?fertilization, IVF and intracytoplasmic sperm injection, ICSI) cycle. Results were analyzed after dividing patients in two groups, group 1 included women of ≤38 years and group 2 > 38 years of age. Non parametric variables were expressed as median (Interquartile range) and compared by Kruskal-Wallis test. Categorical variables were expressed as numbers with proportions (%) and compared by Fisher’s exact test. Results: There was no statistical difference in body max index, level of antimullerian hormone (AMH), follicle stimulating hormone (FSH), dose of gonadotrophins used and cycles cancellation rate in two groups. Although number of oocytes retrieved (median 5), clinical pregnancy (18.4%) and ongoing pregnancy rate beyond 20 weeks (18.4%) was higher in group 1, there was no statistical difference between the two groups. There was one miscarriage in group 2. Conclusion: Women with extremely low-serum AMH levels can still have clinical pregnancy and ongoing pregnancies beyond 20 weeks after ART, though chances will be lower than women with normal ovarian reserve.

不明原因生育能力低下且妊娠预测为中等水平的夫妇在控制性超排卵下的宫内人工受精与期待疗法的疗效比较:一项随机临床试验

Background: Intrauterine insemination with controlled ovarian hyperstimulation is commonly used as first-line treatment for couples with unexplained subfertility. Since such treatment increases the risk of multiple pregnancy, a couple’s chances of achieving an ongoing pregnancy without it should be considered to identify those most likely to benefit from treatment. We aimed to assess the incremental effectiveness of intrauterine insemination with controlled ovarian hyperstimulation compared with expectant management in couples with unexplained subfertility and an intermediate prognosis of a spontaneous ongoing pregnancy. Methods: 253 couples with unexplained subfertility and a 30- 40% probability of a spontaneous ongoing pregnancy within 12 months were randomly assigned either intrauterine insemination with controlled ovarian hyperstimulation for 6 months or expectant management for 6 months. The primary endpoint of this hospital-based study was ongoing pregnancy within 6 months. Analysis was by intention to treat. This trial is registered with the Dutch Trial Register and as an International Standard Randomised Clinical Trial, number ISRCTN72675518. Findings: Of the 253 couples enrolled, 127 were assigned intrauterine insemination with controlled ovarian hyperstimulation and 126 expectant management. In the intervention group, 42 (33% ) women conceived and 29 (23% ) pregnancies were ongoing. In the expectant management group, 40 (32% ) women conceived and 34 (27% ) pregnancies were ongoing (relative risk 0.85, 95% CI 0.63- 1.1). There was one twin pregnancy in each study group, and one woman in the intervention group conceived triplets. Interpretation: A large beneficial effect of intrauterine insemination with controlled ovarian hyperstimulation in couples with unexplained subfertility and an intermediate prognosis can be excluded. Expectant management for 6 months is therefore justified in these couples.

Testosterone deficiency and treatment in older men： definition, treatment, pitfalls

Two manuscripts were recently published in the New England Journal of Medicine that relate to testosterone deficiency and treatment in older men. To many readers, both these studies will seem to be dealing with the same topic in a complementary manner： the first looks at how to define an illness and the second looks at how to treat it （or maybe not treat it）. If perceived as having stringent logical （and clinical） progression, these papers could have a major impact not only on andrology but on medicine in general.

单胚泡期与单卵裂期胚胎行体外受精的比较

BACKGROUND: Single-embryo transfer has been recommended to reduce the incidence of multiple gestations when in vitro fertilization is performed in women under 36 years of age. We designed a prospective, randomized, controlled trial to determine whether there were any differences in the rates of pregnancy and delivery between women undergoing transfer of a single cleavage-stage (day 3) embryo and those undergoing transfer of a single blastocyst-stage (day 5) embryo. METHODS: We studied 351 infertile women under 36 years of age who were randomly assigned to undergo transfer of either a single cleavage-stage embryo (176 patients) or a single blastocyst-stage embryo (175 patients). Multifollicular ovarian stimulation was performed with a gonadotropin-releasing hormone antagonist and recombinant follicle-stimulating hormone. RESULTS: The study was terminated early after a prespecified interim analysis (which included 50 percent of the planned number of patients) found a higher rate of pregnancy among women undergoing transfer of a single blastocyst-stage embryo (P = 0.02). The rate of delivery was also significantly higher in this group than in the group undergoing transfer of a single cleavage stage embryo (32.0 percent vs. 21.6 percent; relative risk, 1.48; 95 percent confidence interval, 1.04 to 2.11). Two multiple births occurred, both of monozygotic twins, both of which were in the group undergoing transfer of a single cleavage-stage embryo. CONCLUSIONS: These findings support the transfer of a single blastocyst-stage (day 5) embryo in infertile women under 36 years of age.

Functional sperm produced after spermatogonial stem ：ell transplantation into rhesus

Spermatogonial stem cell （SSC） transplantation is a promising technique to circumvent sterility in prepubertal boys undergoing gonadotoxic treatments. While the cryopreservation of spermatogonial stem cells is being introduced in clinical practices worldwide, a lot of unanswered questions remain regarding their eventual transplantation. In this paper autologous and allogeneic SSC transplantations in the testes of sterilized macaques were performed and spermatogenesis could be restored from donor SSCs. The spermatozoa obtained were competent to fertilize oocytes. This report proves the feasability of SSC transplantation in a primate model, hence reinforcing the hope that this strategy will eventually find its way into clinical practice.

Relationship between Endometriosis and Subfertility

An association between minor endometriosis and subfertility is shown by prevalence studies but a clear causal relationship has not yet been demonstrated. This review presents the evidence for pituitary-ovarian dysfunction as a cause for subfertility in women with minor endometriosis. Using tubal infertility cases as controls, group comparison has shown effects on the following: follicular growth (impaired) , preovulatory circulating oestradiol levels (reduced) and early luteal phase oestradiol and progesterone (reduced) , and LH surge patterns (disordered), preovulatory follicular fluid LH concentration (reduced) , and granulosa cell steroidogenic capacity (impaired) . However, these findings are not consistent in the literature. Compared with controls, reduced oocyte fertilisation and implantation rates are reported in natural and go-nadotrophin stimulated cycles. An inherent disorder of follicular function is possible as a cause, with LH surge impairment probably a secondary phenomenon. Natural sub-fertility is substantially disordered as a result of oocyte fertilisation impairment. However, as excess numbers of oocytes are available in bitrofertility in vitro fertility (IVF) is still successful.

另眼看全胚冷冻方案：SWOT分析

“全胚冷冻策略”是将IVF治疗程序分割开来，即用GnRH拮抗剂方案降调节、GnRH激动剂扳机、选择性玻璃化冷冻全部胚胎，并在随岳的周期中行冻融胚胎移植。该策略越来越流行，但仍然存在不足。本文采用SWOT分析（优势、劣势、机会、风险）阐述了这一策略的各个方面。

Preimplantation genetic diagnosis and the biopsy technique: Important considerations

Preimplantation genetic diagnosis allows to test the genetic status of embryos prior to implantation. In order to obtain genetic material, on which carry out a genetic diagnosis, a procedure named embryo biopsy is required. In the last two decades, embryo biopsy at the cleavage stage has been the mostly performed procedure. However, recently, alternative methods allowing the retrieval of a larger number of cells (blastocyst stage biopsy), or representing a valid alternative to overcome ethical issues (polar body biopsy) have obtained increasing consensus. This article reviews different methods of embryo biopsy and points out their positive and negative aspects.

Mental health impact on Black,Asian and Minority Ethnic populations with preterm birth:A systematic review and meta-analysis

BACKGROUND Preterm birth(PTB)is one of the main causes of neonatal deaths globally,with approximately 15million infants are born preterm.Women from the Black,Asian,and Minority Ethnic(BAME)populations maybe at higher risk of PTB,therefore,the mental health impact on mothers experiencing a PTB is particularly important,within the BAME populations.AIM To determine the prevalence of mental health conditions among BAME women with PTB as well as the methods of mental health assessments used to characterise the mental health outcomes.METHODS A systematic methodology was developed and published as a protocol in PROSPERO(CRD420-20210863).Multiple databases were used to extract relevant data.I2 and Egger's tests were used to detect the heterogeneity and publication bias.A trim and fill method was used to demonstrate the influence of publication bias and the credibility of conclusions.RESULTS Thirty-nine studies met the eligibility criteria from a possible 3526.The prevalence rates of depression among PTB-BAME mothers were significantly higher than full-term mothers with a standardized mean difference of 1.5 and a 95%confidence interval(CI)29%-74%.The subgroup analysis indicated depressive symptoms to be time sensitive.Women within the very PTB category demonstrated a significantly higher prevalence of depression than those categorised as non-very PTB.The prevalence rates of anxiety and stress among PTB-BAME mothers were significantly higher than in full-term mothers(odds ratio of 88%and 60%with a CI of 42%-149%and 24%-106%,respectively).CONCLUSION BAME women with PTB suffer with mental health conditions.Many studies did not report on specific mental health outcomes for BAME populations.Therefore,the impact of PTB is not accurately represented in this population,and thus could negatively influence the quality of maternity services they receive.

Profile of abortion in Chile, with extremely restrictive law

Chile, together with El Salvador, Malta and Nicaragua has the most restrictive abortion laws. In these countries there is very little information on pregnancies that end in abortions. An analysis is made of official information regarding hospital discharges for abortion in Chile between 2001 and 2010, classified according to age and according to the WHO ICD 10. The Chilean Ministry of Health’s Statistics Office (DEIS) collected the data. In 334,485 hospital discharges for abortion, Ectopic Abortion (O00), the Hydatidiform Mole (O01) and Other Abnormal Products of Conception (O02) corresponded to 37.2% of hospital discharges. Spontaneous Abortion (O03) reached 15% and Non Specified Abortion (O06) reached 35.5% and most probably included complications of induced abortions. 77% of hospital discharges corresponded to women between 20 and 34 years of age. Adolescents correspond to 11% of hospital discharges. In the annual average of 33,500 hospital discharges, Other Abnormal Products of Conception (O02), Other Abortions (O05), and Non Specified Abortions (O05) contribute to 72.7% of hospital discharges. This is explained by incomplete diagnoses, by means of the omission of induced abortion as this would mean jail for the woman and legal red-tape for the health personnel involved. Maternal mortality has not fallen. Abortion Mortality and Fatality rates do not change. There is a discrepancy between the law and hospital discharge diagnoses for abortion. The antiabortion law remains unheeded and obeys an ideological bias that brings damage and abuse to Chilean women. The aim of this study is to gain better information from a country that does not allow abortion under any circumstance, and its usefulness to countries in similar situations, together with its negative consequences on woman’s health and rights.

应用重组卵泡刺激素和促性腺激素释放激素拮抗剂诱发排卵的体外受精患者,卵泡期延长可导致较低的继续妊娠率

Objective To assess the effect of altering the timing of hCG administ ration on ongoing pregnancy rates in patients stimu-lated with recombinant FSH (rec-FSH ) and GnRH antagonists for IVF. Design Prospective, randomized, controlled trial . Setting Tertiary referral center. Patient(s) Four hundred thirteen patients un dergoing IVF. Intervention(s) Rec-FSH stimulation starting on day 2 of the cycl e combinedwith daily GnRH antagonist starting on day 6 of stimulation. Patients were randomized to receive 10,000 IU of hCG either as soon as at least three fol licles were ≥17 mm on ultrasound (early-hCG group, 208 patients) or 2 days lat er after this criterion was met (late-hCG group, 205 patients). Main outcome me asure(s) Ongoing pregnancy rate. Result(s) Fertilization rates and number and qu ality of embryos transferred did not differ between the two groups. However, a s ignificantly lower ongoing pregnancy rate was present in the late-hCG as compar ed with the early-hCG group (25.0%vs. 35.6%, respectively). Conclusion(s) Pro longation of the follicular phase in patients stimulated with rec-FSH and GnRH antagonists for IVF does not affect oocyte or embryo quality but is associated w ith a significantly lower ongoing pregnancy rate.

冻融后的完整胚胎与局部损伤的冻融胚胎采用激光辅助孵化技术去除坏死的卵裂球及进行选择后潜在存活能力的比较

Objective: Partially damaged frozen and thawed embryos are currently considered to have a lower viability than intact ones. This study was undertaken to compare the performance of intact frozen and thawed embryos with that of partially damaged embryos after removal of the necrotic blastomeres. Design: Observational clinical series. Setting: Private hospital. Patient(s): Three hundred twenty-six infertile couples undergoing frozen embryo transfer. Intervention(s): Removal of necrotic blastomeres from frozen-thawed human embryos. Main Outcome Measure(s): Pregnancy and implantations rates. Result(s): Outcomes of frozen embryo transfer cycles in which all embryos were fully intact (group 1) were compared with those in which all embryos have lost 1-2 blastomeres (group 2) or 3-4 blastomeres (group 3). Laser-assisted hatching was performed in all embryos, and necrotic blastomeres were removed from partially damaged embryos on this occasion. Only embryos that resumed mitotic activity after thawing were transferred. Comparable clinical pregnancy rates (PR) (38.7%, 39.6%, and 29.4%), delivery rates (34.4%, 34.0%, and 29.4%), and implantation rates (21.6%, 21.4%, and 17.2%) were obtained in groups 1, 2, and 3, respectively. Conclusion(s): The developmental potential of partially damaged frozen and thawed embryos can be equivalent to fully survived embryos if the necrotic blastomeres are removed from the partially damaged embryos and only those of them that show post-thaw cleavage are selected for transfer.

限制胚胎移植数量对多胎妊娠率的影响

To study the impact of the introduction of reimbursement of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) laboratory costs in Belgium which is linked to an embryo transfer strategy leading to prevention of multiple pregnancies. The impact on the incidence of multiple and twin pregnancy rate as well as on ongoing pregnancy rate in our centre is calculated. Study design: Observational cohort study of all patients in the first year (July 1, 2003- June 30, 2004)- since the implementation of the law and comparison of ongoing pregnancy rate and multiple pregnancy rate of our centre with Belgian data. Results: Our results of one year of IVF/ICSI since reimbursement of laboratory costs show a total conception rate of 42.2% with 29.7% ongoing pregnancies beyond 25 weeks amenorrhea. The multiple pregnancy rate was 8.5% including five monozygotic twin pregnancies. These data show an important decline of multiple pregnancy ratewhen compared to Belgian data (2002) with 24.4% multiple pregnancy rate in the year prior to reimbursement. Conclusion: The introduction of reimbursement of IVF/ICSI laboratory costs coupled to a restriction in the number of embryos for transfer has reached the goal of halving the multiple pregnancy rate since its introduction while maintaining an optimal ongoing pregnancy rate.

子宫颈根治切除术后放置Malecot导管有助于胚胎移植

Objective: To describe the use of a Malecot catheter as a stent after radical trachelectomy (RT). Design: Case report. Setting: Assisted conception unit at a teaching hospital in the United Kingdom. Patient(s): A 36-year-old woman undergoing IVF after her cervix had been excised for cervical carcinoma. Previous attempts at embryo transfer (ET) had been very traumatic and required a transmyometrial transfer on one occasion. Intervention(s): A Malecot catheter was inserted into the uterine cavity after a dilatation procedure had been performed and removed before ovarian stimulation. Main Outcome Measure(s): Ease of ET. Result(s): The subsequent ET was much more straightforward. Conclusion(s): This technique can facilitate ET after RT if the passage is found to be stenosed.