Extra-abdominal removal of placenta during cesarean section: a prospective randomized controlled trial of a novel technique.

AIM: To evaluate intraoperative and early postoperative outcomes of a novel placenta delivery technique; extra-abdominal removal vs. intra-abdominal removal of the placenta during cesarean section (CS). METHODS: A total of 210 women delivering by CS at term in a tertiary university hospital between March 2014 and January 2015 were randomized to extra-abdominal removal vs. intra-abdominal removal of the placenta. The women were randomly allocated to the extra- (group 1) or intra-abdominal removal group (group 2) according to random sampling method, where women with even and odd numbers were allocated to intra- and extra-abdominal groups, respectively. The amount of intra-abdominal hemorrhagic fluid accumulation, the duration of operation and estimated blood loss during operation were the primary outcomes. The secondary outcomes included the mean difference between pre- and post-operative hemoglobin and hematocrit levels, the mean postoperative pain score, any additional need of analgesia, postoperative bowel function, postoperative endometritis and wound infections. RESULTS: The amount of aspirated hemorrhagic fluid was significantly higher in the intra-abdominal group compared to the extra-abdominal group (34.6±22.2 mL vs. 9.4±4.8 mL, P<0.001). Mean duration of the operation, intraoperative blood loss, postoperative requirement of additional analgesia, postoperative pain scores, postoperative endometritis or wound infection, and length of hospital stay were not significantly different between the intra- and extra-abdominal placental removal groups. CONCLUSION: By extra-abdominal removal of the placenta, the accumulation of bloody fluid in the abdominal cavity is significantly less compared to the intra-abdominal removal method, which, in turn, provides avoidance of excessive mounted-gauze use, intra-abdominal manipulations, or iatrogenic trauma.

Factors affecting the outcome of "endometrial scratch" in women with recurrent implantation failure.

OBJECTIVE: To examine factors affecting the outcome of the endometrial scratch in women with recurrent implantation failure. STUDY DESIGN: A total of 57 eligible patients with a history of recurrent implantation failure underwent an endometrial biopsy in the luteal phase of the menstrual cycle in the month immediately preceding the embryo transfer cycle. The comparative group consisted of a retrospective cohort of 66 women with recurrent implantation failure but without endometrial biopsy. There were no significant differences between the intervention and control groups in terms of age, follicle-stimulating hormone (FSH), free androgen index, anti-Müllerian hormone, body mass index, the number of embryos transferred, and the number of embryo transfer cycles. RESULTS: The clinical pregnancy rate in the intervention group (53%) was significantly (p < 0.001) higher than that of the control group (15%). The only predictive factor was FSH. Women with FSH < or =10 IU/L had a pregnancy rate of 57.8%, significantly (p < 0.05) higher than that (20%) of women with FSH >10 IU/L. CONCLUSION: Women with a normal FSH are more likely to derive benefit from endometrial scratch.

Sequential (hFSH + recFSH) vs homogenous (hFSH or recFSH alone) stimulation: clinical and biochemical (cumulus cell gene expression) aspects.

FSH is a key hormone in the regulation of follicular development. Together with the EGF network, these molecules mediate oocyte maturation and competence in preparation for the action of LH. FSH isoforms regulate distinct biological pathways and have specific effects on granulosa cell function and maturation of the ovarian follicle. Their dynamic interactions occur during the follicular cycle; short-living forms are predominant in the pre-ovulatory phase, whereas long-acting molecules characterize the luteal-follicular transition. Recombinant FSH (rFSH) molecules have a reduced number of isoforms and are less acidic, with a shorter half-life. We have investigated sequential stimulation, comparing hFSH + rFSH, vs. rFSH alone and hFSH alone for the entire stimulation phase. Sequential stimulation leads to an E2 per MII oocyte ratio that is much lower than is seen during treatment with the two drugs individually. Although there is a positive tendency in favor of the sequential treatment, there was no significant difference in pregnancy rates, even taking frozen embryos into consideration. The cumulus cell transcriptome varies considerably between the treatments, although with no clear significance. When comparing pregnant vs. non-pregnant patients, in general a decrease in mRNA expression can be observed in the pregnant patients, especially in expression of folic acid receptor 1 and ovostatin 2. This indicates that material has been transferred from CC to the oocyte. However, a common observation in the literature is that variations in the transcriptome of the cumulus cells are highly dependent upon the patient genotype; the potential for applying this strategy as a basis for selecting embryos is, at the very least, questionable.

Recurrent implantation failure: definition and management.

Recurrent implantation failure refers to failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years. The failure to implant may be a consequence of embryo or uterine factors. Thorough investigations should be carried out to ascertain whether there is any underlying cause of the condition. Ovarian function should be assessed by measurement of antral follicle count, FSH and anti-Mu¨llerian hormone. Increased sperm DNA fragmentation may be a contributory cause. Various uterine pathology including fibroids, endometrial polyps, congenital anomalies and intrauterine adhesions should be excluded by ultrasonography and hysteroscopy. Hydrosalpinges are a recognized cause of implantation failure and should be excluded by hysterosalpingogram; if necessary, laparoscopy should be performed to confirm or refute the diagnosis. Treatment offered should be evidence based, aimed at improving embryo quality or endometrial receptivity. Gamete donation or surrogacy may be necessary if there is no realistic chance of success with further IVF attempts.

Globozoospermia is mainly due to DPY19L2 deletion via non-allelic homologous recombination involving two recombination hotspots.

To date, mutations in two genes, SPATA16 and DPY19L2, have been identified as responsible for a severe teratozoospermia, namely globozoospermia. The two initial descriptions of the DPY19L2 deletion lead to a very different rate of occurrence of this mutation among globospermic patients. In order to better estimate the contribution of DPY19L2 in globozoospermia, we screened a larger cohort including 64 globozoospermic patients. Twenty of the new patients were homozygous for the DPY19L2 deletion, and 7 were compound heterozygous for both this deletion and a point mutation. We also identified four additional mutated patients. The final mutation load in our cohort is 66.7% (36 out of 54). Out of 36 mutated patients, 69.4% are homozygous deleted, 19.4% heterozygous composite and 11.1% showed a homozygous point mutation. The mechanism underlying the deletion is a non-allelic homologous recombination (NAHR) between the flanking low-copy repeats. Here, we characterized a total of nine breakpoints for the DPY19L2 NAHR-driven deletion that clustered in two recombination hotspots, both containing direct repeat elements (AluSq2 in hotspot 1, THE1B in hotspot 2). Globozoospermia can be considered as a new genomic disorder. This study confirms that DPY19L2 is the major gene responsible for globozoospermia and enlarges the spectrum of possible mutations in the gene. This is a major finding and should contribute to the development of an efficient molecular diagnosis strategy for globozoospermia.

Intravenous calcium infusion as a novel preventive therapy of ovarian hyperstimulation syndrome for patients with polycystic ovarian syndrome.

OBJECTIVE: To evaluate the effectiveness of IV calcium infusion on prevention of ovarian hyperstimulation syndrome (OHSS) in patients with polycystic ovary syndrome undergoing assisted reproductive techniques cycles. DESIGN: A retrospective comparative study. SETTING: Assisted reproduction techniques centre in Turkey. PATIENT(S): Four hundred fifty-five women with high risk for OHSS. INTERVENTION(S): The patients in group I (n = 84) were administered IV calcium gluconate for prevention of OHSS, and the patients in group II (n = 371) comprised the control group, with no manipulation for prevention of OHSS and were age- and body mass index-matched with the study group. MAIN OUTCOME MEASURE(S): Ovarian hyperstimulation syndrome rate, clinical pregnancy rate. RESULT(S): Mean (±SD) ages of the women in the calcium infusion group (group I) and the control group (group II) were comparable (30.5 ± 4.3 vs. 31.4 ± 3.9, respectively). Ovarian hyperstimulation syndrome was found in 16.2% (60 patients) in group II, whereas in group I, only 3 patients (3.6%) developed OHSS. Interestingly, all the hyperstimulation cases in group I were mild, and there was no severe effect. Implantation rates were similar in both groups. Furthermore, we obtained clinical pregnancy in nearly 40.5% in group I and 28.8% in group II. The live-birth rate was 38.1% in the calcium infusion group and 24.8% in the control group. CONCLUSION(S): Intravenous calcium infusion resulted in a significantly lower rate of development of OHSS for patients with polycystic ovary syndrome and high risk of OHSS. This novel therapy may be used for prevention of OHSS effectively.

Zinc concentrations in serum and follicular fluid during ovarian stimulation and expression of Zn2+ transporters in human oocytes and cumulus cells.

Serum and follicular fluid zinc concentrations were investigated in patients undergoing assisted reproductive treatment. No correlation was found between zinc and oestradiol concentrations in serum. At the time of oocyte retrieval, zinc concentrations in follicular fluid were significantly lower than serum concentrations (P<0.0001). The expression of the two families of zinc transporters, ZnT and ZiP, as well as the metal regulatory transcription factors, MTF1 and 2, and metallothioneins, which are both involved in regulatory aspects of zinc transport, was assayed in cumulus cells and in germinal-vesicle oocytes. Most of the zinc transporters, metallothioneins and metal regulatory transcription factor are expressed in oocytes and not in cumulus cells. This may indicate an important role for zinc, in particular with potential linking to genome stability during early embryonic development. In contrast, cumulus cells seem to be at the end of their life's journey, with weak expression of transcriptional activity linked to cellular housekeeping.

Successful birth following transfer of frozen-thawed embryos produced from in-vitro matured oocytes.

It is well established that ovarian hyperstimulation syndrome (OHSS) is more frequent in patients with polycystic ovarian syndrome. In-vitro maturation (IVM) of immature oocytes presents a potential alternative for the fertility treatment and prevention of OHSS for these patients. This report describes the case of a 26-year old woman with a successful pregnancy and delivery following the transfer of frozen-thawed embryos derived from in-vitro matured oocytes. She had three failed cycles of ovarian stimulation (using low-dose step-up gonadotrophin protocol) with or without intrauterine insemination cycles, an ovulation-induction cycle with luteal long protocol, two fresh IVM cycle and one frozen-thawed IVM cycle. During the IVF cycle, she developed moderate OHSS and required hospitalization for 3 weeks. Following four unsuccessful IVF or IVM cycles, 15 months after the last cryopreservation, six fertilized oocytes were thawed for a scheduled embryo transfer. Following thawing, four fertilized oocytes survived and cleaved. Four frozen-thawed embryos were transferred. Six weeks after embryo transfer an ongoing intrauterine single pregnancy with fetal heartbeat was confirmed by transvaginal ultrasound. An uneventful pregnancy and delivery via Caesarean section at 39 weeks resulted in the birth of a normal healthy infant.

Comparison of microdose flare-up and antagonist multiple-dose protocols for poor-responder patients: a randomized study.

OBJECTIVE: To compare the efficacy of the microdose flare-up and multiple-dose antagonist protocols for poor-responder patients in intracytoplasmic sperm injection-ET cycles. DESIGN: A randomized, prospective study. SETTING: Center for assisted reproductive technology in Turkey. PATIENT(S): Ninety patients with poor ovarian response in a minimum of two previous IVF cycles. INTERVENTION(S): All women were prospectively randomized into two groups by computer-assisted randomization. The patients in group 1 were stimulated according to the microdose flare-up protocol (n = 45), while the patients in group 2 were stimulated according to antagonist multiple-dose protocol (n = 45). MAIN OUTCOME MEASURE(S): The mean number of mature oocytes retrieved was the primary outcome measure, and fertilization rate, implantation rate per embryo, and clinical pregnancy rates were secondary outcome measures. RESULT(S): The mean age of the women, the mean duration of infertility, basal FSH level, and the number of previous IVF cycles were similar in both groups. The total gonadotropin dose used was significantly higher in group 2, while the number of oocytes retrieved was significantly greater in group 1. Although the fertilization and clinical pregnancy rates were nonsignificantly higher in group 1 compared with group 2, the implantation rate was significantly higher in the microdose flare-up group than in the multiple-dose antagonist group (22% vs. 11%). CONCLUSION(S): The microdose flare-up protocol seems to have a better outcome in poor-responder patients, with a significantly higher mean number of mature oocytes retrieved and higher implantation rate.

Preserving fertility before assisted reproduction in women with endometrial carcinoma: case report and literature review.

Fertility-preserving treatment with progestin may be considered in nulliparous women with well-differentiated endometrial carcinoma. Recently, assisted reproductive treatments have been performed to achieve a rapid pregnancy in such cases. This report evaluates a 39-year-old woman who admitted with menorrhagia and primary infertility. Owing to persistent menstrual irregularity and thick endometrium, a diagnostic office hysteroscopy with endometrial biopsy was performed and revealed a well-differentiated adenocarcinoma. Although the woman wished to retain her childbearing potential with conservative management followed by an assisted reproduction cycle, the repeated endometrial biopsies during progestin treatment revealed persistent adenocarcinoma. Complementary surgery was performed due to persistent endometrial malignancy, which noted well-differentiated endometrioid adenocarcinoma without myometrial invasion or extrauterine disease. A review of cases with endometrial carcinoma that have been treated with conservative management and a subsequent assisted cycle is also presented here. To date, there are 14 such reports, including 15 women and 21 healthy infants. However, obtaining remission and maintaining the reproductive capability may not always be possible, even in early-stage cases. Therefore, patient and physician should always consider carefully if fertility-preserving management is preferred after diagnosis of endometrial carcinoma.

Regional clinical practice patterns in reproductive endocrinology: a collaborative transnational pilot survey of in vitro fertilization programs in the Middle East.

BACKGROUND: This research describes current clinical and demographic features sampled from reproductive endocrinology programs currently offering in vitro fertilization (IVF) in the Middle East. METHODS: Clinic leadership provided data via questionnaire on patient demographics, demand for IVF services, annual cycle volume, indications for IVF, number of embryos transferred, twinning frequency, local regulations governing range of available adjunct therapies, time interval between initial enrollment and beginning IVF as well as information about other aspects of IVF at each center. RESULTS: Data were received from representative IVF clinics (n = 13) in Cyprus, Egypt, Iran, Israel, Jordan, Lebanon, Qatar, Saudi Arabia and Turkey. Mean (+/- SD) age of respondents was 47.8 +/- 8 yrs, with average tenure at their facility of 11.2 +/- 6 yrs. Estimated total number of IVF programs in each nation responding ranged from 1 to 91. All respondents reported individual participation in accredited CME activity within 24 months. 76.9% performed embryo transfers personally; blastocyst transfer was available at 84.6% of centers. PGD was offered at all sites. In this population, male factor infertility accounted for most IVF consultations and the majority (59.1%) of female IVF patients were < 35 yrs of age. Prevalence of smoking among female IVF patients was 7.2%. Average number of embryos transferred was 2.4 (+/- 0.4) for patients at age < 35 yrs, and 2.9 (+/- 0.8) at age > 41 yrs. For these age categories, twinning (any type) was observed in 22.6 (+/- 10.8)% and 13.7 (+/- 10.4)%, respectively. In 2005, the average number of IVF cycles completed at study sites was 1194 (range 363-3500) and 1266 (range 263-4000) in 2006. Frozen embryo transfers accounted for 17.2% of cycles at these centers in 2005. Average interval between initial enrollment and IVF cycle start was 8 weeks (range 0.3-3.5 months). CONCLUSION: This sampling of diverse IVF clinics in the Middle East, believed to be the first of its kind, identified several common factors. Government registry or oversight of clinical IVF practice was limited or nonexistent in most countries, yet number of embryos transferred was nevertheless fairly uniform. Sophisticated reproductive health services in this region are associated with minimal delay (often < 8 weeks) from initial presentation to IVF cycle start. Most Middle East nations do not maintain a comprehensive IVF database, and there is no independent agency to collect transnational data on IVF clinics. Our pilot study demonstrates that IVF programs in the Middle East could contribute voluntarily to collaborative network efforts to share clinical data, improve quality of care, and increase patient access to reproductive services in the region.

Aphasia: an early uncommon complication of ovarian stimulation without ovarian hyperstimulation syndrome.

Thromboembolic disease associated with assisted reproductive techniques is extremely rare. A 21-year-old woman with primary infertility underwent an ovulation induction cycle with luteal long protocol. Twenty-four hours following oocyte retrieval, the patient complained of difficulty in speaking. On neurological examination, mild disorientation, motor aphasia, and right-sided hypoesthesia were noted. Brain computed tomography scanning without contrast revealed left parietal lob infarct. Brain magnetic resonance imaging (MRI), MRI angiography (MRA) and perfusion MRI demonstrated an occlusion of the posterior division of the left middle cerebral artery (MCA). Physical, ultrasound examinations and laboratory test evaluation failed to reveal ovarian hyperstimulation syndrome. Except for ovarian stimulation, no additional risk factors for stroke were shown. Following anticoagulation and speech therapy, the patient recovered completely within eight months. One year after the left MCA thrombosis, she conceived spontaneously and had an uncomplicated vaginal delivery of a live male infant weighing 2900 g at 38 weeks gestation. This case supports that ovulation induction and assisted reproductive techniques may be a newly recognized cause of cerebral infarction in otherwise healthy women.

Comparison of the effects of tibolone and estrogen therapy on hemostasis in surgical menopause: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To examine the effects of unopposed estrogen (E) and tibolone therapy on coagulation and natural anticoagulant systems in surgical menopause. DESIGN: A randomized, double-blind, placebo-controlled study. SETTING: University hospital clinic in Turkey. PATIENT(S): Ninety healthy surgically postmenopausal women. INTERVENTION(S): Ninety surgically postmenopausal women were randomized into three groups: unopposed conjugated ET (0.625 mg/d, group 1), tibolone (2.5 mg/d, group 2), and identical tablets of placebo (group 3). MAIN OUTCOME MEASURE(S): Effects on parameters in the clotting cascade at baseline and after 24 weeks of treatment. RESULT(S): After 6 months, fibrinogen, lipoprotein (a), and factor VIIa were decreased, and activated partial thromboplastin time was increased significantly in the ET group compared with in the placebo group. However, tibolone significantly decreased only the serum levels of factor VIIa and factor IX and prolonged the activated partial thromboplastin time, compared with placebo group. In addition, conjugated ET caused a significantly greater decrease in serum fibrinogen level than did tibolone. CONCLUSION(S): Neither E nor tibolone therapy led to activation of coagulation in the surgically menopausal women. Both preparations changed the overall hemostatic balance to a more fibrinolytic state.

Effect of endometrioma cystectomy on IVF outcome: a prospective randomized study.

The study was conducted to investigate the effect of conservative surgery of ovarian endometriomas before an ICSI cycle. Ninety-nine patients with endometriomas who were referred to an intracytoplasmic sperm injection (ICSI) cycle were enrolled in the study. The patients were prospectively randomized into two groups; group I (49 patients) underwent conservative ovarian surgery before the ICSI cycle and group II (50 patients) underwent the ICSI cycle directly. The stimulation was started 3 months after the operation in group I and directly in group II. In the ovarian surgery group, stimulation was significantly longer (14.0 days in group I and 10.8 days in group II; P = 0.001), total recombinant FSH dose was significantly higher (4575 IU in group I and 3675 IU in group II; P = 0.001), and mean number of mature oocytes was significantly lower (7.8 in group I and 8.6 in group II; P = 0.032). There was no difference in terms of fertilization (86% in group I and 88% in group II), implantation (16.5% in group I and 18.5% in group II) and pregnancy rates (34% in group I and 38% in group II). Ovarian surgery resulted in longer stimulation, higher FSH requirement and lower oocyte number, but fertilization, pregnancy and implantation rates did not differ between the groups.

Use of laser-assisted intracytoplasmic sperm injection (ICSI) in patients with a history of poor ICSI outcome and limited metaphase II oocytes.

In this study, laser-assisted intracytoplasmic sperm injection (ICSI) improved the fertilization rate and the embryo quality in patients with a history of poor ICSI outcome and with limited metaphase II oocytes. This technique is less traumatic to the oocytes during the procedure, and the use of the technique may be expanded.

Why and how should multiple pregnancies be prevented in assisted reproduction treatment programmes?

Although most professional societies have issued guidelines to diminish the number of embryos to be transferred during assisted reproductive techniques, the incidence of multiple pregnancies remains unacceptably high. The burden of morbidity and mortality seems to increase substantially with each fetus in a multiple gestation. As a result, there has been growing debate on the need to prevent multiple pregnancies. The infertility specialists who can solve the infertility problem are usually shielded from the complications of multiple pregnancies. If they were involved in the delivery and, more particularly in the care of multiple pregnancies (both financially and socially), their attitude would probably change. IVF centres should gradually reduce the mean number of embryos per transfer in terms of the cost:benefit ratio. A further reduction to one single embryo per transfer in good cases would be similarly acceptable. Laboratory expertise is of vital importance, especially in terms of embryo culture, embryo selection, and freezing and thawing techniques in embryo transfer programmes for reducing the number of transferred embryos.

Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure.

The study was conducted to evaluate if the diagnosis and treatment of intrauterine lesions with office hysteroscopy is of value in improving the pregnancy outcome in patients with recurrent in-vitro fertilization and embryo transfer failure. Four hundred and twenty-one patients who had undergone two or more failed IVF-embryo transfer cycles were prospectively randomized into two groups. Group I (n = 211) did not have office hysteroscopic evaluation, Group II (n = 210) had office hysteroscopy. The patients who had normal hysteroscopic findings were included in Group IIa (n = 154) and patients who had abnormal hysteroscopic findings were included in Group IIb (n = 56). Intrauterine lesions diagnosed were operated during the office procedure. Fifty-six (26%) patients in Group II had intrauterine pathologies and the treatment was performed at the same time. No difference existed in the mean number of oocyte retrieved, fertilization rate, number of embryos transferred or first trimester abortion rates among the patients in groups. Clinical pregnancy rates in Group I, Group IIa and Group IIb were 21.6%, 32.5% and 30.4% respectively. There was a significant difference in the clinical pregnancy rates between patients in Group I and Group IIa (21.6% and 32.5%, P = 0.044, respectively) and Group I and Group IIb (21.6% and 30.4%, P = 0.044, respectively). There was no significant difference in the clinical pregnancy rate of patients in Groups IIa and IIb. Patients with normal hysterosalpingography but recurrent IVF-embryo transfer failure should be evaluated prior to commencing IVF-embryo transfer cycle to improve the clinical pregnancy rate.

Twin pregnancy after ICSI in a patient with ovarian cancer complicated with maternal hepatitis C: case report.

Fertility sparing surgery was carried out for an epithelial ovarian cancer patient. After adjuvant chemotherapy, she underwent assisted reproduction and gave birth to twins. She was given alpha-Interferon therapy for hepatitis C during pregnancy.

Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial.

BACKGROUND: This study aims to evaluate the impact of metformin on ovarian response when co-administered during recombinant (r)FSH using the low-dose step-up protocol in clomiphene citrate-resistant polycystic ovarian syndrome (PCOS) patients with normal glucose tolerance. METHODS AND RESULTS: Thirty-two patients were randomized to metformin (n = 16) and placebo (n = 16) groups. Hormonal assessment, a 75 g oral glucose tolerance test (OGTT) and a frequently sampled i.v. glucose tolerance test (FSIGTT) were performed before and after oral administration of metformin (850 mg twice daily) or placebo for 6 weeks. Recombinant FSH treatment was undertaken, thereafter, in women who did not ovulate on metformin (n = 10) or placebo (n = 15). There was no significant change in all insulin sensitivity indices in both groups. The only change noted was a decline in mean serum free testosterone concentration in the metformin group (P = 0.049). One patient on placebo and six patients on metformin ovulated spontaneously (P < 0.05). All parameters of ovarian response were comparable between the two groups during rFSH treatment. Combining the 6 week placebo or metformin-only period with a single rFSH treatment cycle, the overall ovulation rates were 75 and 94% in the placebo and metformin groups respectively (P > 0.05). The respective figures for pregnancy were 6.3 and 31.3% (P > 0.05). CONCLUSIONS: Metformin may restore ovulation with no improvement on insulin resistance in clomiphene citrate-resistant PCOS patients with normal glucose tolerance, but has no significant effect on ovarian response during rFSH treatment.