Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.

BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB). OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA). SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles. SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB. MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75). AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures.

The aim of this review was to summarize previously published classifications for ovarian hyperstimulation syndrome (OHSS), as well as to analyse the available methods for preventing OHSS. Withholding hCG and cycle cancellation--once the main methods of preventing OHSS--are now seldom used. There is a growing body of evidence to support the use of coasting to prevent OHSS, without cycle cancellation. However, most studies on coasting are retrospective, and well-designed prospective randomized studies are lacking. There is no current consensus as to how coasting should be carried out. A serum estradiol level of 3000 pg/ml is generally considered optimum for administration of hCG. It appears that intravenous albumin or hydroxyethyl starch at the time of oocyte retrieval is beneficial in preventing OHSS, but does not offer complete protection. There is insufficient evidence to support routine cryopreservation of all embryos for the later transfer of frozen-thawed embryos in high-risk patients. Several uncontrolled studies have reported the protective effect of GnRH agonist to trigger ovulation in preventing OHSS, though the method is applicable solely for gonadotrophin-only or GnRH antagonist cycles. A single dose of recombinant LH to trigger ovulation significantly reduced OHSS as compared with hCG. The possible role of GnRH antagonist protocols in reducing the incidence of OHSS is debatable. The above measures to prevent OHSS were successful in reducing the incidence of the syndrome, but complete prevention is not as yet possible.

Optimizing the embryo transfer technique.

The technique of embryo transfer is very crucial and great attention and time should be given to this step. In order to optimize the embryo transfer technique, several precautions should be taken. The first and most important is to avoid the initiation of uterine contractility. This can be achieved by the use of soft catheters, gentle manipulation and by avoiding touching the fundus. Secondly, proper evaluation of the uterine cavity and utero-cervical angulation is very important, and can be achieved by performing dummy embryo transfer and by ultrasound evaluation of the utero-cervical angulation and uterine cavity length. Another important step is the removal of cervical mucus so that it does not stick to the catheter and inadvertently remove the embryo during catheter withdrawal. Finally, one has to be absolutely sure that the embryo transfer catheter has passed the internal cervical os and that the embryos are delivered gently inside the uterine cavity.

Spontaneous intrauterine pregnancy following salpingectomy for a unilateral hydrosalpinx.

The effect of salpingectomy for unilateral hydrosalpinx with a contralateral normal tube was evaluated in two infertile patients in which unilateral hydrosalpinx, visualized by vaginal ultrasound, was treated by unilateral salpingectomy as a preparatory step before IVF. Spontaneous pregnancy occurred in both patients while waiting to be enrolled in an IVF trial. In conclusion, unilateral salpingectomy for hydrosalpinx in the presence of a contralateral healthy tube could result in spontaneous pregnancy.

Transfer of zona-free embryos improves outcome in poor prognosis patients: a prospective randomized controlled study.

Assisted zona hatching (AZH) has been used in IVF programmes for several years. Recently one group has reported successful pregnancies after transfer of zona-free blastocysts. The aim of our study was to evaluate outcomes after transfer of zona-free day 3 embryos. Two groups of women undergoing intracytoplasmic sperm injection (ICSI) were included in the study. Group A consisted of 52 women under the age of 40 years undergoing their first ICSI attempt. They were alternately randomized to receive zona-free embryos (27 women) and zona-intact embryos (25 women). The second group (group B) included 71 women with a poor prognosis, as defined by age 40 years or more, and/or at least two previous failed IVF/ICSI attempts. They were randomized in a 3:4 ratio (30 zona-free, 41 zona-intact). Acid Tyrode's solution was used to remove the zona pellucida before embryo transfer on day 3 after oocyte collection. The pregnancy rate in group A was not significantly improved when the zona pellucida was removed. However, in the poor prognosis group B, zona removal resulted in a significantly higher pregnancy rate when compared with controls (23 versus 7.3%). We conclude that complete removal of the zona pellucida can improve pregnancy rates in women with poor IVF/ICSI prognosis.

Elevated levels of interleukin-2, soluble interleukin-2 receptor alpha, interleukin-6, soluble interleukin-6 receptor and vascular endothelial growth factor in serum and ascitic fluid of patients with severe ovarian hyperstimulation syndrome.

OBJECTIVE: To investigate the possible role of vascular endothelial growth factor, interleukin-2, soluble interleukin-2 receptor alpha, interleukin-6 and soluble interleukin-6 receptor in the pathogenesis of ovarian hyperstimulation syndrome. STUDY DESIGN: The study group consisted of 10 healthy women who developed severe ovarian hyperstimulation syndrome, group A (n=10), following ovarian stimulation by long GnRHa/hMG protocol for IVF. A control group B=10 patients underwent stimulation with the same protocol and did not develop OHSS. Blood and ascitic fluid samples were assayed for VEGF, IL-2, sIL-2Ralpha, IL-6 and sIL-6R by ELISA. RESULTS: The mean serum levels of IL-2, sIL-2Ralpha, IL-6, sIL-6R and VEGF in OHSS group were 297.5+/-190, 6588+/-5566, 40.6+/-16.6, 5280+/-3326 and 492+/-165 pg/ml as compared to 50.8+/-17.4, 1100+/-391.6, 8.5+/-3.5, 516+/-342 and 167+/-31.3 pg/ml in the control group, respectively, P<0.001. The mean ascitic fluid IL-2, sIL-2Ralpha, IL-6, sIL-6R and VEGF in the OHSS group were 282.5+/-191.5 pg/ml, 26020+/-13 995, 90.5+/-36, 14900+/-2789 and 660+/-359 pg/ml as compared to 32+/-14.8, 1206+/-429.4, 12.6+/-1.7, 614+/-240 and 151+/-20.5 pg/ml, respectively, P<0.001. CONCLUSIONS: The significantly high levels of VEGF in patients with severe OHSS suggest that VEGF is a major capillary permeability agent in OHSS. Elevated levels of IL-6 in serum and peritoneal fluid support the hypothesis that IL-6 may serve as a marker of OHSS. Although serum and ascitic fluid levels of IL-2 were elevated, accumulating evidence does not support a pivotal role for IL-2 in the pathogenesis of OHSS. However, it may have a peripheral role in mediating an increase in vascular permeability. Soluble IL-2Ralpha and sIL-6R may be considered to be involved in OHSS. However, the patho-physiologic mechanism is the subject of further investigations. Clinical application of VEGF-receptors in the management of OHSS is awaited with interest.

Management of long-standing unexplained infertility: A prospective study.

OBJECTIVE: Our purpose was to evaluate a protocol for the management of long-standing unexplained infertility. STUDY DESIGN: A prospective study was conducted at an in vitro fertilization-embryo transfer center with 485 patients with the diagnosis of long-standing unexplained infertility. Patients were treated by means of controlled ovarian hyperstimulation and intrauterine insemination for a maximum of 3 cycles. Those who did not become pregnant underwent in vitro fertilization and intracytoplasmic sperm injection on sibling oocytes. RESULTS: Among 485 patients, 921 cycles of controlled ovarian hyperstimulation and intrauterine insemination were performed. The pregnancy rate was 15.7% per cycle and 29.8% per patient. Among those who did not become pregnant, 131 patients underwent in vitro fertilization and intracytoplasmic sperm injection into sibling oocytes; 48 women became pregnant (36.7%). There was total failure of the in vitro fertilization oocytes in 23 cycles (17.6%). CONCLUSION: Management of long-standing unexplained infertility with controlled ovarian hyperstimulation and intrauterine insemination resulted in a reasonable pregnancy rate. Treatment by means of in vitro fertilization and intracytoplasmic sperm injection into sibling oocytes among patients who did not become pregnant resulted in a good pregnancy rate. The overall results showed that the proposed protocol for management of unexplained infertility is satisfactory.

Multifetal pregnancy reduction: modification of the technique and analysis of the outcome.

OBJECTIVE: To modify the technique of multifetal pregnancy reduction and to study the outcome of reduced twins in comparison with nonreduced twins and high-order multiple gestations. DESIGN: Prospective controlled study. SETTING: The Egyptian IVF-ET Center, Cairo. PATIENT(S): Seventy-five patients with high-order multiple pregnancies resulting from assisted reproduction. Controls were 40 nonreduced twin pregnancies and 22 high-order multiple gestations. INTERVENTION(S): Transvaginal ultrasonically guided multifetal pregnancy reduction was performed. The first 30 cases were done using KCl as a cardiotoxic agent. The modified technique was used for the last 45 cases at an earlier gestational age (approximately 7 weeks) by eliminating the use of KCI and by aspirating the embryonic parts. MAIN OUTCOME MEASURE(S): Miscarriage rate, gestational age at delivery, birth weight, and pregnancy complications. RESULT(S): Using the modified technique, the miscarriage rate was 8.8% and 41 patients delivered between 32 and 39 weeks of gestation (mean+/-SD, 36.9+/-2.45 weeks). The mean (+/-SD) birth weight was 2,450.51+/-235.44 g. The miscarriage rate, fetal wastage rate, mean gestational age, and mean birth weight were similar in reduced and nonreduced twins and were significantly better than in nonreduced triplets and quadruplets. CONCLUSION(S): The modified technique of multifetal pregnancy reduction significantly improved outcomes, which were similar to those of nonreduced twins resulting from assisted reproduction and significantly better than those of nonreduced triplets and quadruplets.

Elevated concentrations of angiogenin in serum and ascitic fluid from patients with severe ovarian hyperstimulation syndrome.

This study was conducted to investigate the possible role of angiogenin in the pathogenesis of ovarian hyperstimulation syndrome (OHSS). The study group consisted of 10 healthy women who developed severe OHSS (group A) following ovarian stimulation by a long protocol of gonadotrophin-releasing hormone analogues/human menopausal gonadotrophin for in-vitro fertilization. A control group B (n = 10) underwent stimulation by the same protocol and did not develop OHSS. Blood samples were taken from group A on day of admission to hospital for treatment of OHSS and, in group B, 1 week after oocyte retrieval. In group A, ascitic fluid was routinely aspirated as a treatment for severe OHSS, and a peritoneal fluid sample was aspirated transvaginally before oocyte retrieval in group B. In group A, the mean serum angiogenin, the mean ascitic fluid angiogenin, the mean serum oestradiol concentration on day of human chorionic gonadotrophin and the mean haematocrit were 8390 +/- 6836 ng/ml, 2794 +/- 1024 ng/ml, 6300 +/- 2450 pg/ml and 46.6 +/- 4.4 respectively, as compared with 234 +/- 91 ng/ml, 254 +/- 105 ng/ml, 1850 +/- 1100 pg/ml and 36.8 +/- 4.6 in group B respectively. The differences between groups were highly significant for all parameters. Angiogenin seems to be strongly associated with the formation of neovascularization responsible for the development of OHSS.

Moderate ovarian hyperstimulation syndrome complicated by deep cerebrovascular thrombosis.

This report describes two cases that developed moderate ovarian hyperstimulation syndrome (OHSS) without evidence of haemoconcentration. Both patients developed serious cerebrovascular thrombosis resulting in hemiparesis, and recovered after treatment with anticoagulants. This report emphasizes that other factors may contribute to vascular thrombosis, and illustrates that cerebrovascular accidents may complicate even moderate OHSS.

Uterine myomata and outcome of assisted reproduction.

The aim of this work was to study the effect of uterine myomata on the implantation rate and outcome in in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Among 406 patients, 51 (12.6%) were found to have uterine corporeal myomata. Twelve patients were excluded from the study as they had large myomata, submucous myomata or intramural myomata encroaching on the cavity. These patients were advised to have myomectomy before being enrolled in the IVF/ICSI programme. The remaining patients (n = 39) were sorted according to the number, site and size of the myomata as assessed by transvaginal sonography. Three patients had more than one myoma. Most of the myomata were subserous (72.7%) and the mean diameter of the myomata was 3.5 +/- 0.9 cm. A control group (n = 367) was chosen with normal uteri and no history of uterine reconstruction surgery. The mean age of myoma patients was 34.7 +/- 3.6 years as compared to 34.0 +/- 4.4 years in the control group. The age, period of infertility, body mass index, duration and number of human menopausal gonadotrophin ampoules needed for stimulation, oestradiol levels, number of oocytes retrieved and the fertilization rate were not significantly different in the myoma patients compared to the control group. Fifteen myoma patients (38.5%) subsequently showed one or more pregnancy sacs on ultrasonography of which three (20%) spontaneously aborted during the first trimester and two (13.3%) had preterm labour, as compared to 123 (33.5%), 19 (15.5%) and nine (7.3%) respectively, among the control group (P = 0.27, 0.33 and 0.21). In conclusion, uterine corporeal myomata, not encroaching on the cavity and <7 cm in mean diameter, do not affect the implantation or miscarriage rates in IVF or ICSI.

Controversies in the modern management of hydrosalpinx.

The management of hydrosalpinx is a difficult clinical problem. Surgical treatment includes fimbrioplasty for patients with fimbrial obstruction and salpingostomy to fashion a stoma in the distal Fallopian tube in patients with a damaged fimbrial end. Surgery is only suitable for a small thin-walled hydrosalpinx with healthy mucosa. These operations can be performed via laparoscopy or open microsurgery. The proper selection of patients for surgical treatment and of the type of surgical technique are essential to achieve good results. The results of open microsurgery and laparoscopic surgery are summarized. In general, the prognosis of surgery is poor; however, in well selected cases, good results can be achieved by an experienced surgeon. In-vitro fertilization (IVF) is the main line of treatment for infertility caused by hydrosalpinx. In 1991, our group was the first to report on fluid accumulation in the uterine cavity before embryo transfer as a possible hindrance for implantation. Later, several publications reported an association between patients with hydrosalpinx and a reduced pregnancy rate when treated by IVF. The cause of a low pregnancy rate could be due to mechanical, chemical or toxic effects of the tubal fluid on the endometrium preventing implantation. All these mechanisms are reviewed in detail. The literature is controversial concerning the effect of transvaginal aspiration of hydrosalpinx on the outcome of IVF. Several reports suggest that surgical correction of the hydrosalpinx may improve the outcome of IVF. Further studies are required to verify this assumption and to find out the most suitable surgical procedure and if there is a subgroup of patients who could benefit most from salpingectomy.

Intracytoplasmic sperm injection in obstructive and non-obstructive azoospermia.

We compared the results of intracytoplasmic sperm injection (ICSI) in: (i) obstructive versus non-obstructive azoospermia, (ii) obstructive azoospermia using epididymal versus testicular spermatozoa and (iii) acquired versus congenital obstructive azoospermia due to congenital absence of the vas deferens (CAVD). A retrospective analysis was done of 241 consecutive ICSI cycles done in 103 patients with non-obstructive azoospermia and 119 patients with obstructive azoospermia. In the obstructive group, 135 ICSI cycles were performed. Epididymal spermatozoa were used in 44 cycles and testicular spermatozoa in 91 cycles. In the non-obstructive group, 106 cycles were performed. The fertilization and pregnancy per cycle rates were 59.5 and 27.3% respectively using epididymal spermatozoa, 54.4 and 31.9% respectively using testicular spermatozoa in obstructive cases, and 39 and 11.3% respectively in non-obstructive cases. The fertilization and pregnancy per cycle rates were 56.6 and 37% respectively in acquired obstructive cases, and 55.2 and 20.4% respectively in CAVD. In conclusion, ICSI using spermatozoa from patients with acquired obstructive azoospermia resulted in significantly higher fertilization and pregnancy rates as compared to CAVD and non-obstructive cases.

Fertilization and pregnancy rates after intracytoplasmic sperm injection using ejaculate semen and surgically retrieved sperm.

OBJECTIVE: To compare the fertilization rates and pregnancy rates (PRs) in intracytoplasmic sperm injection (ICSI) using sperm from ejaculates of normal and abnormal semen, epididymal sperm, and testicular sperm of obstructive and nonobstructive azoospermic patients. DESIGN: Retrospective study. SETTING: The Egyptian IVF-ET Center. PATIENT(S): Three hundred fifty patients underwent 366 ICSI cycles. INTERVENTION(S): ICSI, epididymal sperm aspiration, and testicular biopsy. MAIN OUTCOME MEASURE(S): Fertilization rates and PRs. RESULT(S): Patients were divided into five groups according to the quality and source of sperm. Patients in group 1 underwent 102 cycles of ICSI using ejaculated abnormal semen, group 2 underwent 44 cycles using epididymal sperm, group 3 underwent 82 cycles using testicular sperm from obstructive azoospermia, group 4 underwent 80 cycles using testicular sperm from nonobstructive azoospermia, and group 5 underwent 58 cycles using normal semen. There was no significant difference in the fertilization rates and PRs among groups 1, 2, and 3. In group 4, the fertilization rate and PR were significantly lower than in all other groups. In group 5, the fertilization rate was significantly higher than in all other groups. CONCLUSION(S): The fertilizing ability of sperm in ICSI is highest with normal semen and lowest with sperm extracted from a testicular biopsy in nonobstructive azoospermia. There was no significant difference in fertilization rates and PRs between ejaculated sperm of different parameters and surgically retrieved sperm in obstructive azoospermia.

Oocyte quality in patients with severe ovarian hyperstimulation syndrome.

OBJECTIVE: To study the oocyte quality in patients with ovarian hyperstimulation syndrome (OHSS). DESIGN: Retrospective study. SETTING: The Egyptian IVF-ET Center. PATIENT(S): Forty-two patients who developed severe OHSS (group A) were studied for the mean number of oocytes retrieved, percentage of high-quality oocytes, embryo quality, and fertilization, implantation, and pregnancy rates; these patients were compared with an age-matched control group who did not develop OHSS (group B; n = 183) after superstimulation for IVF or intracytoplasmic sperm injection. INTERVENTION(S): In vitro fertilization and ICSI. MAIN OUTCOME MEASURE(S): Fertilization and pregnancy rates. RESULT(S): In group A, the mean number of oocytes retrieved was significantly higher, whereas the percentage of high-quality oocytes and the fertilization rate were significantly lower than that in group B. There were no statistically significant differences in the quality of embryos transferred or the implantation or pregnancy rate between the groups. The percentage of high-quality oocytes and the fertilization rate were significantly lower in patients with polycystic ovaries (PCO) in both groups. CONCLUSION(S): The inferior quality and maturity of oocytes in OHSS reduced the fertilization rate but did not affect the quality or the number of embryos transferred or the pregnancy rate. The effect on oocyte quality could be due to the prevalence of PCO in this group of patients.

Prospective controlled randomized study of in vitro fertilization versus intracytoplasmic sperm injection in the treatment of tubal factor infertility with normal semen parameters.

OBJECTIVE: To compare the results of IVF and intracytoplasmic sperm injection (ICSI) in tubal factor infertility with normal semen parameters. DESIGN: A prospective randomized study. SETTING: The Egyptian IVF-ET Center. PARTICIPANTS: One hundred sixteen patients infertile due to tubal factor were divided randomly into two groups. Group A(n = 58) was treated with IVF and group B(m = 58) was treated with ICSI. INTERVENTION: In vitro fertilization and ICSI. MAIN OUTCOME MEASURE: Pregnancy rate. RESULTS: In group A, 736 oocytes were retrieved and normal (two pronuclear [2pN] fertilization occurred in 477 oocytes (64.8%). In group B, 748 oocytes were retrieved, 572 metaphase II oocytes were injected, and 2PN fertilization occurred in 400 oocytes (70% per injected oocyte and 53.5% per retrieved oocyte). Clinical pregnancy was diagnosed in 18 patients in group A (31%) and 19 patients in group B (32.8%). There was no significant difference in the pregnancy rate between the two groups. The fertilization rate per retrieved oocytes was significantly higher in group A. CONCLUSIONS: Intracytoplasmic sperm injection does not offer a higher pregnancy rate as compared with IVF in the treatment of tubal factor infertility with normal semen.

Recombinant follicle-stimulating hormone in the treatment of patients with history of severe ovarian hyperstimulation syndrome.

OBJECTIVE: To compare the low-dose recombinant FSH and hMG protocols in treatment of patients with history of severe ovarian hyperstimulation syndrome (OHSS). DESIGN: A prospective study on 22 patients with history of severe OHSS. Group A (n = 14) was treated with low-dose recombinant FSH 40 cycles and group B (n = 8) was treated with low-dose hMG in 26 cycles. SETTING: The Egyptian IVF-ET Center, Cairo, Egypt. PATIENT(S): Twenty-two patients with a history of severe OHSS. INTERVENTION(S): Ovulation induction. MAIN OUTCOME MEASURE(S): Estradiol, number of follicles, number of hMG ampules, pregnancy rate (PR), and the development of OHSS. RESULT(S): The cancellation rate, mean E2 level on day of hCG, mean number of days of stimulation, and the mean number of ampules per cycle were 10%, 523 +/- 166 pg/mL (conversion factor to SI unit, 3.671), 17.8 +/- 5.4, and 19 +/- 6.5 in group A and 19.2%, 554 +/- 152 pg/mL, 14.6 +/- 2.5, and 16.1 +/- 3.6 in group B, respectively. Treatment resulted in eight pregnancies (20% per cycle) and two abortions (25%) in group A. In group B, four pregnancies resulted (15.4% per cycle) and two patients aborted (50%). No cases of OHSS developed in both groups. There were no significant differences in all parameters between the two groups. CONCLUSION(S): Recombinant FSH low-dose protocol proved to be as effective as low-dose hMG in producing reasonable ovulation and PRS in polycystic ovary syndrome patients with a history of severe OHSS and the protocol was safe concerning the risk of development of OHSS.

Successful intracytoplasmic sperm injection without performing cytoplasmic aspiration.

OBJECTIVE: To compare the effect of cytoplasmic aspiration versus no aspiration before intracytoplasmic sperm injection (ICSI) on the rate of oocyte damage, fertilization rate, and embryo quality. DESIGN: A randomized prospective study on sibling oocytes. SETTING: The Egyptian IVF-ET Center, Cairo, Egypt. PARTICIPANTS: Fifty-eight patients who were infertile due to male factor who underwent 60 ICSI cycles. INTERVENTION: Intracytoplasmic sperm injection was performed on randomly allocated metaphase II oocytes with cytoplasmic aspiration in group I and without cytoplasmic aspiration in group II before sperm injection. MAIN OUTCOME MEASURE: Fertilization rate, oocyte damage rate, and embryo quality. RESULTS: Normal fertilization rate per injected oocyte was 61.4% in group I compared with 62.5% in group II. The damage rate per injected oocyte was 16.8% in group I compared with 4.6% in group II. Grade I embryos were 24.5% in group I compared with 48.5% in group II. CONCLUSION: Cytoplasmic aspiration before sperm injection in ICSI is not essential for oocyte activation. It did not improve the rate of normal fertilization. On the other hand, it increased the damaged oocyte rate and the rate of cytoplasmic fragments.