Controlled natural cycle IVF with antagonist use and blastocyst transfer.

A method of controlled natural cycle IVF (CONCIVF) was sought to provide simpler and shorter treatment without the risks of ovarian hyperstimulation syndrome and multiple pregnancies. A total of 138 couples with normal ovulation and normal sperm parameters, in whom the women were <40 years old, were the candidates for this study. Gonadotrophin-releasing hormone antagonist was used before human chorionic gonadotrophin (HCG) administration if LH increased to a concentration of 10 mIU/ml before HCG injection. Treatment was initiated at > or =16 mm follicular growth and at oestradiol concentrations > or =400 pmol/l with 5000 IU HCG induction. All the embryos were cultured to the blastocyst stage and transferred only if they reached early or advanced blastulation. A total of 126 patients underwent oocyte retrieval. In 102 cases, one oocyte was retrieved; 95% of the oocytes fertilized, 99% cleaved and 47.9% achieved the blastocyst stage. The implantation rate per blastocyst transfer was 53.3% and the live-birth rate per embryo transfer was 40%. Therefore, CONCIVF with blastocyst transfer gives acceptable blastocyst development and implantation rates without the long- or short-term side effects of ovulation induction.

Maternal serum levels of interferon-gamma and interleukin-2 soluble receptor-alpha predict the outcome of early IVF pregnancies.

BACKGROUND: Elevated maternal serum levels of interleukin-2 soluble receptor-alpha (IL-2 sRalpha), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) have been associated with pregnancy loss. The aim of our study was to evaluate the predictive value of these cytokines in the outcome of early IVF pregnancies. METHODS: One hundred and fifty-nine consecutive IVF patients who were subsequently diagnosed to have a biochemical pregnancy (n = 23), a first-trimester miscarriage (n = 19) or a normal term delivery (n = 117) were included in this study. Serum was collected from the initial pregnancy test, 11 days after a day 3 embryo transfer, and all samples were analysed for IL-2 sRalpha, TNF-alpha and IFN-gamma by commercially available enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: IL-2 sRalpha levels were significantly higher in patients with an early pregnancy loss compared with patients with a normal term delivery (849.5 +/- 69.6 versus 693.5 +/- 31.2 pg/ml, P = 0.02), and a cut-off point of IL-2 sRalpha >1000 pg/ml predicted a poor pregnancy outcome (44.4 versus 22.7% pregnancy loss, IL-2 sRalpha >or=1000 versus IL-2 sRalpha <1000 pg/ml; P = 0.02). IFN-gamma-positive patients had twice the risk for poor IVF pregnancy outcome compared with IFN-gamma-negative subjects (40.8 versus 20.0%, respectively; P < 0.02), including a significantly lower implantation rate (37.6 +/- 0.05 versus 50.0 +/- 0.03%, respectively; P = 0.02). There was no difference in pregnancy outcome based upon serum levels, or the ability to detect the presence of TNF-alpha. No differences in levels of these cytokines were found based on the aetiology of the patients' infertility. CONCLUSIONS: Elevated maternal serum levels of IL-2 sRalpha and IFN-gamma as early as 11 days after embryo transfer are associated with poor IVF pregnancy outcome.

Placenta accreta--summary of 10 years: a survey of 310 cases.

The objective was to study the incidence, risk factors, and outcome of pregnancies complicated by placenta accreta in our population. Retrospective analysis of all deliveries between the years 1990-2000, and identification of all cases of placenta accreta, defined by clinical or histological criteria. For comparison purposes we defined two sub-groups: (i) all cases that ended with severe outcome and (ii) all patients who had a previous event of placenta accreta in one or more of their previous deliveries. We evaluated the potential risk factors leading to these conditions. The SPSS software package was used for statistical analysis. Univariate and multivariate analyses were performed by stepwise logistic regression. The study covered 34 450 deliveries from which 310 cases of placenta accreta were diagnosed (0.9 per cent). The risk factors associated with placenta accreta were previous cesarean delivery (12 per cent), advanced maternal age, high gravidity, multiparity, previous curettage and placenta previa (10 per cent). Hysterectomy was performed in 11 patients (3.5 per cent) with one case of maternal death, whereas 21 per cent of the patients required postpartum blood products transfusion. Antenatal diagnosis of placenta accreta or percreta by ultrasound or MRI, was achieved only in eight of the cases. In the sub-group of 15 patients (4.8 per cent) with severe outcome, the only significant risk factors were increased parity (O.R.=1.29, 95 per cent CI 1.056-1.585), anteriorly low placenta (O.R.=6.1, 95 per cent CI 1.4-25.3) and repeated cases of caesarean sections (O.R.=3.3, 95 per cent CI 0.9-12.5), whereas in the 49 (16 per cent) patients with repeated cases of placenta accreta the only significant risk factor was the number of deliveries (O.R.=1.5, 95 per cent CI 1.0-2.2). Repeated cesarean delivery, high parity, and anteriorly low placental location are associated with severe outcome in case of placenta accreta. Women with repeated events of placenta accreta may have better outcome and a genetic factor may serve as a cause for this condition.

A high predictive value of the first testicular fine needle aspiration in patients with non-obstructive azoospermia for sperm recovery at the subsequent attempt.

BACKGROUND: The objective of this retrospective study, which included 51 men with non-obstructive azoospermia, was to evaluate the predictive value of the results of the first sperm recovery attempt on the probability for sperm recovery in a second attempt. METHODS AND RESULTS: A positive testicular fine needle aspiration (TEFNA) was defined as the recovery of any number of mature sperm. At the first and second TEFNA attempts, mature sperm were recovered in 33 (64.7%) and 25 (49%) of 51 patients respectively. In 23 of the 33 (69.7%) patients with a positive first TEFNA, sperm were recovered at both attempts, whereas in only two of 18 (11.1%) with a negative first TEFNA, sperm were recovered at the second attempt. Our analysis revealed a high predictive value of the first TEFNA for sperm recovery at the subsequent attempt, with a mean positive predictive value of 69.7%, with the highest probability being 90.9% in hypospermatogenesis, 72.7% in Sertoli cell-only pattern, 75% in tubular hyalinization, and the lowest being 28.6% in maturation arrest. The mean negative predictive value was 88.9%, which was high in all categories (80% in Sertoli cell-only pattern and 100% in maturation arrest and tubular hyalinization). CONCLUSION: A second TEFNA attempt should be offered to all non-obstructive azoospermic patients with a positive first TEFNA. Patients with a negative first TEFNA may undergo a repeated attempt, but a donor sperm back-up is strongly advised.

The kinetics of leptin in Meigs' syndrome.

OBJECTIVE: The aim of this study was to assess the kinetics and possible role of leptin in the pathophysiology of Meigs' syndrome. METHODS: We report on a 62-year-old patient admitted for a large ovarian tumor, hydrothorax, and ascites. The patient underwent abdominal hysterectomy and bilateral adnexectomy revealing a benign ovarian fibroma and no evidence of malignant cells in the pleural or peritoneal fluids. Analysis of serum, peritoneal, and pleural fluids from this patient was performed before, during, and after the operation. RESULTS: Preoperatively, the patient had low levels of leptin in the serum, peritoneal, and pleural fluids. Serum levels increased after removal of the ovarian tumor along with the resolution of ascites and hydrothorax. CONCLUSION: Leptin levels inversely correlate to tumor burden, third space fluid accumulation, and clinical status in Meigs' syndrome. These findings suggest the involvement of leptin in the pathophysiology of this syndrome.

Markedly elevated levels of vascular endothelial growth factor, fibroblast growth factor, and interleukin 6 in Meigs syndrome.

Analysis of serum and peritoneal and pleural fluid from a patient with Meigs' syndrome revealed high levels of vascular endothelial growth factor, fibroblast growth factor, and interleukin 6. Serum levels declined after removal of the ovarian tumor, along with resolution of ascites and hydrothorax. These findings suggest the involvement of these vasoactive factors in ascites and pleural fluid formation in Meigs' syndrome.

Evaluation and treatment of low responders in assisted reproductive technology: a challenge to meet.

PURPOSE: To investigate the various methods of evaluation and treatment of patients with a low response to controlled ovarian hyperstimulation in assisted reproductive technologies (ART). METHODS: Review and analysis of relevant studies published in the last decade, identified through the literature and Medline searches. RESULTS: While a universally accepted definition for low responders is still lacking, these patients are reported to represent about 10% of the ART population. Several ovarian reserve screening techniques have been proposed; however, currently the best-characterized and most sensitive screening tools available are the basal day 3 serum follicle-stimulating hormone level and the clomiphene citrate challenge test. When abnormal, these tests allow physicians to counsel patients that their prognosis for conception is poor. Although the presence of a normal result does indicate better long-term chances for conception, on age-related decline in fecundity remains and patient age should still be considered when counseling patients with normal screening results. Several stimulation protocols have been applied in the low-response group with varying success. Recent studies show that the use of a minidose gonadotropin-releasing hormone-agonist protocol may result in significantly decreased cycle cancellations as well as increased clinical and ongoing pregnancies, and thus is proposed as a first-line therapy. Studies evaluating supplementary forms of treatment to the ovulation induction regimen show improved outcome when pretreating with oral contraceptives, whereas there seems to be no benefit from cotreatment with growth hormone or glucocorticoids. Blastocyst culture and transfer and assisted hatching in low responders are still under evaluation, whereas natural cycle in vitro fertilization may be used in cases of repeated failures as a last option before resorting to oocyte donation or adoption. Future possible forms of treatment like in vitro maturation of immature human oocytes, cytoplasm, and nuclear transfer currently are experimental in nature and their efficacy has still to be proven. CONCLUSIONS: The evaluation and treatment of low responders in ART remains a challenge. Understanding of the underlying etiology and pathophysiology of this disorder may help the clinician to approach it successfully.

Ultrasonographic prenatal diagnosis of microcephalic osteodysplastic primordial dwarfism types I/III.

Microcephalic osteodysplastic primordial dwarfism is a rare disease characterized by unique clinical appearance and specific radiographic findings, and distinctive brain abnormalities. We describe the prenatal diagnosis of two siblings with microcephalic osteodysplastic primordial dwarfism types I/III at 23 and 26 weeks of gestation, respectively. Early detection by sequential antenatal sonographic evaluation is important for counselling families known to be at risk of this rare disease.

BRCA1 and BRCA2 gene mutations: decision-making dilemmas concerning testing and management.

The identification of the BRCA genes, and their possible etiologic relationship with various forms of inherited cancer, has been recognized universally as a cornerstone in the search of cancer's genetic susceptibility. Female BRCA gene mutation carriers are found to carry an increased risk of developing breast or ovarian cancer and to a lesser degree, colon cancer, and male BRCA mutation carriers are also related to an increased risk of breast, colon, or prostate cancer. Although genetic testing promises a possible future presymptomatic determination and treatment of women who are genetically susceptible to cancer, current data reveal certain dilemmas and uncertainties regarding our ability to interpret the results from testing and offer effective management options. In addition, several complex ethical, legal, and social issues have been revealed with the advent of this new information, which also confirm the need for additional research regarding the most effective use of this genetic information and for the establishment of appropriate clinical management strategies.

Ethics and assisted reproduction.

In vitro fertilization and assisted reproductive technology have made great progress during the last 20 years. Genetic material donation, human embryo cryopreservation, selective embryo reduction, preimplantation genetic diagnosis and surrogacy are currently practiced in many countries. On the other hand, embryo research is practiced only in a small number of nations, whereas human cloning has thus far been universally condemned. The rapid evolution and progress of all these techniques of assisted reproduction has revealed certain ethical issues that have to be addressed.

Ethical aspects of reproduction in the next century.

Doubtless, the technological advancements achieved in the current century in the area of young women's reproductive health care have also led to the evolution of very important ethical issues that will have to be dealt with in the coming century. Abortion, perhaps the most controversial issue of all, continues to raise a number of ethical issues related to the rights of the women versus the rights of the fetus, which, in addition to the risk of sexually transmitted diseases including the human immunodeficiency virus, emphasize the need for adequate family planning and sexual education. Genetic testing for late-onset diseases, disease susceptibilities, and carrier status may offer medical or psychological benefits; however, several complex ethical, legal, and social issues have been revealed with the advent of this new information. New family structures deviating from the traditional heterosexual couple, consisting of either single or lesbian mothers, have appeared, raising serious disputes regarding the welfare of the child. Important demographic changes are expected in the world population in the 21st century, characterized mainly by a significant increase of the older age groups.

Human umbilical cord blood banking and transplantation: a state of the art.

Human umbilical cord blood has proven to be a feasible alternative source of hematopoietic stem cells for pediatric and some adult patients with major hematologic disorders. This has promoted the establishment of cord blood banks for use in unrelated transplants worldwide. The banking of umbilical cord blood offers many advantages: absence of donor risk, absence of donor attrition, immediate availability, and the ability to expand available donor pools in targeted ethnic and racial minorities currently underrepresented in all bone marrow registries. Preliminary clinical experience suggests that, due to the immunological immaturity of cord blood cells, graft versus host disease might be lower than when using bone marrow from adult donors and HLA restrictions might be less stringent. Techniques to improve the efficacy of blood banks are currently under investigation. Closed cord blood collection methods have proven to be superior to open in reducing the risk of microbial contamination. Efficient banking requires volume reduction of cord blood units without significant loss of progenitor cells, in order to decrease storage space and cost, and this may be achieved by using the separation techniques. Cryopreservation and thawing techniques have been established and do not seem to affect the viability and progenitor cell recovery or the feasibility of CD34(+) selection and ex vivo expansion. Nevertheless, many scientific, ethical, and social questions have arisen in connection with cord blood banking that need to be addressed.

Maternal-fetal conflict.

Advances in prenatal care have brought about a greater understanding as to the special status of the fetus to the point that it is considered a patient in its own regard. Pregnant women generally follow the medical recommendations of their physicians that are intended for the benefit of their baby. Any situation where maternal well-being or wishes contradict fetal benefit constitutes a maternal-fetal conflict. Such situations include a broad range of possible interventions, non-interventions, and coercive influences. In such cases, the attending physician is expected to attain an attitude that involves either the respect of the woman's autonomy and right to privacy, which precludes any approach other than to accept her decision, or to modify this absolute for the beneficence of the fetus. Current ethical viewpoints range from absolute respect for maternal autonomy with no persuasion allowed, to gentle persuasion and to others which permit intervention and overriding of the woman's autonomy. Court-ordered decisions enforcing the pregnant woman to undergo a procedure in order to improve fetal outcome have been criticized as an invasion of a woman's privacy, limitation of her autonomy, and taking away of her right to informed consent.

Postpartum umbilical cord blood collection for transplantation: a comparison of three methods.

OBJECTIVE: This study was undertaken to compare 3 methods of collection of human umbilical cord blood. STUDY DESIGN: Seventy-five women with uncomplicated vaginal deliveries were divided equally into 3 groups. One of 3 cord blood collection methods was applied to each woman. Method 1 was collection of cord blood into a standard donation blood bag. Methods 2 and 3 used a syringe to perform a sodium chloride solution flush and drain, which included withdrawal of cord blood by a syringe until the delivery of the placenta, followed by flushing through a catheter one of the umbilical arteries with sodium chloride solution and collection of the cord blood either into an open sterile container (method 2) or into a standard donation blood bag (method 3). Analyses included comparisons among the 3 groups of volume collected, total number of white blood cells, and bacterial contamination rates (positive culture results). In addition a correlation was made between the different variables and the collected cord blood nucleated cells. RESULTS: Cord blood collection by the blood bag method (method 1), which is presently the standard clinical practice, resulted in a mean blood volume of 76.4 +/- 32.1 mL and a mean total white blood cell count of 835 +/- 507 x 10(6) cells. With collection methods 2 and 3, in which as much blood as possible was withdrawn by syringe while the placenta was still in utero followed by a second collection after infusion of the umbilical artery with sodium chloride solution, the mean volume collected was significantly higher (P <.05) at 174.4 +/- 42.8 mL and 173.7 +/- 41.3 mL, respectively, with significantly higher (P <.001) mean total white blood cell counts of 1624 +/- 887 x 10(6) cells and 1693 +/- 972 x 10(6) cells, respectively. A direct correlation was observed between the cord blood volume collected and placental weight, whereas no correlations were observed with maternal age, pregnancy duration, or the neonate's weight. Bacterial contamination was significantly higher (P =.04) in cord blood collections obtained by method 2 (48%) than by methods 1 (16%) and 3 (19%). CONCLUSIONS: The syringe-assisted sodium chloride solution flush collection method with a blood bag (method 3) was found to be the most effective method for human umbilical cord blood collection. This method doubles the total white blood cells collected with respect to current yields, which may make cord blood transplantation applicable for adults.

Voluntary and involuntary sterilization: medical, ethical, legal and religious aspects.

Surgical voluntary sterilization has become one of the most widely used methods of contraception, with vasectomy and tubal sterilization being the most commonly employed techniques, associated with a low failure, morbidity, mortality, and long-term sequelae rate. As sterilization is related with the elimination of the possibility for procreation, a number of ethical, legal and religious issues have arisen, leading often to personal misjudgements, legal disputes, and failures in applying family planning. Involuntary sterilization is currently not practiced, except in cases of severely mentally retarded people, who are unable to appreciate the consequences of their acts or care for their children and who may have a high likelihood of propagating hereditary disease.

A laparoscopic technique for obtaining ovarian cortical biopsy specimens for fertility conservation in patients with cancer.

OBJECTIVE: To evaluate the efficacy of a newly designed round biopter as a practical and safe method for collecting ovarian tissue for cryopreservation in young women with cancer before chemotherapy. DESIGN: Prospective study of young women volunteering for research (Leeds, United Kingdom) and patients with cancer (Jerusalem, Israel and Leeds, United Kingdom) undergoing laparoscopic ovarian cortical tissue biopsy and cryopreservation before administration of high-dose radiochemotherapy. SETTING: Two university-based tertiary referral centers of oncology and gynecology (Hadassah Medical Center, Israel; Leeds General Infirmary, United Kingdom). PATIENT(S): Twenty female volunteers undergoing routine laparoscopic gynecologic procedures (age, 25-34 years) and 20 young women (age, 11-30 years) with advanced cancer requiring potentially sterilizing radiochemotherapy. INTERVENTION(S): Cortical ovarian tissue biopsies performed under laparoscopy with use of the round biopter. RESULT(S): The laparoscopic sampling procedure was uncomplicated in all cases. In treated patients, five to six samples were obtained (5 mm in diameter; 2-3 mm in depth) using the round biopter, and radiochemotherapy was administered without delay. In volunteers, no adhesions were noted at repeat laparoscopy (9 patients). All biopsy specimens were cryopreserved, and histologic examination confirmed the presence of many primordial follicles. CONCLUSION(S): Laparoscopic ovarian biopsy performed with the round biopter is a safe and efficient method for collecting ovarian tissue for cryopreservation in patients with cancer.

Social aspects in assisted reproduction.

In-vitro fertilization (IVF) and assisted reproductive techniques have become common practice in many countries today, regulated by established legislation, regulations or by committee-set ethical standards. The rapid evolution and progress of these techniques have revealed certain social issues that have to be addressed. The traditional heterosexual couple, nowadays, is not considered by many as the only 'IVF appropriate patient' since deviations from this pattern (single mother, lesbians) have also gained access to these treatments. Genetic material donation, age limitation, selective embryo reduction, preimplantation genetic diagnosis, surrogacy and cloning are interpreted differently in the various countries, as their definition and application are influenced by social factors, religion and law. Financial and emotional stresses are also often described in infertile couples. Information as deduced from the world literature regarding IVF regulation, as well as about the existing religious, cultural and social behaviours towards these new technologies, is presented in this article in relation to the social aspects of assisted reproduction.

A historical perspective of the clinical evolution of the assisted reproductive technologies.

The practice of assisted reproduction technology today is the result of the dedicated patient care, observation, research, and experimentation undertaken by previous generations of physicians. The building blocks of progress have been assembled over past decades, by scientists whose primary objective has been to push forward the frontiers of knowledge, in order to offer more effective methods of infertility treatment. And fortunately that process continues today. Amongst the many scientific developments that have led to the modern practice in assisted reproductive technology, a small number stand out as having had a unique importance. This historical review redraws the path through which in vitro fertilization went from an experimental to an accepted infertility treatment.

Preimplantation genetic diagnosis principles and ethics.

Preimplantation genetic diagnosis (PGD) followed by implantation of unaffected embryos offers high-risk couples the option to decrease the risk of genetic disease in their offspring without the dilemma of a prenatal diagnosis that may be followed by a termination of pregnancy. Polar body, blastomere and blastocyst biopsies are currently being performed, whereas the two major technologies used for single-cell genetic analysis involve the polymerase chain reaction and fluorescence in-situ hybridization. PGD, similar to other prenatal diagnosis methods, raises many ethical and legal dilemmas. The high cost of practice and the low pregnancy rate achieved are still considered the major drawbacks of this new procedure.

Gaucher's disease and pregnancy.

Gaucher's disease is an autosomal recessive lysosomal storage disease, resulting from a deficiency of the enzyme glucocerebrosidase, which is required for the lysosomal degradation of glycolipids. The clinical manifestations of the disease show a large heterogeneity, including hepatosplenomegaly, "bone crisis" and fracture, anemia, thrombocytopenia and, in the rarest types II and III, neurological decompensation. Type I, the most common form, usually presents with less severe symptoms and at a more advanced age. More than 30 mutations within the glucocerebrosidase gene have been recognized, and certain mutations seem to be related with a particular phenotype expression of the disease. Modern diagnosis of Gaucher's disease is performed by either determining the enzyme activity in peripheral blood leukocytes or through DNA-based analysis. Pregnancy concurrent with Gaucher's disease has several risks, including an increased severity of anemia and thrombocytopenia that can potentiate postpartum bleeding, and increased risk of infection and possibly an increased spontaneous abortion rate. Nevertheless, the majority of these pregnancies seem to proceed to term without significant complications. The effects that pregnancy might have on the course of the disease are still unresolved. Enzyme replacement therapy with alglucerase is the treatment of choice for patients with Gaucher's disease, but it is yet to be shown whether alglucerase reduces the risk of these complications during pregnancy and whether its use has any adverse effect on fetal development. We present an extensive review of the current literature regarding Gaucher's disease with special emphasis on pregnancies coexistent with this disease and, an analysis of the genetics, relevant prenatal diagnostic issues, and current treatment modalities.