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ART in women 40 and over. Is the cost worth it?

OBJECTIVE: To determine the efficacy and cost of assisted reproductive techniques in older women (40 years or older) in comparison to younger women (less than 30 years old). STUDY DESIGN: Retrospective review of records from one university-based infertility practice. RESULTS: Women 40 years or older were significantly less likely to achieve pregnancy with human menopausal gonadotropin (hMG)/intrauterine insemination as compared to women under age 30. The older women were also significantly less likely to achieve pregnancy with in vitro fertilization (IVF). The use of donor oocytes resulted in the highest pregnancy rates in older women. Costs per cycle were similar, however, for both groups. CONCLUSION: Older women will consume an equal amount of medical resources per cycle in infertility treatment as compared to younger women (aged < 30 years). However, older women utilizing assisted reproductive techniques are four to five times less likely to achieve pregnancy than the younger group. This poor prognosis for success in older women adds significantly to the mean cost per pregnancy as compared to younger women. Donor oocytes may be the most cost-effective option for achieving pregnancy in older women.

Adult↗

First trimester screening with free beta-hCG, PAPP-A and nuchal translucency in pregnancies conceived with assisted reproduction.

OBJECTIVE: To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on free beta-human chorionic gonadotrophin (beta-hCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT). METHODS: First trimester maternal dried whole blood specimens from 74 singleton pregnancies (32 by IVF and 42 by ICSI) and 30 twin pregnancies (16 by IVF and 14 by ICSI) in which conception was achieved with assisted reproduction techniques were matched with five controls resulting in 370 singleton controls and 150 twin controls. NT was measured using the Fetal Medicine Foundation protocol. Free beta-hCG, PAPP-A and NT levels were compared between the IVF and control groups and between the ICSI and control groups using the Mann-Whitney U test. RESULTS: In singleton pregnancies, the only significant difference was a 21% (95% CI: -35%--7%) reduction in PAPP-A in IVF cases. In twin pregnancies, the only significant difference was a 12% (95% CI: -34%--3%) reduction in NT in IVF cases. In singleton pregnancies, the false-positive rate for Down syndrome screening was 1.4% and 1.9% greater for the IVF and ICSI groups, respectively, compared to controls for a general screening population. CONCLUSIONS: Patients undergoing assisted reproduction techniques should be counseled about the possibility of increased false-positive rates. Larger studies are needed to confirm this observation and to develop appropriate adjustment factors to reduce false-positive rates.

Biomarkers↗

Somatic chromosomal abnormalities in infertile men and women.

Infertility--the inability to achieve conception or sustain a pregnancy through to live birth--is very common and affects about 15% of couples. While chromosomal or genetic abnormalities associated with azoospermia, severe oligozoospermia or primary ovarian failure were of no importance for reproduction prior to the era of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), advances in assisted reproductive techniques (ART) now enable many infertile couples to have children. These developments have raised the question of the genetic consequences of ICSI: concerns of the potential harm of the invasive procedure and concerns about the genetic risk. The infertile male and female definitely have an increased risk to carry a chromosomal abnormality. Detection of such an abnormality is of fundamental importance for the diagnosis of infertility, the following treatment, the evaluation of the risk for the future child and the appropriate management of the pregnancy to be obtained. Therefore, cytogenetic screening of both partners is mandatory prior to any type of ART. The present review is based on several surveys on male and female infertility and analyzes the types and frequencies of the different reported chromosome abnormalities according to the type of impairment of spermatogenesis and the type of treatment planned or performed. With regard to assisted reproductive techniques (especially ICSI) the main types of chromosomal abnormalities are discussed and their potential risks for ICSI. If available, reported cases of performed ICSI and its outcome are presented. The detection of an abnormal karyotype should lead to comprehensive genetic counselling, which should include all well-known information about the individual type of anomaly, its clinical relevance, its possible inheritance, the genetic risk of unbalanced offspring, and the possibilities of prenatal diagnosis. Only this proceeding allows at-risk couples to make an informed decision regarding whether or not to proceed with ART. These decisions can be made only when both partners have clearly understood the genetic risks and possible consequences when ART is used.

Chromosome Aberrations↗

FSH: urinary and recombinant.

Infertility affects approximately 10-15% of couples. To enhance the chances of conception, assisted reproductive techniques (ART) have been improved and, in the last 5 years, thousands of babies have been delivered after IVF or ICSI procedures. To obtain an appropriate and controlled ovarian hyperstimulation (COH), clinicians have introduced many drug protocols based on GnRH agonists or antagonists for pituitary down-regulation and FSH or HMG for ovarian stimulation. Currently FSH is the most common drug used for ovulation induction. It is a glycosylated protein with a molecular weight of 28000-30000Da, normally secreted by the anterior pituitary gland. The recombinant preparations of follicle stimulation hormone (r-FSH) are characterized by a higher level of purity, reduced batch to batch variability and no risk of infection. The purpose of this review was to establish the efficacy of different trials based on the use of r-FSH and urinary FSH (u-FSH) comparing published data from randomised studies on the ovulation induction for assisted reproductive techniques. Unfortunately, we did not find any paper with sufficient power to detect a clinically significant difference in pregnancy rates, however, recent meta-analysis among homogeneous trials indicates that the use of r-FSH is to be preferred to u-FSH because more oocytes were collected in cycles with better embryo quality and with more pregnancies. Recombinant FSH has a higher cost per ampoule than urinary FSH, but also a higher effectiveness. A recent cost-effectiveness analysis on follitropin alfa compared to urinary FSH-HP, using a Markov model, confirmed other previous studies that, considering the ongoing pregnancies beyond 12 weeks gestation, r-FSH is the most effective therapy for ovulation induction in ART.

Female↗

45,X/46,X,r(Y) karyotype transmitted by father to son after intracytoplasmic sperm injection for oligospermia. A case report.

BACKGROUND: The advent of assisted reproductive techniques, such as intracytoplasmic sperm injection (ICSI), has permitted conception and successful pregnancy for an increasing population of infertile men. Approximately 13.7% of infertile men with aspermia and 4.6% with oligospermia have a coexistent chromosome abnormality. Although the ICSI procedure appears safe thus far, early studies are in progress to evaluate outcomes of such pregnancies. For men whose infertility is linked to genetic conditions, it is an unprecedented challenge to predict the potential effects on their offspring. CASE: At 18 weeks' gestation, a 45,X/46,X,r(Y) karyotype was found on genetic amniocentesis performed for advanced maternal age. The pregnancy was achieved by ICSI using sperm from the husband, who was infertile due to severe oligospermia. Subsequently the same karyotype was found in the father. To our knowledge, this is the first reported case of familial transmission of ring Y chromosome. CONCLUSION: It is strongly recommended that ICSI and other new assisted reproductive techniques be preceded by genetic screening for male infertility as well as other indications warranted by the family history since traditional risk assessment may require revision and outcomes may be uncertain in some cases.

Adult↗

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.

Adult↗

[Heterotopic pregnancy].

The heterotopic pregnancy is a combination of an intra-uterine and extra-uterine pregnancy, at the same time. The spontaneous heterotopic pregnancy is a rare illness with an estimated frequency below one per 20,000 and one per 30,000. The first case was reported in France by Duverney in 1708 during an autopsy. The frequency of this pregnancy has increased with the implementation of assisted reproduction techniques. This paper is the report of a case of spontaneous heterotopic pregnancy seen at the Angeles Mexico Hospital. A 32 year old woman, gravida 1; dilatation and curettage was performed on 13th February because of a blighted ovum, a lot of products of conception were obtained. The patient was discharged the next day only with analgesics. She returns to the emergency room on February 16th with hypovolemic shock and acute abdomen. A normocitic normocromic anemia was found on the hematic biometry, the transvaginal ultrasound reported amount of blood in the cul-de-sac, echogenic adnexal mass, suggesting a gestational sac with embryo. An emergency laparotomy was used to perform a left cornual resection; the findings were 600 cc of hemoperitoneum and a left ruptured ectopic pregnancy. She had an uneventful postoperative course, and was discharged 72 hours later without complications. Heterotopic pregnancy is a rare illness and must always be considered for the increase in pregnancy related with assisted reproduction techniques, although, it should be considered in a spontaneous pregnancy too.

Adult↗

Reproductive biotechnologies for endangered mammalian species.

Assisted reproductive techniques (gamete cryopreservation, artificial insemination, embryo transfer, and in vitro fertilization) allow to propagate small fragmented populations of wild endangered species or domestic breeds. There are the best way for producing several offspring from selected genitors in order to avoid inbreeding depression. However, few mammalian species have been well studied for their reproductive biology whereas huge differences have been observed between these species. Furthermore, materials, methods and experimental designs have to be adapted for each case and each limiting factor (wildness, poor quantity of biological material, disparate locations). Genome resource banking is currently arising and the most applied reproductive biotechnology remains artificial insemination. Assisted reproductive techniques currently developed in domestic species (intracytoplasmic sperm injection, nuclear transfer) may offer new opportunities for the propagation of endangered species.

Animals↗

New indication of testis biopsy for azoospermia: a clinical study in Japanese patients.

Because of the progress made with assisted reproductive techniques, we decided to clarify the indication for testis biopsy in Japanese azoospermic patients. A total of 88 azoospermic patients were recruited with testis histologies obtained by bilateral biopsy. Testicular histology was evaluated using Johnsen's score count. Patients with at least 1 testis containing sperm were assigned to the active spermatogenesis group. Patients whose testes had no sperm were assigned to the hypospermatogenesis group. Differences in terms of the clinical data between the 2 groups were analyzed. Clinical data consisted of past history, physical examination and hormone concentrations. The unpaired t test was generally used to examine the statistical significance of any differences between the 2 groups. 1) There were significant differences between the 2 groups in the levels of serum testosterone and luteinizing hormone. 2) There were markedly significant differences between the 2 groups in terms of testis volume and the concentration of serum follicle-stimulating hormone (FSH). 3) The smallest testis volume and the highest serum FSH value in the active spermatogenesis group were 7 ml and 32.7 mlU/ml (normal range 2.9-8.2), respectively. In conclusion, although the presence or absence of active spermatogenesis can be accurately predicted by measuring the testis volume and serum FSH, testis biopsy should be carried out in patients with a testis volume greater than 7 ml or a serum FSH less than 4 times normal when the use of assisted reproductive techniques are planned.

Adult↗

Ascites and liver test abnormalities during severe ovarian hyperstimulation syndrome.

OBJECTIVE: Severe ovarian hyperstimulation syndrome is an uncommon cause of ascites that is being increasingly recognized because of the high number of women undergoing assisted reproductive techniques, mainly in vitro fertilization. This prospective study investigates the clinical and biochemical characteristics of a large series of patients with this syndrome and ascites, including renal and electrolyte abnormalities, activity of neurohormonal systems participating in the regulation of extracellular fluid volume, and liver function tests. METHODS: This was a prospective longitudinal study including 50 consecutive patients with ascites due to severe ovarian hyperstimulation syndrome. Renal function, serum electrolytes, body weight, mean arterial pressure, pulse rate, plasma renin activity, plasma concentration of aldosterone, norepinephrine, antidiuretic hormone and atrial natriuretic peptide, and standard liver function tests were measured during the syndrome and 4-5 wk after recovery. A sample of ascitic fluid was obtained from eight patients for protein measurement and cell count. RESULTS: At diagnosis, patients had ascites associated with low urinary sodium excretion, oliguria, and hyponatremia. They had also markedly low arterial pressure and increased pulse rate in association with marked activation of vasoconstrictor and antinatriuretic factors. The ascitic fluid was characterized by a high protein concentration, low leukocyte count, and relatively high number of red blood cells. Fifteen (30%) patients had abnormal liver tests characterized by mild to moderate increases in AST (mean 103 +/- 17.1 IU/L) and ALT (76 +/- 8.3 IU/L), which were associated in some cases with increases in gamma-glutamyl transpeptidase or alkaline phosphatase. All abnormalities reverted to normal after the resolution of the syndrome. CONCLUSIONS: With the increasing use of assisted reproductive techniques, physicians should be aware of severe ovarian hyperstimulation syndrome as a cause of ascites. The syndrome is associated with sodium retention, hyponatremia, arterial hypotension, and marked activation of vasoconstrictor and antinatriuretic systems. In one third of patients, liver tests abnormalities are present.

Adult↗

Heparin and Ca2+-free medium can enhance release of bull sperm attached to oviductal epithelial cell monolayers.

The success of assisted reproductive techniques, such as IVF, could be enhanced by being able to select the most competent spermatozoa in a sample. Attachment and subsequent release of spermatozoa from oviductal epithelial cells (OEC) could provide populations of functionally superior spermatozoa for use in these protocols. The objective of the present study was to investigate the ability of heparin and Ca2+-free medium to induce spermatozoa release from bovine OEC. Epithelial cells were grown to confluence in 24-well plates and pooled frozen bull semen was added to a final concentration of 1 x 10(6) spermatozoa/well. Spermatozoa were allowed to bind to OEC for 2 h. Medium with unbound spermatozoa was removed and replaced by Sperm-TALP, only (control), with heparin (5, 10, or 15 IU/mL), or Ca2+-free with 2 mM EGTA. Treatments were left on sperm-OEC co-cultures for 0.5, 1, 2, 3, or 5 h. At each time, the media were recovered and spermatozoa from each treatment were counted and evaluated for acrosome integrity and motility. The total number of spermatozoa attached to OEC after 2 h of co-culture was considered 100%. Spermatozoa release is expressed as percentage of the total number of sperm cells bound to OEC after 2 h of co-culture. Data were analyzed by ANOVA and results are expressed as mean +/- SEM from three independent replicates. Beginning at 0.5 h, more sperm cells (P < 0.05) were released from OEC in the heparin groups (10 and 15 IU/mL, 77.3 +/- 6.2% and 84.0 +/- 6.2%, respectively) as compared to the control (46.4 +/- 6.2%). The Ca2+-free medium also induced spermatozoa release when compared with the control, but the effect was not significant until 3 h (38.2 +/- 1.9% vs 59.5 +/- 6.9%; P < 0.05). The percentage of acrosome reacted spermatozoa was not affected by heparin treatment. Heparin at 10 IU/mL increased (P < 0.05) the percentage of motile spermatozoa, whereas Ca2+-free medium caused the opposite effect at 0.5 h after addition of treatments. We conclude that both heparin and Ca2+-free medium are able to promote spermatozoa displacement from OEC attachment. Based on motility and acrosome status data, we predict that released sperm cells may be used for IVF and other assisted reproductive techniques.

Animals↗

[Oocyte donation in France and national balance sheet (GEDO). Different European approaches].

Oocyte donation (OD), a technique successfully used in Assisted reproductive techniques (ART), has been effective for 20 years as the palliative treatment of certain exocrine ovarian failures. Its indications have also been extended to cover some genetic diseases and documented occult ovarian insufficiency. In France, after an extensive judicial and ethical deliberation, OD was deemed legal and its practice was proscribed in the Bioethics Laws 94-653 and 94-654 of 29 July 1994. Its essential underlying principles are: voluntary, free, anonymous and confidential OD; according to a French decree to meet safety concerns, OD-derived embryos must be quarantined for six months. In vitro fertilization (IVF) programs using donated oocytes are conducted in authorized centers under the responsibility of physicians authorized to retrieve and manipulate donated oocytes. The managers of these programs are the system's keystone, as their role includes, among other, the verification of indications, legal documents, public health safety, anonymous pairing of donor and recipient, and the collection of outcome data. At present, depending of the year, French programs have achieved 17-22% clinical pregnancy rates from transferred OD-derived frozen-thawed embryos, and follow-up studies reported excellent results concerning family relationships, and the physical and psychological development of the children. However, difficulties encountered in the daily practice of OD have led concerned physicians to form the Study group for OD (GEDO) to explore different topics with the aim of improving the overall management of this form of ART. We discussed these points herein, in comparison with the approaches of other European countries.

Adult↗

Assisted human reproductive techniques--emerging ethical and legal implications.

The unprecedented and rapid advances in medical sciences have revolutionized modern medicine and surgery in a number of ways. These advances such as human embryo cloning, trans-genetic manipulation, in-vitro fertilization and surrogate motherhood have been able to cure infertility to a large extent by offering 'made to measure or super babies' and can cure a number of conventional diseases and improve the quality of life. Scientists and sociologists are concerned about moral and ethical issues, which have arisen due to these advances in medicine. The new biotechnology and the achievements in bio-engineering offered hope to those couples in fulfilling their yearning for children. What we witness today is just the beginning and not the end of the adventurous march of science in unravelling the mysteries of nature. The moot point now is how can nature be engineered to yield positive results without offending values of human morality, ethics and decency. It is high time that governments and society take stock of the current dilemma, as these advances in biosciences pose a threat to the moral and ethical fabric of modern society.

Ethics, Medical↗

[Gynecologic surgery evolution during the 50 years of professional career in surgery].

This is a retrospective analysis of how gynecological surgery has changed over the last 50 years; these practices have been modified from mutilative and extirpative to conservative and with the least invasion possible. The major breakthroughs-apart from changes in pathology-have been those with use of microsurgery techniques, endoscopic surgery, and assisted reproductive techniques; this highlights the fact that each day surgeon gynecologists are better prepared. Also, there has occurred the notable evolution of methods of detection and diagnosis such as laboratory test, MRI, ultrasound, CT, etc. as well as anesthetic procedures. We describe the most notable changes of gynecological surgery techniques with different examples and figures. Surgical obstetric procedures will be shown in another communication.

Female↗

Flow cytometry in human reproductive biology.

Flow cytometry (FC) is an analytical cytology technique which has been extensively used for decades. It has many advantages compared with other similar methods for the study of cell biology, even on a molecular basis. FC allows the cell-by-cell analysis of many optical or immunological features in the same sample, at the same time, and at a rate of thousands of cells per second, generating immense quantities of data and thus providing almost limitless information which is statistically robust due to the number of units studied. The aim of this review is to describe the contribution of FC to the study of physiological and pathological processes related to human reproduction, and to discuss how this technique has been used in research, as well as its clinical applications in this field. We have used some practical examples selected from the most relevant studies within a wide range of investigations published in the literature, and we have also drawn on our own experience of using flow cytometry to study different phenomena related to reproduction. It is conclued that FC is a useful instrument for basic investigation of gynecological issues, as well as for the study of male reproductive characteristics, either in research applications or directly for clinical diagnostic purposes. Future development of these techniques will permit further advances both in our knowledge and in the improvement of assisted reproduction techniques.

Acrosome Reaction↗

Detection and characterization of hepatitis C virus RNA in seminal plasma and spermatozoon fractions of semen from patients attempting medically assisted conception.

To investigate the risk of transmission of hepatitis C virus (HCV) via semen in assisted reproduction techniques, semen samples from 32 men chronically infected with HCV attending a center for assisted procreation were tested for HCV RNA by a reverse transcription-PCR protocol by using a modified version of the Cobas AMPLICOR HCV assay (version 2.0; Roche Diagnostics). The sensitivity of the test was 40 copies/ml. Four of 32 seminal plasma samples (12.5%) were found to be positive for the presence of HCV RNA. The median HCV load in blood was significantly higher in patients who were found to be positive for the presence of HCV RNA in semen than in those who tested negative (P = 0.02). In one man, seven consecutive seminal plasma samples tested positive for HCV RNA, as did two consecutive motile spermatozoon fractions; the corresponding fractions obtained after migration of the spermatozoa remained negative. Despite the absence of the proven infectivity of virus in semen samples that test positive for HCV RNA, these findings highlight the fact that seminal fluid may exhibit prolonged HCV RNA excretion. The usefulness of HCV RNA detection in both seminal plasma and spermatozoon fractions before the start of a program of medically assisted reproduction in couples in whom the male partner is chronically infected with HCV would need to be evaluated prospectively with a larger population of subjects exhibiting HCV RNA in their semen.

Adult↗

Assisted reproduction versus spontaneous conception: a comparison of the developmental outcomes in twins.

The use of assisted reproductive technology is increasing rapidly. Research, although sparse, has resulted in inconsistent findings as to the developmental prognosis for infants conceived by assisted reproductive techniques such as in vitro fertilization and the use of fertility drugs. In the present study, the authors compared twins who were spontaneously conceived with those who were conceived through assisted reproductive technology. The authors found differences in birth weight and gestational age. Infants conceived by assisted reproductive technology fared worse than did those who were spontaneously conceived. The authors found no differences between the groups in mental development at 24 months of age, but they found evidence of differences in physical development. Implications of the findings are discussed.

Adult↗

Transcervical tubal transfer of gametes and embryos.

The benefit of intrafallopian transfer techniques is still disputable in assisted reproductive techniques. On this background, alternatives to laparoscopic transfer procedures are in development. Current transcervical intrafallopian transfers of gametes and embryos are lacking success and reproducibility of results. New developments in catheter techniques and optical systems are offering new concepts for more successful transcervical approaches and preparing the basis for truly prospective studies.

Embryo Transfer↗