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PubMed1990

An ethical issue for reproductive technologies.

The establishment of "new birth technologies" (such as ovulation induction, in vitro fertilization and gamete intrafallopian transfer) has raised many ethical issues. One such issue is "selective fetal reduction", a process advocated in the management of excessive multiple pregnancy. The ethics of "selective fetal reduction" involve consideration of not only the efficacy of the process and the destruction of fetuses per se, but more specifically consideration of the moral dilemma of destroying some fetuses for the probable benefit of the remainder. The latter I consider here. Following from this ethical analysis it is suggested that the law regarding abortion should permit selective reduction in high multiple pregnancies, that is pregnancies of 4 or above. I contend that the law should prohibit deliberate exposure (in an infertility programme) to significant risk of high multiple pregnancy, when there is full intention to reduce any subsequent pregnancy of high multiple size.

Abortion, Induced↗
PubMed2001

Multiple gestations in assisted reproductive technology: can they be avoided with blastocyst transfers?

OBJECTIVE: Blastocysts are advanced-stage embryos with high implantation potential; theoretically, limited numbers of blastocysts can be used for embryo transfer to achieve good pregnancy rates with low multiple pregnancy rates. Clinical outcomes of a newly implemented blastocyst transfer program were evaluated. STUDY DESIGN: This study is a retrospective analysis of 553 blastocyst transfer cycles performed by a university-based in vitro fertilization program; risk factors associated with multiple gestations were analyzed. RESULTS: An average of 2.2 embryos were used for embryo transfer. The overall clinical pregnancy rate per embryo transfer was 45.1%; multiple gestation, twin, and triplet rates were 40.9%, 36.5%, and 4.3%, respectively. Multiple gestations increased significantly (1) when embryo transfer was done on day 5, (2) when > or =2 blastocysts were present on day 5, and (3) when maternal age was < or =30 years. CONCLUSION: In spite of a conservative approach to the number of blastocysts used for embryo transfer, the overall multiple pregnancy rate was high, and triplet pregnancies did occur.

Blastocyst↗
PubMed1999

Endometriosis and assisted reproductive technologies.

The association between endometriosis and infertility is well established, and different mechanisms have been postulated to cause infertility depending on the stage of endometriosis. Controlled ovarian hyperstimulation improves pregnancy outcome for minimal to mild endometriosis; however, there are no randomized controlled studies of this technique in patients with severe disease. Further, ART appears to have an overall beneficial effect for all stages of endometriosis. Based on the current staging system, several studies have not been able to demonstrate a significant difference in true outcomes for different stages of the disease. The limitations of these studies have been discussed above. Similarly, the effect of endometriomas when considered independent of the stage is still unclear. In addition to ART, pretreatment with GnRH analogues or surgical intervention may be beneficial and needs to be addressed in randomized controlled studies. It is evident that we urgently need large randomized studies to answer several questions about the treatment of endometriosis-associated infertility with ART. Although our current practice is based primarily on retrospective observational studies and small randomized studies, the overall impact on pregnancy outcome is beneficial.

Endometriosis↗
PubMed2000

Human chorionic gonadotropin as a predictor of outcome in assisted reproductive technology pregnancies.

OBJECTIVE: To determine whether serum hCG and progesterone levels obtained 16 days after ovulation are reliable predictors of pregnancy outcome. DESIGN: A retrospective study. SETTING: The data were obtained from two integrated Adelaide-based clinics: the Queen Elizabeth Hospital and Wakefield Clinic. PATIENT(S): Women who have achieved a pregnancy through ART treatment. MAIN OUTCOME MEASURE(S): Analysis of data using logistic regression (STATA v.5.0) to predict a binary outcome: ongoing pregnancy or miscarriage. Ongoing pregnancy was defined as progression to >20 weeks' gestation. Miscarriage included spontaneous abortion, biochemical and ectopic pregnancies, and blighted ovum. RESULT(S): Human chorionic gonadotropin was found to be the main determinant of ongoing pregnancy. Age and progesterone had minor effects, whereas stimulation, luteal support, and treatment types were nonpredictive. Low hCG levels between 25 and 50 IU/L are associated with a low probability of ongoing pregnancy (<35%), whereas levels of >500 IU/L predict a >95% chance of ongoing pregnancy. CONCLUSION(S): A single serum hCG level 16 days after ovulation provides a useful predictor of pregnancy outcome.

Abortion, Spontaneous↗
PubMed2002

Children born after assisted reproductive technology.

Since the birth of Louise Brown in July 1978 and the birth of the first intracytoplasmic sperm injection (ICSI) child in January 1992 many couples with longstanding female-factor or male-factor infertility can be helped to overcome their infertility resulting in a delivery and birth of a child. The final and ultimate goal of all infertility treatments has been to give the large population of infertile couples a chance to fulfil their childwish and experience the happiness of having a healthy child. Major advances have been made in the different treatment protocols for infertility during the last 25 years. It is, however, surprising that only a limited number of studies have been carried out assessing the health of the children born after ART. In this review we shall comment on the limitations of follow-up studies on ART children and we shall review existing data on the outcome of in vitro fertilization (IVF) and ICSI pregnancies. The most important outcome data consist of information on minor and major congenital malformations obtained prenatally or after birth, as well as on the further development of the children.

Chromosome Aberrations↗
PubMed2005

Resolving methodological and clinical issues in the design of efficacy trials in assisted reproductive technologies: a mini-review.

The validity, importance and relevance of randomized controlled trials depend on identifying an appropriate target population, ensuring adequate power, careful attention to the details of randomization and blinding, and selection of an endpoint that is important to the target population. With efficacy trials more than effectiveness trials, additional constraints are needed to reduce the variability that is typical of clinical practice: a narrowly defined sample, unvarying pre-randomization procedures and post-randomization treatments and follow-up that are as identical as possible for all patients. Efficacy trials comparing ovarian stimulation protocols should have strict protocol definitions, specific concomitant medications and minimal variability between centres with respect to stimulation goals and dose adjustments. Additionally, there should be narrowly defined criteria for administration of chorionic gonadotrophin, type of luteal support, embryo transfer and freezing policies. The goal of efficacy trials is to minimize the variability that is extrinsic to the comparison. When efficacy has been proven, effectiveness trials are needed to determine whether the effect of the new intervention is robust in the variability of typical clinical settings.

Adult↗
PubMed2001

Microsurgical varicocelectomy in the era of assisted reproductive technology: influence of initial semen quality on pregnancy rates.

OBJECTIVE: To evaluate the natural history of infertile couples in whom the man underwent varicocelectomy. DESIGN: Retrospective study. SETTING: University infertility clinic. PATIENT(S): 159 infertile couples. INTERVENTION(S): Microsurgical varicocelectomy. MAIN OUTCOME MEASURE(S): Standard semen parameters and pregnancy rates (assisted and unassisted). RESULT(S): Postoperative sperm concentration and motility increased significantly compared to before the varicocelectomy (28.9 +/- 3.0 vs. 22.5 +/- 2.1 x 10(6)/mL and 33.9 +/- 1.9 vs. 22.1 +/- 1.3%, respectively). Overall, 48% (76/159) of the couples achieved a spontaneous pregnancy at the mean of 30 months' follow-up. An additional 10% (16/159) and 11% (18/159) of couples achieved a pregnancy following intrauterine insemination and in vitro fertilization/intracytoplasmic sperm injection, respectively. Significantly higher spontaneous pregnancy rates were observed in couples in whom the man's initial sperm concentration was greater than or equal to 5 million sperm per milliliter compared to those in whom the man's initial sperm concentration was less than 5 million sperm per milliliter (61% vs. 8%, respectively). CONCLUSION(S): Our data demonstrate that, in couples in whom the man undergoes varicocelectomy for treatment of varicocele, close to 70% achieve a pregnancy. The initial sperm concentration is predictive of unassisted pregnancy outcome in this population.

Adult↗
PubMed2004

Implantation failure in assisted reproduction technology and a critical approach to treatment.

In this article, we review the literature and our personal experience regarding the many factors that appear to influence implantation rate. Oocyte quality, as determined by patient age and aneuploidies, probably plays a major role in RIF. However, a panoply of other factors have been brought under investigation, quite often with contradictory results and additional intriguing questions to be studied. Infections of the vagina, cervix, and endometrium, the role of mucus aspiration and washing of the cervix on transfer, the role of catheter guidance for a correct transfer and potion of embryos, the effect of mock transfer, and the role of hysteroscopy and its timing before transfer procedures are analyzed both as a review of the literature and as opinions and data from our experience. Many of these factors are interlaced and from the apparently simple issue of trauma, to infections and immune modulation of hatching and implantation, a biological continuum can easily be identified. The impact of abnormalities of the immune system and of homeostasis abnormalities is also covered in a brief overview of reported works and our experience. These latter areas probably constitute the common biological background of all other external factors that, however, the skilled must equip themselves for improving implantation success.

Embryo Implantation↗
PubMed2004

Degradation of paternal mitochondria after fertilization: implications for heteroplasmy, assisted reproductive technologies and mtDNA inheritance.

Maternal inheritance of mitochondrial DNA has long been regarded as a major paradox in developmental biology. While some confusion may still persist in popular science, research data clearly document that the paternal sperm-borne mitochondria of most mammalian species enter the ooplasm at fertilization and are specifically targeted for degradation by the resident ubiquitin system. Ubiquitin is a proteolytic chaperone that forms covalently linked polyubiquitin chains on the targeted proteinaceous substrates. The polyubiquitin tag redirects the substrate proteins to a 26-S proteasome, a multi-subunit proteolytic organelle. Thus, specific proteasomal inhibitors reversibly block sperm mitochondrial degradation in ooplasm. Lysosomal degradation and the activity of membrane-lipoperoxidating enzyme 15-lipoxygenase (15-LOX) may also contribute to sperm mitochondrial degradation in the ooplasm, but probably is not crucial. Prohibitin, the major protein of the inner mitochondrial membrane, appears to be ubiquitinated in the sperm mitochondria. Occasional occurrence of paternal inheritance of mtDNA has been suggested in mammals including humans. While most such evidence has been widely disputed, it warrants further examination. Of particular concern is the documented heteroplasmy, i.e. mixed mtDNA inheritance after ooplasmic transplantation. Intracytoplasmic sperm injection (ICSI) has inherent potential for delaying the degradation of sperm mitochondria. However, paternal mtDNA inheritance after ICSI has not been documented so far.

DNA, Mitochondrial↗
PubMed1992

Endocrine abortion in assisted reproduction technologies (ART).

Luteal function, endometrial receptivity, endometrial prolactin and glycoprotein secretions, blastocyst-secreted immunomodulant factors and embryo quality are nowadays considered the main determinants involved in embryo implantation control. The endometrial factors are progesterone-dependent. Out of 128 cycles of ART (AIH-IU, GIFT, IVF-ET), performed in 67 women at the Dept. of Obstetrics and Gynaecology of Parma during the period 1986-1991, 31 conceptions were obtained (pregnancy rate: 24.21%), 7 of which miscarried (abortion rate: 22.58%). According to these data, ART high abortion rate is possibly connected with poor luteo-endometrial function and poor embryo quality. Controlled ovarian hyperstimulation is thought to inhibit embryo implantation after IVF-ET by decreasing endometrial receptivity. Such a situation can be treated either by exogenous progesterone administration or by tubal techniques (GIFT, TET) performed in non-tubal infertility. Both strategies showed to better endometrial receptivity. A delayed intrauterine embryo transfer at blastocyst stage, when cocultures allow to, is supposed to raise the implantation rate in tubal infertility by enhancing embryo selection and endometrial receptivity. This paper also reports preliminarily on the predictive value of beta-HGC and estradiol levels, as well as of endometrial thickness, on early pregnancy outcome.

Abortion, Threatened↗
PubMed1999

Impact of the "physician factor" on pregnancy rates in a large assisted reproductive technology program: do too many cooks spoil the broth?

OBJECTIVE: To determine whether in one program with unified treatment protocols, patients can expect varying treatment outcomes with different physicians. DESIGN: Retrospective data analysis. SETTING: University-affiliated infertility center with 14 physicians. PATIENT(S): One thousand eight hundred fifty IVF cycles performed consecutively between August 1995 and June 1997. INTERVENTION(S): The pregnancy rate and implantation rate per ET were evaluated for individual physicians between August 1995 and June 1996 (phase I). Physicians with lower success rates underwent strict supervision from July 1996 to June 1997 (phase II). MAIN OUTCOME MEASURE(S): Variations in success rates between physicians. RESULT(S): The pregnancy rate varied among the physicians from 13.2%-37.4%, and the implantation rate varied from 4.4%-14%. Some physicians' outcomes improved between phase I and phase II of the study, whereas others' did not. The pregnancy and implantation rates varied significantly for some physicians, depending on whether they were responsible for the choice of stimulation protocol, supervision of cycle monitoring, or ET in their own or other physicians' patients. CONCLUSION(S): Outcomes of IVF vary depending on the treating physician. Lower than expected pregnancy and implantation rates usually are not caused by poor ET techniques alone, but appear to be disproportionately the consequences of poor cycle stimulation.

Embryo Implantation↗
PubMed1999

Parenting stress and psychosocial well-being among parents with twins conceived naturally or by reproductive technology.

This study compared parenting stress and psychosocial well-being among parents with 1 year old twins conceived in three different ways: (i) spontaneously without any medical assistance (54 families), (ii) spontaneously following hormonal treatment (25 families) and (iii) following in-vitro fertilization (IVF) or artificial insemination (AI) with the semen of the social father (24 families). The investigation included the Parenting Stress Index (PSI) and the General Health Questionnaire (GHQ-30). Since the presence of older children differed significantly between the three groups, this factor was included in the statistical analysis. Overall, no significant differences were found between the three study groups, either for the mothers or for the fathers. Nevertheless, we found a main effect of the presence of older children and an interaction effect of the presence of older children and the conception mode on some of the scales for the mothers: first-time mothers showed significantly higher stress related to parental competence, health and the partner relationship compared with mothers who had older children. First-time mothers with a history of infertility obtained significantly higher stress scores for parental competence and health and showed lower psychosocial well-being compared with naturally conceiving first-time mothers and mothers with a history of infertility who already had children.

Adult↗
PubMedDate not supplied

DNA fragmentation of spermatozoa and assisted reproduction technology.

Despite the ever-increasing knowledge of the fertilization process, there is still a need for better understanding of the causes of sperm DNA fragmentation and its impact on fertilization and pregnancy. For this reason, human sperm DNA fragmentation was investigated by means of the terminal deoxynucleotidyl transferase-mediated dUDP nick-end labelling (TUNEL) assay and the production of reactive oxygen species (ROS) in the ejaculate and in the spermatozoa themselves. These data were correlated with fertilization and pregnancy data from IVF and intracytoplasmic sperm injection (ICSI) patients. Sperm DNA fragmentation did not correlate with fertilization rate, but there was a significantly reduced pregnancy rate in IVF patients inseminated with TUNEL-positive spermatozoa. ICSI patients exhibited the same tendency. This implies that spermatozoa with damaged DNA are able to fertilize an oocyte, but at the time the paternal genome is switched on, further development stops. The determination of ROS in the ejaculate and the percentage of ROS-producing spermatozoa revealed markedly stronger correlations between sperm functions (i.e. motility) and the percentage of ROS-producing spermatozoa. The influence of seminal leukocytes, known to produce large amounts of oxidants, on sperm DNA fragmentation should not be neglected.

DNA Damage↗
PubMed1999

Psychosocial stress and treatment outcome following assisted reproductive technology.

This study investigated the association between psychosocial stress and outcome of in-vitro fertilization and gamete intra-Fallopian transfer treatment. Ninety women, enrolled for treatment at a private infertility clinic, completed two self-administered psychometric tests (Bi-polar Profile of Mood States, POMS; and State-Trait Anxiety Inventory, STAI) and a questionnaire to ascertain demographic and lifestyle characteristics before the start of treatment. Approximately 12 months later an outcome measure was determined for each participant in terms of whether she was pregnant or not pregnant and the number of treatment cycles undertaken to achieve clinical pregnancy. The women's scores on the psychological tests were similar to published normative scores. On univariate analysis, history of a previous pregnancy was positively related to the probability of pregnancy and full-time employment, a more 'hostile' mood state and higher trait anxiety were associated with a lower cumulative pregnancy rate. A Cox multiple regression model found previous pregnancy history, trait anxiety, and the POMS agreeable-hostile and elated-depressed scales to be the most important lifestyle and stress variables predictive of pregnancy. The results emphasize the importance of psychosocial stress in treatment outcome but indicate that the relationships are complex. Further studies are required to validate whether these findings can be generalized to other populations.

Adult↗
PubMed2003

Safety issues in assisted reproduction technology: Should men undergoing ICSI be screened for chromosome abnormalities in their sperm?

The incidence of aneuploidy in gametes of men undergoing ICSI has raised the prospect of there being risks associated with ICSI and the question of whether or not to screen men for sperm aneuploidy before treatment. We report results of a questionnaire undertaken to address how IVF staff perceive this problem, whether ICSI men are already being screened for sperm aneuploidy and the extent to which IVF specialists feel that there is merit in such a test. The results suggest that this is seen as a problem but most feel the risks outweigh the benefits. Most claimed their clinics do not screen sperm for aneuploidy but feel that there is merit in doing so. There are considerable benefits to screening i.e. couples would get additional information about the genetic repercussions of ICSI and could make informed decisions before treatment; screening would also facilitate the design of a large research study to give clearer answers on the safety of ICSI. However, we acknowledge counter arguments i.e. families would not necessarily benefit as most would have the ICSI procedure regardless of screen results; sex chromosome trisomies clinically are not severe enough to worry about in this context and there are other potential risks of ICSI that screening would not address.

Aneuploidy↗
PubMed2005

Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study.

The objective of this prospective, randomised study was to compare the efficacy, safety and tolerability of vaginal micronised progesterone with oral dydrogesterone as luteal phase support after in-vitro fertilisation (IVF). A total of 430 women underwent IVF/intracytoplasmic sperm injection (ICSI) treatment. Long protocol gonadotropin releasing hormone analogue down-regulation was followed by gonadotropin stimulation. Human chorionic gonadotropin was given when two or more follicles reached > or = 17 mm. After 36 h, oocytes were retrieved and IVF was performed. Embryo transfer was done at the 4-8 cell embryo stage. Luteal support was initiated from the day of embryo transfer and continued for up to 14 days. Patients were randomised to luteal supplementation with either intravaginal micronised progesterone 200 mg three times daily (n=351) or oral dydrogesterone 10 mg twice daily (n=79). In cases of a positive pregnancy test, luteal support was continued for 12 weeks. Both dydrogesterone and micronised progesterone were associated with similar rates of successful pregnancies. Vaginal discharge or irritation were reported by 10.5% of patients given micronised progesterone. Significantly (p<0.05), more patients given dydrogesterone than micronised progesterone were satisfied with the tolerability of their treatment. There were no differences between the treatments with regard to liver function tests.

Administration, Intravaginal↗
PubMed2004

Prognostic role of preimplantation genetic diagnosis for aneuploidy in assisted reproductive technology outcome.

BACKGROUND: Preimplantation genetic diagnosis (PGD) for aneuploidy is recommended to couples at risk of generating chromosomally abnormal embryos. The aim of this study was to demonstrate that PGD for aneuploidy has an important role in the prognosis of subsequent treatments. METHODS: A total of 389 couples underwent their first PGD for aneuploidy due to either female age >or=38 years (n = 266) or >or=3 previous unsuccessful cycles (n = 123). After the first PGD followed by an unsuccessful treatment cycle, 141 couples underwent 175 subsequent PGD cycles. These patients were divided into three groups depending on the number of euploid embryos available for transfer in their first PGD cycle: group A included patients where no euploid embryos were diagnosed; group B included patients who had only one euploid embryo; and group C included patients with at least two normal embryos resulting from chromosomal analysis. RESULTS: In subsequent cycles, group A patients underwent significantly fewer transfers (45%) compared with group B (69%, P < 0.05) and group C patients (85%, P < 0.001). The pregnancy rate per transfer was significantly decreased in group A (15%) compared with group B (36%; P < 0.02) and group C (30%; P < 0.03). Accordingly, the live birth rate per patient was significantly lower in group A compared with group C (8.5% versus 30%; P < 0.005). CONCLUSIONS: The outcome of the first PGD for aneuploidy may have a predictive role for subsequent attempts.

Adult↗
PubMed2002

Ovarian hyperstimulation syndrome and assisted reproductive technologies: why some and not others?

BACKGROUND: alpha(2)-Macroglobulin (alpha(2)M) is a multifactorial binding protein, found in follicular fluid, that is a naturally occurring inhibitor of vascular endothelial growth factor (VEGF). The aim of this study was to determine if there is a relationship between serum VEGF levels, alpha(2)M levels and the development of OHSS in hyperstimulated subjects undergoing IVF (those with 15 or more oocytes). METHODS: Venous blood was collected at the time of oocyte retrieval from subjects who yielded 15 or more oocytes. Serum samples were analysed for VEGF and alpha(2)M concentrations. RESULTS: There was no statistically significant difference in serum VEGF levels at the time of oocyte retrieval between hyperstimulated subjects who did and did not subsequently develop OHSS [3.95 (3.3-4.4) versus 3.85 (3.3-4.5); P = 0.79]. By contrast, the serum level of alpha(2)M was statistically significantly higher in the group of subjects who did not develop OHSS [2.27 (1.91-2.58) versus 1.67 (1.45-1.73)]. CONCLUSIONS: These results suggest that elevated alpha(2)M levels are associated with a decreased risk of developing OHSS. alpha(2)M may act by 'removing and inactivating' VEGF, with higher levels providing increased protection against the syndrome. alpha(2)M measurements may help to differentiate those for whom it is safe to proceed with embryo transfer from those for whom it is not, because of the risk of OHSS.

Adult↗