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The 45/2003 Spanish Act tries to solve the problem of the cryoconserved human embryos produced in in vitro fertilization (IVF) programmes. The new law, which modifies the 35/1988 Act on Artificial Reproduction Techniques, is analyzed from the scientific, ethical and legal points of view.
Over the past 40 years, our increased understanding and development of cell and molecular biology has allowed even greater advances in reproductive biology. This is most evident by the development of various aspects of assisted reproductive techniques (ART), generation of transgenic animals, and most recently generation of mammals through somatic cell cloning. To date, cloning from adult somatic cells has been successful in at least 10 mammalian species. Although generating viable cloned mammals from adult cells is technically feasible and the list of successes will only continue to grow with time, prenatal and perinatal mortality is high and live cloned offspring have not been without health problems. The success of many of the proposed applications of the cloning technique obviously depends upon the health and survival of founder animals generated by nuclear transfer. This article summarizes the health consequences of cloning in mice, and discusses possible mechanisms through which these conditions may arise. In addition, we discuss the effects of ART in animal models and in humans. ART also involves some of the same procedures used in cloning, and there are reports that offspring generated by ART sometimes display aberrant phenotypes as well. It is important to point out that although these techniques do sometimes produce abnormalities, the majority of offspring are born apparently normal and survive to adulthood. Additionally, we must emphasize that the effects of ART and cloning observed in animal models do not necessarily indicate that they will occur in humans. In this article, we review studies examining the phenotype of animals generated by cloning and various ART, and discuss clinical implications of these findings.
OBJECTIVE: To assess the incidence of spontaneous embryo reduction as well as the obstetric and neonatal outcome of triplet gestations after assisted reproductive techniques (ART). METHODS: We analyzed the spontaneous outcome of 38 pregnancies in which three gestational sacs were identified with vaginal ultrasound between 21 and 28 days after ART. Weekly follow-up visits were scheduled during the first trimester until referral to a high-risk obstetrician. After delivery, each patient was interviewed individually and, if necessary, the obstetrician was contacted. RESULTS: The triplets delivery rate was 47.4%, whereas 31.6% delivered twins, 18.4% delivered singletons, and only one patient miscarried all three cases (2.6%). Finding three fetal heart beats was associated with a triplet delivery rate of 69.2%, a twin incidence of 19.2%, and a singleton birth rate of 11.6%. Embryo resorptions were observed mainly during the first 7 weeks of gestation and did not occur beyond the 14th week. The mean gestational age at delivery and neonatal birth weight were significantly lower among triplets (32.8 weeks and 1,740 g versus 35.3 weeks and 2,352 g in twins and 39.1 weeks and 3,122 g for singletons). Triplets had a 100% prematurity and cesarean section rate compared with 67% and 75% in twins and 0% and 43% in singletons, respectively. Hospitalization at the Neonatal Intensive Care Unit was required in 83% of newborn triplets, 29% of twins, and 0% of singletons, with a mean stay of 34 and 21 days for triplets and twins, respectively. One stillbirth and no neonatal deaths were reported, with an overall perinatal mortality rate of 11.9 per 1,000. CONCLUSIONS: Spontaneously, approximately 50% of triplet pregnancies will experience at least one embryo resorption. The ongoing triplets demand a complex and more expensive perinatal management, a strong argument to consider limiting the number of oocytes-embryos transferred in ART.
From July 1992 to May 1994, 31 cases of obstructive azoospermia-induced infertility underwent 35 epididymal sperm aspiration procedures and assisted reproductive techniques. These included in-vitro fertilization (IVF), zygote intra-Fallopian transfer (ZIFT), subzonal insemination (SUZI) and intracytoplasmic sperm injection (ICSI) with embryo transfer or tubal embryos transfer. The motile spermatozoa were retrieved using a gauge 24 Medicut cannula and flush medium. Total oocyte fertilization rate was 23.4% and the clinical pregnancy rate was 12.5% (four out of 32 treatment cycles). Congenital absence of the vas deferens was found in 16 cases (51.6%) and secondary genital duct obstruction was present in 15 cases (48.4%). In all, 29 aspirations were retrieved from the caput of the epididymis and six from the epididymal body or tail. The fertilization rate for the caput spermatozoa was much less than that for other areas of the epididymis (P < 0.05). Though there were no predictable differences in fertilization rates between the congenital and acquired groups, by using epididymal spermatozoa for assisted reproduction, the congenital group seemed to have a stronger tendency to achieve pregnancy (20 versus 5.9%).
The author discusses the ruling by the Spanish Constitutional Court (116/99, 17 June) in the matter of the challenge on grounds of alleged inconstitutionality lodged against the Law on Assisted Reproduction Techniques back in 1989. Other circumstances concerning the application and development of said law are examined also and a detailed critical study is made of the legal points used in the Ruling. The article concludes with some thoughts on the main issues arising therefrom.
OBJECTIVE: To determine whether twin pregnancies conceived by assisted reproductive techniques are at increased risk for obstetric complications or perinatal morbidity. METHODS: A computerized perinatal data base was reviewed for all twin pregnancies managed by private obstetricians and delivered between 1990 and 1995. The obstetric and neonatal outcomes of those conceived following in vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT) were compared to the outcomes of those conceived spontaneously. RESULTS: There were 105 twin deliveries following IVF or GIFT and 279 following natural fertilization. Discordant birth weight and low birth weight occurred more frequently in pregnancies conceived by IVF or GIFT (adjusted odds ratio [OR] 2.11, 95% confidence interval [CI] 1.14, 3.91; OR 1.65, 95% CI 0.98, 2.79, respectively). Elective cesarean delivery was more frequent in twin pregnancies conceived after IVF GIFT (relative risk [RR] 4.02, 95% CI 1.28, 12.6). There were no statistically significant differences in the frequency of antepartum or intrapartum complications, preterm delivery, or mean gestational age at delivery. There was no statistically significant increase in the frequency of neonatal complications among infants born after IVF GIFT. CONCLUSION: Although twin pregnancies following IVF or GIFT are more likely to result in discordant birth weight infants, the perinatal outcome is comparable to that of spontaneously conceived twin pregnancies.
To assess successful implantation and early post-implantation embryonic development in assisted reproduction techniques, serum human chorionic gonadotropin (hCG) levels in early gestation in pregnancies with a singleton live birth as the outcome were evaluated. The study was performed as a prospective cohort study of patients undergoing in vitro fertilization (IVF) or artificial insemination by husband (AIH) following ovarian stimulation. Serum hCG levels on days 14, 16, 20 and 27 following ovulation induction with hCG were examined. Serum hCG values were significantly lower in early gestation in IVF compared with AIH, but no difference in hCG doubling times was observed. No difference in serum hCG values between IVF treatment with or without gonadotropin-releasing hormone agonist (GnRHa) was observed. Significantly lower hCG values but no difference in doubling times in early gestation in IVF compared with AIH may be explained by late but successful implantation in IVF. The mechanism for this assumed late implantation is not clear. Altered endometrial receptivity or factors of embryonic origin might explain the observed variation in hCG values and the assumed late implantation.
The objectives of this study was to assess the efficacy and clarify how many intrauterine insemination cycles can justifiably be proposed, in terms of cost and benefits for the patient, as alternative to other assisted reproduction procedures. Two hundred and twenty infertile couples were referred to our centre and six intra-uterine insemination cycles in combination with controlled ovarian hyperstimulation were proposed for them. A total of 650 treatment cycles were completed. The indications of intra-uterine insemination were male factor (147 couples), cervical factor (31 couples), male and cervical factor (30 couples) and unexplained infertility (12 couples). Superovulation was induced in 92 patients with human menopausal gonadotrophins, in 90 with clomiphene citrate, in 22 with FSH HP, while in 16 patients the intra-uterine inseminations were carried out during spontaneous cycles. Considering the entire population, a mean monthly pregnancy rate equal to 8.9% was obtained and a cumulative pregnancy rate equal to 39% at the end of six intra-uterine insemination cycles. In particular, in the patients treated with HMG+hCG, a mean monthly pregnancy rate equal to 10.9% and a cumulative pregnancy rate to 46% at the end of the six cycles were obtained. In conclusion, when the indications allow, we believe it is justified to propose six cycles of intra-uterine insemination in combination with controlled ovarian hyperstimulation with HMG and hCG. The theoretical probability of success at the end of six cycles has proved comparable and advantageous in terms of cost and risks for the patient, if compared with other assisted reproduction techniques.
The predictive value of sperm chromatin integrity for pregnancy outcome following in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) was studied in 24 men attending a university-based assisted reproductive techniques laboratory using the flow cytometric sperm chromatin structure assay (SCSA). The SCSA is a measure of the susceptibility of sperm DNA to low pH-induced denaturation in situ. The mean percentage of spermatozoa in the neat sample demonstrating DNA denaturation was significantly lower in the seven men that initiated a pregnancy (15.4 +/- 4.6, P = 0.01) than in the 14 men who did not initiate a pregnancy (31.1 +/- 3.2). No pregnancies resulted if > or =27% of the spermatozoa in the neat semen sample showed DNA denaturation. These data demonstrate that SCSA parameters are independent of conventional semen parameters. Furthermore, the SCSA may allow physicians to identify male patients for whom IVF and ICSI will be unlikely to result in pregnancy initiation.
The objective of this study was to investigate the size of singleton vs twin pregnancies at the time of a second trimester dating scan. The analysis included 86 infants from 63 pregnancies achieved with assisted reproductive techniques, comprising 40 singletons and 46 twins. Measurements of second trimester biparietal diameter (n = 85) and femur length (n = 74) were plotted against the precisely known gestational age. A common regression line was calculated for each parameter and the residuals for singletons and twins were compared. Gestational age and weight at birth were also analysed for each group. There was no significant difference between singletons and twins in biparietal diameter or femur length in second trimester. In contrast, twins had a lower mean birthweight, gestational age at birth, and weight-for-gestational age centile compared with singletons. Singleton babies from these pregnancies had an average birthweight centile of 49.8% (i.e. close to the median for spontaneously conceived pregnancies in our population). We concluded that the same pregnancy dating charts can be used for singletons and twins. At corresponding gestational age, twins are smaller than singletons at birth because of slower growth in the third trimester.
A growing number of children around the world are conceived through third-party reproductive techniques. The increased demand for these programs has resulted in an ongoing trend towards greater openness and less anonymity in gamete donation. This has led to changes in public policy regarding the identity of donors, to a greater concern for the well-being of donors, and to calls for disclosure to offspring about their donor gamete conception.
BACKGROUND: The assertion of a causal relationship between celiac disease and infertility is suggested by several lines of research. Nevertheless, robust evidence has not yet been provided. The present study evaluated, for the first time, the prevalence of celiac disease in women undergoing assisted reproduction techniques (ART). METHODS: Serum samples from 200 Italian women undergoing ART were evaluated for celiac disease by endomisium antibody (EMA) and transglutaminase antibody (t-TGA)-two highly sensitive and specific serological markers. Two hundred women not reporting reproductive problems and having delivered at least one child served as controls. In cases of positive serology, the diagnosis was confirmed by jejunal biopsy. RESULTS: Five (2.5%) women from the study group and two (1.0%) from the control group were found to have celiac disease (P = 0.44). The main indications for ART in women found to have celiac disease were tubal factor in two cases and male infertility in three cases. None of these women reported major gastrointestinal complaints. Extra intestinal signs linked to celiac disease were noted in four out of five patients. CONCLUSION: This study raises the issue of celiac disease screening in ART programmes. Given the available evidence in the literature combined with our observations from this study, the value of serological testing for celiac disease in infertile women remains uncertain. Further studies to address this issue are required.
BACKGROUND: Sterility in men with cystic fibrosis (CF) raises the question of the use of assisted reproductive techniques (ART). A multidisciplinary network including adult CF centre and reproductive medicine units was set up to answer requests for ART. METHODS: This retrospective study included 25 men with CF between 1994 and 2004. Clinical status, semen analysis, CF mutations analysis and artificial insemination by donor (AID) or ICSI after surgical retrieval of sperm were monitored. RESULTS: All CF men had azoospermia. Two chose AID first (one delivery); 23 chose ICSI. Sperm were surgically retrieved in 21 cases, and ICSI was performed in 19. Pregnancies occurred in 12 of these 19 couples (63%) (two ectopic pregnancies, two spontaneous abortions, one termination of pregnancy for polymalformed twins and 11 single deliveries in nine couples). Two couples tried AID after ICSI failed; one had twins. Another adopted a child, and two had a spontaneous pregnancy. After a follow-up of 4.1+/-2.3 years, two patients died, two underwent lung transplantation and 21 remained stable. CONCLUSION: ART can help men with CF to become a father, but their health status and short survival need careful counselling and multidisciplinary medical care.
Medical assistance for procreation in a couple where one or both parents has hepatitis C viral infection (HCV) raises the issue of the transmission of the infection to the baby and/or of possible contamination of both the technicians and the gametes or embryos from virus-free parents in the laboratory. It becomes essential to assess transmission risk in assisted reproductive techniques in order to define clearly the management of couples according to their viral status. To define the HCV transmissibility risk in assisted reproduction related to the presence of virus in semen from infected infertile men, HCV RNA detection was performed in sera, and semen and sperm fractions obtained after Percoll gradient centrifugation. HCV RNA was detected in 5% (2/39) of the semen samples tested: in the raw semen, in the seminal fluid and in the cell pellet but never after Percoll selection. According to these results, we suggest a strategy for HCV-infected infertile men who need assistance for procreation.
OBJECTIVE: To test the hypothesis that pregnancy rates are low if grade Z1 pre-embryos are not available for transfer and to determine if pronuclear morphology is a better predictor of pregnancy than traditional embryo morphology. DESIGN: Prospective clinical study. SETTING: Academic human reproduction laboratory. PATIENT(S): One hundred couples undergoing IVF with conventional insemination or ICSI. INTERVENTION(S): Embryo quality was assessed using both pre-embryo pronuclear morphology (zygote scoring or Z-scoring) at the time of fertilization evaluation and standard day 2 and day 3 embryo morphology (number of blastomeres and grading based on degree of fragmentation and blastomere size). MAIN OUTCOME MEASURE(S): We tested two decision models, one based on Z-scores and another on morphology, to determine which grading system better predicted pregnancy outcomes in assisted reproductive technique. Zygote score and embryo morphology were measured for all embryos and the transferred embryo pool. Implantation and pregnancy rates resulting from the embryo transfers of all cycles were calculated. RESULT(S): The Z-score distribution of 552 embryos was 27% Z1, 8% Z2, 50% Z3, and 15% Z4. Z1 and Z3 embryos had significantly (P approximately .03) higher quality over Z2 and Z4 embryos. Using the Z-score decision model with Z1 embryos having highest priority for transfer, pregnancy rates were similar between Z1 and Z3 embryos. Using embryo morphology as a decision model, pregnancy rates were highest in transfers containing one or two "best"-quality embryos. CONCLUSION(S): Z1 and Z3 embryos had similar morphology and pregnancy rates. The decision model based on the Z-score model was not better than standard embryo morphology in predicting pregnancy outcome.
The effects of Candida albicans on sperm parameters and the outcome of infertility treatment are unclear. This report describes a lack of fertilization after assisted reproductive techniques and increased sperm DNA fragmentation in an infertile patient with male accessory gland infection due to Candida albicans. He had normal sperm parameters and, therefore, underwent conventional IVF for a female factor of infertility. No spermatozoa or only one spermatozoon per oocyte were found attached to the zona pellucida of the six mature oocytes retrieved. A new semen sample was then requested from the patient to perform intracytoplasmic sperm injection (ICSI) on the same oocytes, but again no fertilization resulted. Candida albicans was detected in the medium where spermatozoa were co-incubated with oocytes and subsequently in the urethral swabs. It did not have any detrimental effect on sperm parameters soon after ejaculation or following separation of motile spermatozoa by swim-up technique. Fertilization failure after assisted reproduction treatment was associated with an increased percentage of motile spermatozoa having chromatin packaging abnormalities, externalization of phosphatidylserine and DNA fragmentation. In conclusion, Candida albicans did not affect sperm parameters, but increased sperm chromatin packaging damage and apoptosis that might have caused fertilization failure after assisted reproduction treatment in this couple.
BACKGROUND: Standard sperm characteristics are poor predictors of the outcome of IVF treatments. On the contrary, sperm genome quality has been emphasized for several years as playing a major role in early embryogenesis, thus in the success of IVF attempt. METHODS: Sperm DNA fragmentation from a selected group of 104 couples undergoing assisted reproductive techniques (ART) (IVF: n = 50; and ICSI: n = 54) was measured by TUNEL assay and correlated with semen and ART outcomes. RESULTS: A negative correlation was found between sperm characteristics and the proportion of sperm showing DNA fragmentation. For fragmentation >10%, a significant decrease of the fertilization rate was observed. No correlation was found between sperm DNA fragmentation and embryo quality. A high proportion of sperm with fragmented DNA was a pejorative factor to obtain pregnancies when ICSI was performed, but there was no relationship when conventional IVF was performed. CONCLUSIONS: The proportion of sperm with DNA fragmentation appears to be potentially useful as a predictor of ICSI outcome, whereas embryo quality based on morphological criteria, appeared unaffected by DNA fragmentation.
BACKGROUND: Granulosa-cells are able to produce and store leptin, suggesting that this hormone is locally involved in the regulation of follicular growth. In this study, the role of follicular fluid (FF) leptin concentration in predicting oocyte fertilization and embryo quality was evaluated in 35 normogonadotrophic women undergoing controlled ovarian stimulation (COS) for assisted reproductive techniques. MATERIALS AND METHODS: Leptin concentration was measured in 47 consecutively collected FF in which a mature oocyte had been found during the ovum pick-up. Embryos deriving from fertilized oocytes were submitted to quality scoring systems. RESULTS: Mean leptin concentration was significantly higher in FF whose oocytes showed 2 pronuclei (no. 25) when compared with those with no evidence of fertilization (no. 22) at the 16-18 h check (26.0+/-6.1 vs 15.3+/-10.6 ng/ml, respectively, p<0.01). Follicular mean diameters were similar in the two groups (21.4+/-3.4 and 21.0+/-5.1 mm, respectively). Logistic regression analysis identified FF leptin levels as the best predictive parameter for oocyte fertilization (p<0.001). When receiving operating characteristics curve was employed, a FF leptin concentration of 20.25 ng/ml was the most reliable cut-off in predicting fertilization of oocytes. FF with leptin concentrations higher than this value (no. 27) had an oocyte fertilization rate of 85.7%. In contrast, FF levels < or =20.25 ng/ml (no. 20) were associated with a rate of 16.7% (p<0.05). No correlation emerged between FF leptin and the score attributed to 15 valuable embryos at the zygote stage (r=-0.01) and at 48 h after insemination (r=0.1). CONCLUSIONS: FF leptin levels are a better predictor of oocyte fertilization success rates than follicular diameter. These results underline the relevance of FF variables in developing methods for oocyte selection.