The acrosome index, radical buffer capacity and number of isolated progressively motile spermatozoa predict IVF results

BACKGROUND: The accuracy by which a number of newly described semen variables can predict either total fertilization failure (TFF) or pregnancy outcome in IVF, has not previously been investigated. The study aim was, therefore, to determine prospectively the predictive value of these variables. METHODS: The semen variables investigated were the post-wash total progressively motile sperm cell count (TPMC(post-wash)), the acrosome index (AI), 'cytoplasmic residues' and normal sperm morphology, evaluated according to the strict criteria ('strict criteria'), as well as the fast and slow total radical trapping antioxidant potential ('fast TRAP' and 'slow TRAP' respectively). RESULTS: The study group (n = 87) showed a mean (+/- SD) number of 10.2 +/- SD retrieved oocytes, 12.6% TFF, a mean fertilization rate of 59.7% and a pregnancy rate of 19.5% (17/87). TFF was significantly predicted by TPMC(post-wash), 'strict criteria', AI and 'cytoplasmic residues' (all P < 0.05). The outcome after embryo transfer was significantly predicted by AI and 'fast TRAP'. Semen samples with an AI <5% and a 'fast TRAP' <1.14 mmol/l in particular did not result in any pregnancies after IVF-embryo transfer. CONCLUSIONS: Of all the measured and calculated semen variables, TPMC(post-wash) was the best predictor of TFF, whilst AI and 'fast TRAP' were the best predictors of pregnancy after IVF.     

Maternal serum beta-HCG and alpha-fetoprotein concentrations in singleton pregnancies following assisted reproduction

BACKGROUND: The reason for the elevated levels of HCG in assisted reproduction pregnancies remains unknown. Our hypothesis was that this increase is caused by the ovarian superovulation therapy. METHODS: We compared the beta-HCG and alpha-fetoprotein (AFP) multiples of the median (MoM) in singleton pregnancies after IVF or ICSI with those achieved by frozen embryo transfer (FET) in spontaneous cycles. RESULTS: The HCG and AFP MoMs (plus minus SEMs) of 59 FET pregnancies were compared with 144 IVF (including 48 ICSI) pregnancies. The maternal HCG of pregnancies following ovarian stimulation was 1.31 plus minus 0.08 MoM compared with 1.35 plus minus 0.12 MoM in the unstimulated ones. The values for AFP were 1.06 plus minus 0.05 versus 1.11 plus minus 0.05 respectively. No significant differences could be observed between pregnancies following stimulated IVF/ICSI and unstimulated FET cycles. CONCLUSIONS: Our results show that second trimester maternal serum HCG is also elevated in singleton pregnancies following spontaneous FET cycles. The increased maternal serum HCG in IVF pregnancies is thus not related to superovulation therapy. Because of the elevated maternal serum HCG levels, serum screening cannot be performed reliably in pregnancies following assisted reproduction technology. Ultrasonographic detection of the nuchal translucency is unaffected and should be used for this group of women undergoing assisted reproduction.     

Morbidity in a Danish national cohort of 472 IVF/ICSI twins, 1132 non-IVF/ICSI twins and 634 IVF/ICSI singletons: health-related and social implications for the children and their families

BACKGROUND: There is a lack of knowledge on child health as well as family well-being in IVF/ICSI twins. METHODS: These data originated from questionnaires completed by mothers taking part in a national cohort study of twin and singleton births occurring in Denmark in 1997. The overall response rate was 83%. The three cohorts consisted of all IVF/ICSI twin children (n = 472), all IVF/ICSI singletons (n = 634) and all non-IVF/ICSI twin children (n = 1132) born in Denmark in 1997. RESULTS: No major differences in physical health were observed between IVF/ICSI twins and non-IVF/ICSI twins. Compared with IVF/ICSI singletons, more IVF/ICSI twins were admitted to a neonatal intensive care unit (NICU) (P < 0.01) and more had surgical interventions (P = 0.03) and special needs (P = 0.02), moreover they had poorer speech development (P < 0.01). Correspondingly, IVF/ICSI twin mothers rated their infant's general health poorer than IVF/ICSI singleton mothers did. All discrepancies between IVF/ICSI twins and singletons disappeared after stratification for birthweight except for NICU admissions and speech development. Multiple logistic regression analyses showed that both IVF/ICSI and non-IVF/ICSI twin parents experienced more marital stress [odds ratio (OR) 2.9, 95% CI 2.2-3.8] and that twins had more impact on the mother's life (OR 1.7, 95% CI 1.2-2.4) compared with singletons. Nevertheless, the only predictor of low divorce/separation risk was IVF/ICSI treatment. CONCLUSION: Our study indicates that physical health of IVF/ICSI twins is comparable with that of non-IVF/ICSI twins. However, physical health of IVF/ICSI twins is poorer and the implications for the families stronger compared with IVF/ICSI singletons.     

Does ICSI affect early serum beta-HCG in pregnancies achieved after IVF?

This study was conducted to compare early serum human chorionic gonadotrophin (HCG) concentrations in singleton pregnancies achieved after intracytoplasmic sperm injection (ICSI), with those achieved after conventional in-vitro fertilization (IVF). Early serum HCG, 14-16 days after embryo transfer, was analysed in 99 IVF pregnancies achieved after ICSI (group A), and compared to 105 conventional IVF pregnancies (group B). All women were treated at the IVF Unit, Lis Maternity Hospital. Records were studied retrospectively. The mean +/- SE serum HCG concentration on day 14 after embryo transfer in group A was 190.5 +/- 17.4 mIU/ml, compared to 195.7 +/- 14.03 mIU/ml in group B. HCG concentration 14 days after embryo transfer in both groups A and B was higher in women with mechanical factor than in couples with male factor infertility or unexplained infertility (246 +/- 31.4, 183.3 +/- 16.4, 177.98 +/- 14.3 mIU/ml respectively). On the 16th day after embryo transfer, the HCG concentration increased, and the difference between the groups was maintained. Only in the subgroup of unexplained infertility did we find a difference in concentrations of HCG between ICSI and conventional IVF: on the 16th day following embryo transfer in this group there was a significant difference in HCG concentrations (395. 8 +/- 21 and 545.6 +/- 45.7 respectively; P = 0.04). HCG concentrations did not differ overall in the conventional IVF pregnancies compared with those achieved by ICSI. However, a statistical difference in early serum HCG concentrations was found in relation to the aetiology of infertility.     

Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. The European Orgalutran Study Group

A multicentre, open-label, randomized study of the gonadotrophin-releasing hormone (GnRH) antagonist ganirelix (Orgalutran((R))/Antagon((TM))) was performed in women undergoing ovarian stimulation with recombinant FSH (rFSH: Puregon((R))). The study was designed as a non-inferiority study using a long protocol of buserelin (intranasal) and rFSH as a reference treatment. A total of 730 subjects was randomized in a treatment ratio of 2:1 (ganirelix:buserelin) using an interactive voice response system which stratified for age, type of infertility and planned fertilization procedure [IVF or intracytoplasmic sperm injection (ICSI)]. The median duration of GnRH analogue treatment was 5 days in the ganirelix group and 26 days in the buserelin group, whereas the median total rFSH dose was 1500 IU and 1800 IU respectively. In addition, in the ganirelix group the mean duration of stimulation was 1 day shorter. During ganirelix treatment the incidence of LH rises (LH >/=10 IU/l) was 2.8% versus 1.3% during rFSH stimulation in the buserelin group. On the day of triggering ovulation by human chorionic gonadotrophin (HCG), the mean number of follicles >/=11 mm diameter was 10.7 and 11.8, and the median serum oestradiol concentrations were 1190 pg/ml and 1700 pg/ml in the ganirelix and buserelin groups respectively. The mean number of oocytes per retrieval was 9.1 and 10.4 respectively, whereas the mean number of good quality embryos was 3.3 and 3.5 respectively. The fertilization rate was equal in both groups (62.1%), and the same mean number of embryos (2.2) was replaced. The mean implantation rates were 15.7% and 21.8%, and the ongoing pregnancy rates per attempt were 20.3% and 25.7% in the ganirelix and buserelin groups respectively. Evaluation of all safety data indicated that the ganirelix regimen was safe and well tolerated. The overall incidence of ovarian hyperstimulation syndrome was 2.4% in the ganirelix group and 5.9% in the reference group. The results of this study support a safe, short and convenient treatment regimen of ganirelix, resulting in a good clinical outcome for patients undergoing ovarian stimulation for IVF or ICSI.     

Perinatal outcome and developmental studies on children born after IVF

Since the first birth after IVF, many scientific papers have been published on the technical aspects of the IVF procedure, but few studies have addressed the issue of the perinatal outcome of IVF pregnancies and of the children's development and well-being. A high rate of adverse outcome has been demonstrated in a large group of IVF pregnancies. Prematurity, low birth weight and perinatal mortality are higher than in the general population. The majority of these complications are related to multiple births, but they are also found in singleton pregnancies. An analysis of the multiple risk factors involved in these complications is needed. The infertile status of IVF patients clearly plays a role in the risk of adverse outcome. Age and parity may be important factors. The role of IVF itself has not been demonstrated convincingly. The effect of ovarian stimulation deserves further study. Most of the studies published on the follow-up of IVF children are reassuring, but it is clear that these studies are not sufficient to eliminate without doubt any adverse effects on the well-being of IVF children. All IVF pregnancies should be followed with great care, not because they are more precious than spontaneous pregnancies, but because they are exposed to an increased risk of complications. The main problem of IVF remains the high rate of multiple pregnancies, including twins.     

Total ovarian volume before human chorionic gonadotrophin administration for ovulation induction may predict the hyperstimulation syndrome

Total ovarian volumes were measured before the administrationof HCG in 42 women undergoing treatment for infertility by in-vitrofertilization (IVF) and embryo transfer and considered to havean exaggerated response to stimulation (>20 follicles). Sevenwomen who subsequently developed moderate or severe ovarianhyperstimulation syndrome (OHSS) (n = 7; group 1) were comparedwith 35 matched controls (five matched controls per case; n= 35; group 2) of similar age, number of follicles and durationof infertility who underwent follicular stimulation, oocyterecovery, in-vitro fertilization and embryo transfer duringthe same period but did not develop moderate or severe OHSS.The mean age, duration of infertility and total number of follicleswere similar but the mean total ovarian volume was significantlyhigher in the group of women who developed moderate or severeOHSS compared with controls (271.00 ± 87.00 versus 157.30± 54.20 ml; P < 0.01). We conclude that total ovarianvolume measured before HCG administration is higher in womenwho develop moderate or severe OHSS compared with controls andmay therefore be used as an additional parameter in the preventativestrategy for the ovarian hyperstimulation syndrome.     

The obstetric outcome of singleton pregnancies following in-vitro fertilization/gamete intra-Fallopian transfer

The present study compares 465 singleton live deliveries fromin-vitro fertilization/gamete intra-Fallopian transfer (IVF/GIFT)pregnancies with a large control population to evaluate theincidence of pre-term delivery and small for gestational age(SGA) or very small for gestation age (VSGA) babies resultingfrom IVF/GIFT pregnancies. Overall the incidence of SGA or VSGAfrom an IVF/GIFT pregnancy is higher than from the normal obstetricpopulation (SGA odds ratio 1.76, 95% confidence interval (CI):1.38–2.25 and VSGA odds ratio 1.61, 95% CI: 1.05–2.46)particularly among primiparous women (SGA odds ratio 1.99, 95%CI: 1.25–3.16 and VSGA odds ratio 1.97, 95% CI: 1.49–2.62).After stratifying by the cause of infertility, only women withunexplained infertility had a significantly higher proportionof SGA/VSGA babies. There was a significantly higher incidenceof pre-term deliveries among the young primiparae (odds ratio5.02, 95% CI: 3.09–8.13). Thus the excess risk of deliveringa SGA/VSGA baby and pre-term delivery from an IVF/GIFT pregnancyseems to be largely confined to women with unexplained infertilityand young primiparae.     

Developmental outcome at 2 years of age for children born after ICSI compared with children born after IVF

BACKGROUND: Since the introduction of ICSI in 1991, medical outcome studies on ICSI children have been performed, but few have addressed developmental outcome. Hence, this outcome was assessed by performing a standard developmental test on children born after ICSI as compared with children born after IVF, at the age of 2 years. METHODS: In a prospective study, the medical and developmental outcome of 439 children born after ICSI (378 singletons, 61 twins) were compared with those of 207 children born after IVF (138 singletons, 69 twins), at the age of 24-28 months. These children were part of a cohort of children followed since birth. Of children reaching the age of 24-28 months between May 1995 and March 2002, 44.3% (2375/5356) were examined by a paediatrician who was unaware of the type of treatment used for each couple. Of all the children born, 12.2% (439/3618) in the ICSI group and 11.9% (207/1738) in the IVF group underwent a formal developmental assessment using the Bayley Scale of Infant Development (mental scale) by a paediatrician blinded to the type of treatment. RESULTS: There was no significant difference in maternal educational level, maternal age, gestational age, parity, birthweight, neonatal complication rate or malformation rate at 2 years between ICSI and IVF singletons, or between ICSI and IVF twins. No significant difference was observed in the developmental outcome using the Bayley scale at the age of 24-28 months (raw scores or test age) between ICSI children or IVF children. A multivariate regression analysis for the singleton children indicated that parity, sex (boys had lower scores than girls) and age had a significant influence on the test result, but that the fertility procedure (ICSI versus IVF) did not influence the test result. ICSI children from fathers with low sperm concentration, low sperm motility or poor morphology had a similar developmental outcome to that of children from fathers with normal sperm parameters. There were no significant differences between the initial cohort and the group lost to follow-up, nor between the psychologically tested and the non-tested group for a number of variables such as maternal educational level, birthweight in singletons and neonatal malformation rate. Although only some of the cohort of ICSI children were evaluated, a representative sample of both ICSI and IVF children was compared. CONCLUSIONS: There is no indication that ICSI children have a lower psychomotor development than IVF children. Paternal risk factors associated with male-factor infertility were found not to play a role in developmental outcome.     

Human follicle-stimulating hormone produced by recombinant DNA technology: a review for clinicians

Human follicle-stimulating hormone (FSH) is now produced in vitro by recombinant DNA technology. FSH being a complex heterodimeric protein, a eukaryotic cell line has been selected for expression work (Chinese hamster ovary cells). The pharmaceutical preparation of recombinant human FSH (r-FSH) differs from that of human menopausal gonadotrophin (HMG) and the first generation of urinary human FSH (u-FSH) in terms of (i) source of bulk materials, (ii) purity and specific activity, (iii) batch to batch consistency, and (iv) complete absence of luteinizing hormone (LH) activity. Pharmacokinetic characterization of r-FSH has shown an absolute bioavailability of approximately 75% after both s.c. and i.m. administration and an apparent terminal half-life of 37 +/- 25 h. These characteristics are very similar to those of u-FSH. Clinical efficacy and safety are currently demonstrated through several randomized, well controlled studies, comparing r-FSH administered s.c. with u-FSH administered i.m. for stimulating follicular development prior to assisted reproduction treatment and in World Health Organization (WHO) group II anovulation. To date, approximately 1000 patients have been treated with r-FSH. Moreover, r-FSH has recently been used successfully in association with recombinant human LH for inducing ovulation and pregnancy in WHO group I anovulatory patients. At this stage of r-FSH preparation assessment, it is likely that r-FSH will replace all urinary-derived FSH preparations for stimulating ovarian follicular development. For clinicians, current experience with r-FSH indicates that it should be used with the regimes and doses applied to u-FSH.