Neonatal outcome in a Danish national cohort of 3438 IVF/ICSI and 10,362 non-IVF/ICSI twins born between 1995 and 2000

BACKGROUND: In Denmark, one-third of twin pregnancies are the result of IVF/ICSI treatment. Limited data on neonatal outcome in IVF/ICSI twins are available in the literature. METHODS: A register study was conducted on neonatal morbidity and mortality in a complete national twin cohort including all 3438 (3393 live-born) IVF/ICSI and 10,362 (10,239 live-born) non-IVF/ICSI twins born between 1995 and 2000. Twins were identified in the National Medical Birth Registry and dichotomized into IVF/ICSI and non-IVF/ICSI by cross-reference with the Danish IVF Registry. Data on neonatal morbidity and mortality were retrieved from the Danish Patient Registry and the Danish Registry of Causes of Deaths. In order to exclude monozygotic twins, sub-analyses on unlike-sex twins were conducted. RESULTS: A birth weight discordance of >20% was observed in 20.6% of IVF/ICSI versus 15.7% of control twin pairs (P < 0.001). The risk of discordant birth weight >20% was OR 1.29 (95% CI 1.04-1.58) in unlike-sex IVF/ICSI twins versus control twins. The risk of delivery at <37 completed weeks and birth weight <2500 g was similar in the two cohorts; however, in unlike-sex IVF/ICSI versus control twins the risk of delivery at <37 weeks and birth weight <2500 g was OR 1.22 (95% CI 1.09-1.38) and OR 1.25 (1.11-1.40) respectively. After stratification for maternal age and parity, these risks disappeared. IVF/ICSI twins carried a higher risk of admittance to a neonatal intensive care unit (NICU) than control twins (OR 1.18, 95% CI 1.09-1.27), and this was even more pronounced in unlike-sex twins [OR 1.34 (95% CI 1.19-1.51)]. No differences were observed in malformation or mortality rates between the two cohorts. CONCLUSIONS: Despite higher birth weight discordance and more NICU admissions among IVF/ICSI twins, neonatal outcome in IVF/ICSI twins seems to be comparable with that of non-IVF/ICSI twins, when only dizygotic twins were considered in the comparisons.     

Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial

The management of poor responders in IVF has always been a big problem. The ideal approach has yet to be formulated. In this study we aim to compare two alternative stimulation protocols. A total of 48 poor responder patients described from previous cycles were included and grouped into two: group I consisted of 24 patients in 24 cycles in which leuprolide acetate (40 microg s.c. per day) was initiated on cycle day 2 followed by exogenous gonadotrophins on cycle day 3; group II consisted of 24 patients in 24 cycles in which ovarian stimulation included gonadotrophin-releasing hormone (GnRH) antagonist (cetrorelix, 0.25 mg daily during late follicular phase) administration. While only the oestradiol concentrations on the day of HCG were lower in group II compared with group I, the clinical pregnancy and implantation rates among groups did not show any significance. The impact of these two regimens in ovarian stimulation of poor responders seem to be same and to establish these results further randomized studies with larger sample sizes are required.     

Andrology: Acrosome reaction inducibility predicts fertilization success at in-vitro fertilization

We prospectively studied the ability of acrosome reaction (AR)inducibility to predict fertilization success in a group of232 infertile patients presenting sequentially for in-vitrofertilization (IVF). The median percentage of eggs fertilizedfor the overall patient population was 25% (interquartile range5–58%), with one to 29 oocytes available for insemination(median, five oocytes). The median percentage of eggs fertilizedat IVF increased as the percentage of spermatozoa able to undergoAR became greater: spermatozoa with a failed AR (5%) fertilizedonly 12% of eggs, while spermatozoa with AR values>9% fertilized50% of eggs. The assay had a specificity of 0.75, a sensitivityof 0.55 and an odds ratio of 2.9; thus, AR-positive patientsare 2.9 times more likely to achieve fertilization than patientswith a failed AR. Receiver operator characteristic (ROC) curveswere constructed for AR, sperm concentration and percentageof normal forms in semen. All three parameters proved to bepotentially useful in predicting the occurrence of fertilization,although AR and morphology appeared to be better than spermconcentration by ROC analysis. Patients were divided into fourclearly defined subgroups according to their traditional semencharacteristics, including morphology. The median percentageof eggs fertilized decreased as traditional semen characteristicsdeteriorated, from a median of 46% for patients with excellentsperm concentration, motility and morphology, to a median of29% for patients with suboptimal semen quality and a medianof 0% for patients with severely impaired semen. Within eachpatient subgroup, the median percentage of eggs fertilized was3-to 4-fold higher for individuals with a positive AR than forthose with a failed AR, indicating that AR has a greater effecton fertilization rate than traditional semen parameters includingmorphology. We now recognize that some men with good semen characteristicshave an unexpectedly poor AR and a markedly reduced fertilizationrate, while other men with poor traditional semen characteristicsunexpectedly retain AR and perform relatively well at IVF. Bycontrast to AR, morphology seemed to have little effect on fertilizationsuccess (two-way analysis of variance not significant). Thewife's age and oocyte quality were evenly distributed amongthe different patient subgroups, indicating that differencesin fertilization rate could not be attributed to either parameter.Our data indicate that AR has a much higher predictive valuefor IVF success than traditional semen parameters includingmorphology. We propose that AR assessment is a clinically usefuldiagnostic tool in determining a patient's likelihood of achievingfertilization at IVF.     

Children conceived using ICSI do not have an increased risk of delayed mental development at 5 years of age

BACKGROUND: Concerns about possible adverse outcomes for children conceived using ICSI were highlighted in 1998 when 1-year-old ICSI children were found to be at increased risk (relative risk = 9.2) of delayed mental development compared with children conceived naturally or using IVF. As the findings were biologically plausible, it was considered important to reassess child development when a more accurate measure of long-term cognitive ability could be obtained. METHODS: The mental development of 97 ICSI, 80 IVF and 110 naturally conceived (NC) children at 5 years of age was assessed using intelligence quotients (IQ) obtained from the Wechsler Preschool and Primary Scales of Intelligence. RESULTS: The mean full-scale IQ was 110 +/- 18 for ICSI, 111 +/- 13 for IVF and 114 +/- 13 for NC children (P = 0.21, non-significant). ICSI children were not at increased risk for delayed (full-scale IQ <85) cognitive development (ICSI 5.2%, IVF 2.5%, NC 0.9%; P = 0.18, non-significant). The only significant independent predictor of below-average full-scale IQ on multivariate analysis was lower maternal education level. CONCLUSIONS: These findings suggest that the genetic influence of parental cognitive ability is more important than the mode of conception in determining the long-term intellectual ability of children conceived using ICSI.     

Non-invasive amino acid turnover predicts human embryo developmental capacity

BACKGROUND: IVF is limited by low success rates and a confounding high multiple birth rate contributing to prematurity, increased neonatal mortality and child handicap. These problems could be overcome if single embryos of known developmental competence could be selected for transfer on day 2/3 of development, but current methods, which rely on morphological appearance, are poor predictors of viability. METHODS: We have measured non-invasively the depletion/appearance (i.e. turnover) of a physiological mixture of 18 amino acids by single human embryos during in-vitro culture using high performance liquid chromatography. RESULTS: From the time of transfer (day 2/3), embryos with future competence to develop to the blastocyst stage (day 5/6) exhibit amino acid flux patterns distinct from those of embryos with similar morphological appearance which arrest. Significantly, the profiles of Ala, Arg, Gln, Met and Asn flux predict blastocyst potentiality at >95%. The amino acid most consistently depleted throughout development by those embryos which form blastocysts was leucine. Of the amino acids which were produced, the most striking was alanine, which appeared in increasing amounts throughout development. CONCLUSIONS: Non-invasive amino acid profiling has the potential to select developmentally competent single embryos for transfer, thereby increasing the success rate and eliminating multiple births in IVF.     

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.