MTHFR SNPs (Methyl Tetrahydrofolate Reductase, Single Nucleotide Polymorphisms) C677T and A1298C Prevalence and Serum Homocysteine Levels in >2100 Hypofertile Caucasian Male Patients

Methylation is a crucially important ubiquitous biochemical process, which covalently adds methyl groups to a variety of molecular targets. It is the key regulatory process that determines the acquisition of imprinting and epigenetic marks during gametogenesis. Methylation processes are dependent upon two metabolic cycles, the folates and the one-carbon cycles. The activity of these two cycles is compromised by single nucleotide polymorphisms (SNPs) in the gene encoding the Methylenetetrahydrofolate reductase (MTHFR) enzyme. These SNPs affect spermatogenesis and oocyte maturation, creating cytologic/chromosomal anomalies. The two main MTHFR SNP variants C677T (c.6777C>T) and A1298C (c.1298A>C) together with serum homocysteine levels were tested in men with >3 years' duration of infertility who had failed several ART attempts with the same partner. These patients are often classified as having "idiopathic infertility". We observed that the genetic status with highest prevalence in this group is the heterozygous C677T, followed by the combined heterozygous C677T/A1298C, and then A1298C; these three variants represent 65% of our population. Only 13.1% of the patients tested are wild type (WT), C677C/A1298A). The homozygous 677TT and the combined heterozygote 677CT/1298AC groups have the highest percentage of patients with an elevated circulating homocysteine level of >15 µMolar (57.8% and 18.8%, respectively, which is highly significant for both). Elevated homocysteine is known to be detrimental to spermatogenesis, and the population with this parameter is not marginal. In conclusion, determination of these two SNPs and serum homocysteine should not be overlooked for patients with severe infertility of long duration, including those with repeated miscarriages. Patients must also be informed about pleiotropic medical implications relevant to their own health, as well as to the health of future children.

Cumulative results including obstetrical and neonatal outcome of fresh and frozen-thawed cycles in elective single versus double fresh embryo transfers.

OBJECTIVE: To assess the efficacy of elective single embryo transfer (e-SET) compared to a double embryo transfer (DET) in a selected population including obstetrical and neonatal outcome of fresh and frozen-thawed cycles. DESIGN: Prospective nonrandomized study. SETTING: Department of reproductive medicine. PATIENT(S): Elective single embryo transfer was proposed to women < 36 years with adequate ovarian function, in their first or second IVF or intracytoplasmic sperm injection (ICSI) attempt with ejaculated sperm, with at least 4 mature oocytes and 2 fertilized top quality embryos. Patients who refused e-SET had two top embryos transferred (DET group). INTERVENTION(S): Medical management and IVF-ICSI. MAIN OUTCOME MEASURE(S): Cumulative delivery rate, twin delivery rate, obstetrical and neonatal outcome. RESULT(S): According to patients' decision, 53 women had an e-SET and 98 a DET. The cumulative delivery rate per patient was 54.7% in the e-SET group and 49.0% in the DET group (P>0.05). Twin delivery rate was significantly different between the two groups (3.5% versus 37.5% respectively, P<0.05). Neonatal outcome in twins resulting from IVF-ICSI was found to be poorer than in singletons, considering the mean gestational age, mode of delivery, birthweight, and risk of neonatal intensive care unit admission for the infants. CONCLUSION(S): In a selected population, the elective transfer of one embryo with high implantation potential helped to avoid twin pregnancies without decreasing delivery rate.

Clinical data and parenthood of 63 infertile and Y-microdeleted men.

OBJECTIVE: To collect follow-up data for infertile men with Y microdeletion. DESIGN: Retrospective, observational survey. SETTING: Multicenter IVF units associated with genetics laboratories. PATIENT(S): Sixty-three patients with Y microdeletion. INTERVENTION(S): Karyotype analysis, Y microdeletion screening, and assisted reproductive technology. MAIN OUTCOME MEASURES: Medical history, karyotype, nature of the AZF deletion, semen parameters, testis biopsy results, choice of assisted reproductive technology, and results of intracytoplasmic sperm injection (ICSI). RESULTS: Abnormal karyotypes were found in 8 men (12.7%), who were azoospermic except 1. Of these 8 men, 5 presented a combined AZFb+c deletion, and 3 had a deletion in AZFc only. Most men (39 of 63) were azoospermic, 3 were cryptoazoospermic, and 19 had extreme oligozoospermia (sperm concentration

From ultrastructural flagellar sperm defects to the health of babies conceived by ICSI.

The objective of this retrospective study was to describe a population of patients displaying impaired sperm motility due to ultrastructural flagellar defects and to analyse the intracytoplasmic sperm injection (ICSI) results and neonatal outcomes in this population. The fertilization rate, embryo quality, clinical pregnancy rate, implantation rate, birth rate and perinatal health of babies were determined. Patients (n = 20) were divided into seven categories according to ultrastructural flagellar abnormalities. The type of flagellar abnormality significantly affected the fertilization rate (P <0.025). Two types of flagellar abnormalities showed slower early embryo cleavage kinetics (P <0.001) when axonemal central structures and periaxonemmal columns were abnormal or absent. Of 53 ICSI attempts, 14 resulted in clinical pregnancies (26.4% per cycle) after fresh and frozen embryo transfer. Three (21.4%) of these pregnancies ended in miscarriages and, in the remaining, 12 infants were born (7.2% of transferred embryos). The outcomes differed according to the ultrastructural defect. This study demonstrates that a high proportion of patients could father a child (45.0%). However, flagellar abnormalities appear to influence ICSI results and fetal development.

Careful cardiovascular screening and follow-up of women with Turner syndrome before and during pregnancy is necessary to prevent maternal mortality.

OBJECTIVE: To report the fatal outcome of a woman with Turner syndrome (TS) undergoing assisted reproductive technology (ART). DESIGN: Case report. SETTING: Reproductive medicine center. PATIENT(S): A 33-year-old woman with TS. INTERVENTION(S): Screening before oocyte donation and treatment of aortic dissection occurring at term pregnancy. MAIN OUTCOME MEASURE(S): Evaluation of cardiovascular risk. RESULT(S): After a normal cardiac screening, a woman with TS got pregnant as a result of oocyte donation. At 16 weeks of gestation, a bicuspid aortic valve was detected and associated with moderate aortic root dilation. Aortic dissection was diagnosed at 38 weeks of gestation, which required emergent cesarean delivery and aortic root replacement. Despite surgical treatment, early maternal death was recorded. CONCLUSION(S): Careful cardiac screening and close follow-up before and during pregnancy are necessary in patients with TS.

Associated ovarian endometrioma is a marker for greater severity of deeply infiltrating endometriosis.

OBJECTIVE: To investigate whether an associated ovarian endometrioma is a marker for severity of deep infiltrating endometriosis (DIE). DESIGN: Observational study between June 1992 and December 2005. SETTING: University tertiary referral center. PATIENT(S): Five hundred patients with histologically assessed DIE. INTERVENTION(S): Complete surgical exeresis of deep endometriotic lesions. MAIN OUTCOME MEASURE(S): Severity of the disease was quantified according to the mean number of DIE lesions and the type of main lesion. RESULT(S): In patients with associated ovarian endometrioma, the number of single isolated DIE lesions was statistically significantly lower (41.9% vs. 61.1%). The mean number of DIE lesions was statistically significantly higher in patients presenting with an associated ovarian endometrioma (2.51 +/- 1.72 vs. 1.64 +/- 1.0). For patients with associated ovarian endometrioma DIE lesions were more severe with an increased rate of vaginal, intestinal, and ureteral lesions. CONCLUSION(S): Associated ovarian endometrioma is a marker for the severity of the DIE. In a clinical context suggestive of DIE, when there is an ovarian endometrioma, the practitioner should investigate the extent of the disease to check for severe and multifocal DIE lesions.

How to manage an accelerated embryo cohort in IVF.

The case of a successful pregnancy is reported here, following intracytoplasmic sperm injection which resulted in a cohort of embryos showing accelerated cleavage kinetics. Pregnancy was not achieved with fresh embryos transferred at the 4-cell stage but was achieved with cryopreserved accelerated embryos. After an ovarian stimulation cycle, 20 mature oocytes were observed. Early cleavage was observed in 19 of these, 26 h post-injection, and 17 were beyond the 4-cell stage 42 h after injection. No pregnancy was obtained after the transfer of two fresh embryos at the 4-cell stage without fragments. Following the transfer of two frozen accelerated embryos, a twin pregnancy was obtained, which resulted in the delivery of two healthy babies. This case report demonstrates that classical scoring systems may need to be adapted to reflect the cleavage kinetics of the whole embryo cohort.

Pregnancy after in vitro fertilization-intracytoplasmic sperm injection obtained with a modified natural cycle in a BRCA1 mutation carrier.

OBJECTIVE: To report a successful pregnancy after a semi-natural IVF cycle for a BRCA1 gene mutation carrier. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 26-year-old patient with BRCA1 gene mutation. INTERVENTION(S): Semi-natural IVF cycle and intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Pregnancy rate. RESULT(S): A modified natural IVF cycle was performed, resulting in pregnancy and delivery. CONCLUSION(S): A modified natural IVF cycle is an effective and safe solution for BRCA1 or BRCA2 mutation gene carrier women with couple infertility.

Artificial versus stimulated cycles for endometrial preparation prior to frozen-thawed embryo transfer.

The objective of this study was to compare the implantation rate, pregnancy rate and endometrial thickness of frozen-thawed embryo transfers using endometrial preparation with either an artificial cycle or stimulated cycle. This was a prospective randomized trial at a single academic IVF centre. Seventy-seven patients undergoing artificial cycles received oral oestradiol; patients with endometrium < 7 mm on day 9-10 were switched to vaginal oestradiol. Eighty-six patients undergoing stimulated cycles received recombinant FSH followed by human gonadotrophin hormone injection. Vaginal progesterone was begun 2 or 3 days prior to embryo transfer. There was no difference in implantation rate (8.5% versus 7.3%), pregnancy rate (16% versus 13%), cancellation rate (both 23%) or endometrium thickness (8.7 +/- 1.1 mm versus 8.7 +/- 1.0 mm) between artificial and stimulated cycles. Stimulated cycles had a higher incidence of thin endometrium (27% versus 5%, P < 0.01). In artificial cycles, patients switched to vaginal oestradiol had improved pregnancy rate (31%) versus patients who received oral oestradiol alone (13%) (P = 0.05). It is concluded that artificial and stimulated cycles produce comparable pregnancy rates, implantation rates, cancellation rates and endometrial thickness, although stimulated cycles have a higher incidence of thin endometrium. Vaginal oestradiol supplementation improved implantation rates.

[Ovulation induction]. / La stimulation de l'ovulation.

Ovulation induction, indicated in anovulatory women, is nowadays a major treatment in any cause of infertility. Ovulation induction can be designed to obtained one or two follicles or to obtain a controlled ovarian hyperstimulation. Mild stimulations are used for anovulatory patients or patient with dysovulation, or for intrauterine insemination. Controlled ovarian hyperstimulation aimed at obtaining high number of follicle in In Vitro Fertilization procedure. All ovulation induction should be strictly monitored to prevent complication and mainly multiple pregnancies and the ovarian hyperstimulation syndrome. All ovulation induction should take place after a careful work up of the couple to determine the cause of infertility. This allows to select the best treatment and to avoid complications.

Conservative versus extirpative management in cases of placenta accreta.

OBJECTIVE: To compare the impact of conservative and extirpative strategies for placenta accreta on maternal morbidity and mortality. METHODS: We retrospectively reviewed the medical records of all patients diagnosed with placenta accreta admitted to our tertiary center from January 1993 through December 2002. Two consecutive periods, A and B, were compared. During period A (January 1993 to June 1997), our written protocol called for the systematic manual removal of the placenta, to leave the uterine cavity empty. In period B (July 1997 to December 2002), we changed our policy by leaving the placenta in situ. The following outcomes over the 2 periods were compared: need for blood transfusion, hysterectomy, intensive care admission, duration of stay in intensive care, and postpartum endometritis. RESULTS: Thirty-three cases of placenta accreta were observed among 31,921 deliveries (1.03/1,000). During period B, there was a reduction in the hysterectomy rate (from 11 [84.6%] to 3 [15%]; P <.001), the mean number of red blood cells transfused (3,230 +/- 2,170 mL versus 1,560 +/- 1,646 mL; P <.01), and disseminated intravascular coagulation (5 [38.5%] versus 1 [5.0%]; P =.02), compared with period A. There were 3 cases of sepsis in period B and none in period A (P =.26). At least 2 women with conservative management subsequently had successful pregnancies. CONCLUSION: Leaving the placenta accreta in situ appears to be a safe alternative to removing the placenta.