Cumulative pregnancy rates after a maximum of nine cycles of modified natural cycle IVF and analysis of patient drop-out: a cohort study

BACKGROUND: In modified natural cycle IVF (MNV-IVF), treatment is aimed at using the one follicle that spontaneously develops to dominance, using a GnRH antagonist together with gonadotrophins in the late follicular phase only. METHODS: In this single-centre cohort study, nine cycles of MNV-IVF were offered to 268 patients. Cumulative pregnancy rates (CPRs) were calculated and drop-out was analysed. The present study is an extension of earlier studies in which three cycles of MNV-IVF were offered to the same patients. RESULTS: A total of 256 patients completed 1048 cycles (4.1 per patient). Embryo transfer rate was 36.5% per started cycle. Ongoing pregnancy rate was 7.9% per started cycle and 20.7% per embryo transfer. Including treatment-independent pregnancies, the observed CPR after up to nine cycles was 44.4% (95% confidence interval 38.3-50.5) per patient. Pregnancy rates per started cycle did not decline in higher cycle numbers (overall 9.9%). Drop-out rates were high (overall 47.8%). We found that cancellation of oocyte retrieval, fertilization failure and failure to reach embryo transfer are repeating phenomena in subsequent cycles and furthermore that these events predispose for drop-out. CONCLUSIONS: CPR after nine cycles of MNV-IVF in this study was 44.4%. Pregnancy rate per cycle did not decline in higher cycle numbers, possibly due to selective drop-out of poor prognosis patients. Due to the low-risk and patient-friendly nature of the MNC protocol, it seems a feasible treatment option for patients requiring IVF.     

Efficacy of natural cycle IVF: a review of the literature

Since the introduction of IVF treatments, natural cycle IVF has been largely replaced by IVF with ovarian stimulation. However, natural cycle IVF has several advantages. It is associated with a close to zero multiple pregnancy rate, and a zero risk of ovarian hyperstimulation syndrome. Per cycle, natural cycle IVF is less time consuming, physically and emotionally less demanding for patients, and cheaper than stimulated IVF, but also less effective. This systematic literature review addresses the issue of effectiveness of natural cycle IVF. Herein, 20 studies describing natural cycle IVF are presented; 12 case series and eight in which a comparison was made between natural cycle IVF and IVF with ovarian stimulation. Good-quality randomized controlled trials and formal cost-effectiveness analyses are lacking. The 20 selected studies comprised a total of 1800 cycles of natural cycle IVF, resulting in 819 embryo transfers (45.5% per cycle) and 129 ongoing pregnancies (7.2% per cycle and 15.8% per embryo transfer). Efficacy of natural cycle IVF is hampered by high cancellation rates because of premature LH rise and premature ovulations. It is concluded that natural cycle IVF is a low-risk, low-cost and patient-friendly procedure. A randomized controlled trial comparing natural cycle IVF with current standard treatment strategies is warranted.     

Andrology: Analysis of the oocyte activating capacity and chromosomal complement of round-headed human spermatozoa by their injection into mouse oocytes

Intracytoplasmic sperm injection (ICSI) in the human is a veryeffective procedure which allows the fertilization of the majorityof oocytes even in cases of extreme oligoasthenoteratozoospermia.Round-headed acrosomeless human spermatozoa, however, form anexception to this rule, because in about half of the coupleswith globozoo-spermia all oocytes remain unfertilized afterinjection. The incapacity of the spermatozoon to activate theoocyte following injection of round-headed spermatozoa couldbe the underlying mechanism. To investigate this hypothesis,activation rates of mouse oocytes injected with spermatozoafrom a patient with globozoospermia were compared with thoseobtained after injection with normal spermatozoa. Of mouse oocytessurviving the injection with donor spermatozoa, 95% underwentactivation, compared to none of the 88 mouse oocytes survivingthe injection with round-headed spermatozoa. After fixation,prematurely condensed sperm chromosomes were found in theseoocytes. Partheno-genetic activation of mouse oocytes (8% ethanolat 40 min after injection) injected with round-headed spermatozoaled to the activation of 96% of oocytes. These oocytes developednormally to the first mitosis and were fixed for analysis ofthe sperm karyotypes. The incidence of chromosomal abnormalitiesof round-headed spermatozoa (6%) was similar to that in spermatozoafrom a fertile donor (9%). These data provide further informationon the basic defect in cases of globozoospermia and demonstratethat globozoospermia is not associated with sperm karyotypeabnormalities.     

Is the birthweight of singletons born after IVF reduced by ovarian stimulation or by IVF laboratory procedures?

Singletons born after IVF are at risk of adverse pregnancy outcome, the cause of which is unknown. The present study investigated the influence of ovarian stimulation and IVF laboratory procedure on birthweight. Birthweight of singleton pregnancies resulting from IVF treatment with (n = 161) and without ovarian stimulation (using a modified natural cycle (MNC) protocol; n = 158), and spontaneous conceptions in subfertile patients (n = 132) were compared. Mean ± SD birthweight of singletons after conventional IVF with ovarian stimulation, MNC-IVF and natural conception were 3271 ± 655, 3472 ± 548 and 3527 ± 582 g (P = 0.001). After adjustment for biological and social confounders, the difference in birthweight between conventional IVF and MNC-IVF was reduced to 88 g and the differences between conventional IVF and MNC-IVF versus spontaneous conceptions to 123 and 23 g, respectively. The results lead to three conclusions. First, a major part of the crude differences in birthweight between the three groups is related to patient and pregnancy characteristics. Second, the IVF laboratory procedure has no influence on birthweight. Third, although a trend towards lower birthweight after ovarian stimulation was found, an adverse effect of ovarian stimulation on birthweight was not substantiated.     

Effectiveness of indometacin to prevent ovulation in modified natural-cycle IVF: A randomized controlled trial

Modified natural-cycle IVF has a lower pregnancy rate per started cycle as compared with IVF with ovarian stimulation due to, for example, premature ovulation. Indometacin administered before ovulation prevents follicle rupture. Therefore, addition of indometacin may improve the effectiveness of modified natural-cycle IVF. This double-blind, randomized, placebo-controlled trial with indometacin or placebo in 120 women aged 27–36 years compared the number of patients without premature ovulation as compared with the number of patients with one or more ovulations in a maximum of six cycles. Indometacin had no significant influence on the probability of a premature ovulation in patients during the six cycles (OR 2.38, 95% CI 0.94–6.04). A subgroup analysis showed a significant influence of indometacin in decreasing the probability of a premature ovulation in cycles without LH surge at the day of human chorionic gonadotrophin administration (OR 8.29, 95% CI 1.63–42.3, P = 0.009). Although this study could not detect a significantly lower ovulation rate in the indometacin group versus the placebo group, the data suggest that a subgroup of patients without LH surge prior to oocyte retrieval might benefit from indometacin in modified natural-cycle IVF.Modified natural-cycle IVF is a mild form of IVF, with a lower pregnancy rate per started cycle as compared with IVF with ovarian stimulation because of several unfavourable cycle events, such as ovulation before oocyte retrieval. Indometacin is a cheap drug, commonly used to reduce fever, pain and swelling caused by inflammation. It has been shown that indometacin administered before ovulation prevents this from happening. Therefore, it has been suggested that indometacin may improve the effectiveness of modified natural-cycle IVF. In this study, we assigned 120 women aged 27–36 years randomly to an indometacin group (60 women) and a group of women who used placebo (also 60 women). We evaluated whether indometacin could indeed prevent ovulation during a maximum of six modified natural-cycle IVF cycles. When we compared the two groups of women, indometacin did not seem to prevent ovulation compared with women who used placebo. Within these groups, however, the patients with a low level of LH (a hormone involved in ovulation) on the day that administration indometacin or placebo was started, indometacin did decrease the chance of an untimely ovulation. So although we could not detect a lower ovulation rate in the indometacin group versus the placebo group, our data suggest that a subgroup of patients with low LH concentrations prior to oocyte retrieval might benefit from indometacin in modified natural-cycle IVF.     

Management of fetal death after 20 weeks of gestation complicated by placenta previa

Objective.?To determine the frequency and risk factors associated with neonatal chemical hypoglycemia in neonates of mothers with type 2 diabetes and gestational diabetes mellitus (GDM).

Research Design and Methods.?A retrospective cohort study of women with type 2 diabetes or GDM and their singleton neonates. The primary outcome measure was the presence of neonatal chemical hypoglycemia (capillary plasma equivalent glucose <45?mg/dl) within 1?h of birth. Statistical methods included bivariate and multivariate analyses.

Results.?242 mother infant dyads were identified. Sixty-eight (28%) were treated with diet, 110 (46%) with glyburide, and 64 (26%) with insulin. The incidence of neonatal chemical hypoglycemia was 18% (44/242). The incidence was significantly higher in those requiring pharmacotherapy (25% vs. 3%, p?p?=?0.58). The frequency of neonatal chemical hypoglycemia was statistically associated with birth weight, macrosomia and ponderal index (p?Conclusion.?Neonatal chemical hypoglycemia occurs more frequently in infants from women with type 2 diabetes and GDM treated with glyburide or insulin. An increased neonatal ponderal index is a strong predictor of significant neonatal chemical hypoglycemia.     

Embryos cultured in vitro with multinucleated blastomeres have poor implantation potential in human in-vitro fertilization and intracytoplasmic sperm injection

The aim of the present study was to investigate pregnancy rates ensuing from transfer of embryos with multinucleated blastomeres. In our in- vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programme, 1735 embryo transfers were performed from January 1, 1995 to August 31, 1996. In 136 of these transfers at least one embryo with one or more multinucleated blastomeres was present per transfer (study group). For each of these 136 transfers, two matched controls with transfer of exclusively mononucleated embryos were selected (control group). Matching was carried out according to age, method of fertilization (IVF or ICSI), number of transferred embryos and quality score of transferred embryos. In the study group, there were eight transfers of exclusively multinucleated embryos from which one pregnancy ensued and 128 transfers in which multinucleated and mononucleated embryos were transferred together leading to 23 pregnancies. The overall clinical pregnancy rate per transfer was 16.9% in the study group versus 28.7% in the control group (P = 0.01). The ongoing pregnancy rate per transfer was 13.2% in the study group versus 23.2% in the control group (P = 0.03). The implantation rate per transferred embryo was 6.0% in the study group versus 11.3% in the control group (P = 0.003). This study shows that embryos with one or more multinucleated blastomeres have a poorer implantation potential than embryos with mononucleated blastomeres. Transfer of embryos with multinucleated blastomeres should hence only be considered when insufficient numbers of embryos with only mononucleated blastomeres are present.      

Minimal stimulation IVF with late follicular phase administration of the GnRH antagonist cetrorelix and concomitant substitution with recombinant FSH: a pilot study

BACKGROUND: The use of the natural cycle for IVF offers the advantage of a patient-friendly and low-risk protocol. Its effectiveness is limited, but may be improved by using a GnRH antagonist to prevent untimely LH surges. METHODS: In this pilot study, minimal stimulation IVF with late follicular phase administration of the GnRH antagonist cetrorelix and simultaneous substitution with recombinant FSH was applied for a maximum of three cycles per patient. Main outcome measures were pregnancy rates per started cycle and cumulative pregnancy rates after three cycles. RESULTS: A total of 50 patients completed 119 cycles (2.4 per patient). Fifty-two embryo transfers resulted in 17 ongoing pregnancies [14.3% per started cycle; 32.7% per embryo transfer; 95% confidence interval (CI) 7.9-20.7% and 19.7-45.7%, respectively]. One dizygotic twin pregnancy occurred after transfer of two embryos, the other pregnancies were singletons. The cumulative ongoing pregnancy rate after three cycles was 34% (95% CI 20.6-47.4%). Live birth rate was 32% per patient (95% CI 18.8-45.2%). CONCLUSIONS: Pregnancy rates after IVF with minimal, late follicular phase stimulation are encouraging. Considering the low-risk and patient-friendly nature of this protocol, it may be a feasible alternative to IVF with ovarian hyperstimulation.