The effect of human papilloma virus vaccination on embryo yield and clinical in vitro fertilisation outcomes: a matched retrospective cohort study.

The effects of HPV vaccination on embryo yield and pregnancy outcomes in IVF cycles with fresh embryo transfer (ET) were investigated. First, embryo yielding rates (EYR) in 2795 cycles with and without HPV vaccination were compared by retrospective cohort study design. EYR of HPV vaccinated and non-vaccinated patients were not significantly different (OR, 1.66; 95% CI, 0.76-3.63). Second, ET outcomes were compared for 155 HPV vaccine + cycles and 465 HPV vaccine - cycles after matching for ages and cycle attempt number. The differences in the number of retrieved oocytes (10.2 ± 6.1, 11.2 ± 6.7; p = .161), mature (MII) oocytes (8.7 ± 5.7, 9.8 ± 6.3; p = .088), two pronuclear zygotes (2PN) (5.4 ± 4.1, 6.1 ± 4.6; p = .110) and fertilisation rates (0.62 ± 0.23, 0.62 ± 0.23; p = .539) were insignificant between the two groups. Moreover, positive (OR, 0.74; 95% CI, 0.47-1.16), clinical (0.60; 0.36-1.01) and the ongoing pregnancy (0.55; 0.30-1.01) rates were lower in the HPV vaccinated group but the difference was not statistically significant.IMPACT STATEMENTWhat is already known on this subject? There are recent case studies that report premature ovarian insufficiency (POI) following a post-vaccination autoimmune response against the HPV vaccine. These studies suggest that the possible trigger for the immune reaction might be the immunogen content of the vaccine. However, the number of clinical studies investigating the effects of the HPV vaccine on reproductive function and in vitro fertilisation outcomes is limited.What do the results of this study add? In contrast to the case reports suggesting impaired reproductive and ovarian functions in HPV vaccinated patients, this study finds that in IVF patients HPV vaccinated and non-vaccinated women have similar EYR, MII, 2PN, oocyte counts, fertilisation rates, positive, clinical and ongoing pregnancy rates.What are the implications of these findings for clinical practice and/or further research? The results suggest the HPV vaccine does not have a negative impact on embryo yielding rates oocyte counts and fertilisation rates, positive, clinical and ongoing pregnancy rates in IVF treatments. Hence, they can be safely used for primary prevention against cervical cancer.

Replacing HMG/FSH by low-dose HCG to complete corifollitropin alfa stimulation reduces cost per clinical pregnancy: a randomized pragmatic trial.

RESEARCH QUESTION: The cost of IVF treatment remains high, among other factors because of the medication needed for ovarian stimulation. This study investigated the effect of using low-dose human chorionic gonadotrophin (HCG) for the second phase of follicular maturation after corifollitropin alfa induction, to replace the more expensive, either recombinant or human menopausal gonadotrophin (HMG), on the cost of ovarian stimulation. DESIGN: One hundred and five patients were randomly divided into two groups: patients in the HCG group (n = 50) received low-dose HCG from Day 7 until the diameter of at least three follicles reached 17 mm or more, while patients in the FSH group (n = 55) received conventional ovarian stimulation with highly purified HMG injections. RESULTS: The clinical pregnancy rate in the HCG group was 38% higher than in the FSH group (number needed to treat, NNT = 13). The cost per pregnancy needed for ovarian stimulation was reduced from €4902 in the FSH group to €2684 in the HCG group. Hence, the cost of ovarian stimulation medication to obtain 10 pregnancies using the conventional FSH protocol is sufficient to attain 18 pregnancies when applying the low-dose HCG protocol. CONCLUSION: This study provides evidence that using HCG instead of HMG/FSH for ovarian stimulation results in a significant reduction in the cost of IVF with, at least, an equivalent pregnancy rate.

Slightly lower incidence of ectopic pregnancies in frozen embryo transfer cycles versus fresh in vitro fertilization-embryo transfer cycles: a retrospective cohort study.

OBJECTIVE: To analyze the incidence of ectopic pregnancies (EPs) in fresh and frozen/thawed cycles. DESIGN: A retrospective cohort study on the incidence of EPs in all fresh IVF cycles from January 2002 until December 2012. This was compared with the incidence of tubal pregnancies in patients undergoing transfer of frozen/thawed embryos during the same time period. SETTING: The IVF program at Fertility Center, AZ Jan Palfijn, Gent, Belgium. PATIENT(S): A total of 11,831 patients undergoing IVF (i.e., the entire population of the IVF Center) were retrospectively analyzed. INTERVENTION(S): The IVF cycles, fresh IVF-ET, frozen/thawed ET. Laparoscopy for treatment of EP. MAIN OUTCOME MEASURE(S): Primary end point: incidence of EPs in both groups. Secondary end points: clinical pregnancy rate (PR), rate of EPs per clinical pregnancy. RESULT(S): In the fresh IVF cycle group, 10,046 patients underwent oocyte retrieval; 9,174 of them had an ET; 2,243 of these patients had a clinical pregnancy. Of these, 43 (0.47%) appeared to have an ectopic localization of their pregnancy. In the group of the patients undergoing frozen/thawed ET (1,785 patients) there were 467 pregnancies and 6 ectopic implants (0.34%). The incidence of the EPs per established clinical pregnancy was 1.92% for the fresh vs. 1.28% for the frozen/thawed cycles. CONCLUSION(S): No significant difference could be demonstrated on the incidence of EP in fresh IVF cycles vs. frozen/thawed cycles in a large cohort of patients.

A multicenter phase IIb study of a novel combination of intramuscular androgen (testosterone decanoate) and oral progestogen (etonogestrel) for male hormonal contraception.

The effect of a novel combination of oral etonogestrel (ENG) and im testosterone decanoate (TD) on suppression of gonadotropins and spermatogenesis as a potential lead for male contraception was investigated. Healthy male volunteers were randomized into two groups receiving 300 microg ENG daily and 400 mg TD every 4 (n = 55) or 6 (n = 57) wk for 48 wk. At wk 48, all men except one in the 6-wk group suppressed sperm concentration to less than 1 million/ml. Faster suppression occurred in the 4-wk group. Gonadotropins were suppressed in both groups and most consistently in the 4-wk group. During treatment, trough testosterone levels increased into the normal range in the 4-wk group but remained just below normal in the 6-wk group. All peak levels were within the normal range. After treatment cessation, recovery of sperm counts and gonadotropins to normal levels occurred in both groups. Minor effects on weight and cholesterol were noted. Fourteen subjects withdrew because of an adverse event with those possibly related to the study medication reported more frequently in the 6-wk group (nine vs. one). In conclusion, the combination of 300 microg ENG with 400 mg TD every 4 wk was superior in terms of efficacy, hormone profiles, and safety. This represents a promising approach to male hormonal contraception.

Cumulative live birth rates after transfer of cryopreserved ICSI embryos.

A cohort follow-up study was designed to assess the efficacy of an intracytoplasmic sperm injection cryopreservation programme through analysis of cumulative live birth rates in successive frozen-thawed cycles in a tertiary referral centre. There were 2013 patients and they underwent 2680 frozen-thawed embryo transfer cycles. The follow-up period was between 1992 and 2001. Only frozen-thawed embryo transfer cycles up to the fourth trial were included. Crude cumulative live birth rates were calculated in five age subgroups, i.e. <30, 30-34, 35-37, 38-39 and >/=40 years old and in surgically or non-surgically retrieved sperm subgroups. Expected cumulative live birth rates were calculated only for the total number of patients. Outcome measure was a live birth occurring after 25 weeks of gestation. Overall, the expected cumulative live birth rate was as high as 26.7% after four cycles while the crude cumulative delivery rate was 10.5%. Multiple cryopreserved embryo transfer cycles increase the chance of a couple to achieve a live birth.

Cumulative delivery rates after ICSI treatment cycles with freshly retrieved testicular sperm: a 7-year follow-up study.

BACKGROUND: The purpose of this study was to assess cumulative delivery rates in patients with non-obstructive or obstructive azoospermia following treatment by testicular sperm extraction (TESE)-ICSI. METHODS: A cohort follow-up study was conducted. Between January 1994 and December 2000, 364 couples with obstructive azoospermia underwent a total of 609 fresh TESE-ICSI treatment cycles. In addition, 303 fresh TESE-ICSI treatment cycles were performed in 235 couples for non-obstructive azoospermia. This study included only patients in whom sperm was recovered. In the non-obstructive group, only patients with maturation arrest, atrophic sclerosis and germ cell aplasia were included. The main outcome measure was a delivery beyond 25 weeks gestation. RESULTS: In patients with obstructive azoospermia, the crude delivery rate after three cycles was 35% while the expected cumulative delivery rate was 48% [95% confidence interval (CI), 41-55]. On the other hand, in patients with non-obstructive azoospermia, the crude cumulative delivery rate after three treatment cycles was 17% while the expected delivery rate was 31% (95% CI, 15-46). A high dropout rate in couples with both non-obstructive and obstructive azoospermia was observed (75 and 50% respectively, after the first cycle). CONCLUSION: This study shows that there is a value in performing several TESE-ICSI attempts in patients with obstructive and non-obstructive azoospermia. The estimates of the non-obstructive group beginning from the third cycle are less reliable due to fewer patients. However, overall, the obstructive group performed better than the non-obstructive group.

An open, randomized single-centre study to compare the efficacy and convenience of follitropin beta administered by a pen device with follitropin alpha administered by a conventional syringe in women undergoing ovarian stimulation for IVF/ICSI.

BACKGROUND: A pen device, similar to an insulin pen, has been recently marketed for the administration of follitropin beta in cartridges. A randomized controlled trial was performed to compare the efficacy and convenience of this pen device delivering follitropin beta with a conventional syringe delivering follitropin alpha. METHODS: A total of 200 patients needing IVF/ICSI treatment and willing to self-inject were enrolled in the study. All subjects had ovarian stimulation according to a long protocol and were randomized to the pen or the conventional syringe group during down-regulation by means of a computer-generated randomization list using random numbers. Patients were asked to fill in a daily local tolerance book after each injection. On the day of hCG the patients scored a Visual Analogue Scale (VAS) for pain and convenience. RESULTS: The average duration, total dose of recombinant FSH and number of cumulus oocyte complexes retrieved were 10.8/12.0 days (P = 0.001), 1880/2226 IU (P < 0.001) and 15.2/13.1 respectively in the pen device and conventional syringe groups; the presence of pain after the daily injection was significantly higher in the conventional syringe group (P = 0.027); the visual analogue scale score was similar for pain but significantly more convenient for the pen device (P < 0.001). The live birth rate per embryo transfer was 32.9 and 34.4% respectively in the pen device and conventional syringe groups. CONCLUSIONS: Self-injection with the pen device is safe and easy, more convenient and less painful for the patient, requires less FSH and shortens the treatment duration.

Intracytoplasmic sperm injection with testicular spermatozoa is less successful in men with nonobstructive azoospermia than in men with obstructive azoospermia.

OBJECTIVE: To assess the efficiency of intracytoplasmic sperm injection (ICSI) using testicular spermatozoa in cases of nonobstructive azoospermia. DESIGN: Retrospective case series. SETTING: Tertiary university-based infertility center. PATIENT(S): Overall, 595 couples were included. In 360 couples, the man had normal spermatogenesis. In 118, 85, and 32 couples the man had germ-cell aplasia, maturation arrest, and tubular sclerosis/atrophy, all with focal spermatogenesis present. INTERVENTION(S): We performed 911 ICSI cycles using fresh sperm obtained after testicular biopsies: 306 ICSI cycles used testicular sperm from men with nonobstructive azoospermia, and 605 ICSI cycles used testicular sperm from men with obstructive azoospermia. MAIN OUTCOME MEASURE(S): Fertilization, cleavage, implantation, and pregnancy rates. RESULT(S): Overall, the 2PN fertilization rate was lower in the nonobstructive group: 48.5% vs. 59.7%. There were no differences in in vitro development or in the morphological quality of the embryos. In the nonobstructive group, a total of 718 embryos were transferred (262 transfers) vs. 1,525 embryos in the obstructive group (544 transfers). Both the clinical implantation rate and clinical pregnancy rate per cycle were significantly lower in the nonobstructive group compared with the obstructive group: 8.6% vs. 12.5% and 15.4% vs. 24.0%, respectively. CONCLUSION(S): A statistically significant lower rate of fertilization and pregnancy results from ICSI with testicular sperm from men with nonobstructive azoospermia, compared with men with obstructive azoospermia.

Prenatal genetic testing by amniocentesis appears to result in a lower risk of fetal loss than chorionic villus sampling in singleton pregnancies achieved by intracytoplasmic sperm injection.

OBJECTIVE: To compare pregnancy outcome after prenatal genetic testing by chorionic villus sampling (CVS) or amniocentesis in singleton pregnancies achieved by intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENT(S): Eight hundred twenty-eight patients with singleton gestations achieved by ICSI. INTERVENTION(S): Midtrimester amniocentesis (685 patients) and first-trimester CVS (143 patients). MAIN OUTCOME MEASURE(S): Fetal loss rate, preterm delivery rate, and proportion of babies born with low or very low birth weight. RESULT(S): A significant difference was observed in fetal loss rate between CVS and amniocentesis (3.7% vs. 0.9%, respectively). On the other hand, a similar preterm delivery rate was present between the two methods (11.2% vs. 12.4%, respectively). No significant difference was observed between amniocentesis and CVS in the proportion of babies with birth weight of either <1,500 g (1.8% vs. 3.8%, respectively) or between 1,500 and 2,500 g (8.2% vs. 4.6%, respectively). CONCLUSION(S): Amniocentesis appears to result in a lower risk of fetal loss as compared with CVS in patients with a singleton pregnancy achieved by ICSI.

Outcome for donors and recipients in two egg-sharing policies.

OBJECTIVE: To assess the effect of two different donation policies on results of egg-sharing. DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENT(S): One hundred five donor-recipient pairs participating in an egg-sharing program between 1998 and 2001. INTERVENTION(S): Egg-sharing was performed according to policy A (retrieval of at least 12 oocytes, with more oocytes allocated to the donor) or policy B (retrieval of at least 8 oocytes, with equal distribution of oocytes between donors and recipients). MAIN OUTCOME MEASURE(S): Delivery rate and cycle cancellation rate. RESULT(S): Policy B resulted in a decreased cycle cancellation rate in the recipient group compared with policy A (9.7% vs. 29.7%, respectively; P

Effect of ovarian stimulation with recombinant follicle-stimulating hormone, gonadotropin releasing hormone antagonists, and human chorionic gonadotropin on endometrial maturation on the day of oocyte pick-up.

OBJECTIVE: To assess the effect of ovarian stimulation with recombinant FSH, GnRH antagonists, and hCG on endometrial maturation on the day of oocyte pick-up. DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENT(S): Fifty-five women undergoing controlled ovarian hyperstimulation for IVF/intracytoplasmic sperm injection (ICSI). INTERVENTION(S): [1] Ovarian stimulation with recombinant FSH, starting on day 2 of the cycle and GnRH antagonist, starting after a median of 6 days of recombinant FSH stimulation (range, 5-12 days); [2] hCG administration for ovulation induction; and [3] aspirational biopsy of endometrium at oocyte pick-up. MAIN OUTCOME MEASURE(S): Endometrial histology at oocyte pick-up by Noyes criteria. RESULT(S): Advancement of endometrial maturation (2.5 +/- 0.1 days) as compared to the expected chronological date was observed in all antagonist cycles at oocyte retrieval. Endometrial advancement at oocyte pick-up increased in line with values of LH at initiation of stimulation and the duration of recombinant FSH treatment before the antagonist was started. CONCLUSION(S): The higher the values of LH at initiation of stimulation and the longer the duration of recombinant FSH treatment before the antagonist is started, the more advanced the endometrial maturation at oocyte pick-up.

Spontaneous pregnancies in couples who discontinued intracytoplasmic sperm injection treatment: a 5-year follow-up study.

OBJECTIVE: To analyze the occurrence of deliveries after spontaneous conception in patients who have discontinued unsuccessful intracytoplasmic sperm injection (ICSI) treatment. DESIGN: Cohort follow-up study. SETTING: Tertiary referral center. PATIENT(S): Between July 1992 and December 1993, 200 Belgian women younger than 37 years underwent 433 consecutive unsuccessful ICSI cycles with freshly ejaculated sperm and eventually discontinued their treatment. INTERVENTION(S): Ultrasound-guided oocyte retrieval and ICSI. MAIN OUTCOME MEASURE(S): Delivery after 25 weeks following a spontaneous pregnancy. RESULT(S): The mean age at the time of the last oocyte pick-up was 31.0 +/- 3.9 years. The mean time interval between the last ICSI and the end of the follow-up period was 47.7 +/- 12.1 months. Twenty-three spontaneous pregnancies ending in delivery after 25 weeks were observed (11.5%). The cumulative delivery rate reached a plateau of 10% after 36 months of follow-up. The mean time interval (from last oocyte retrieval) for spontaneous pregnancy to occur after discontinuing ICSI treatment was 20.2 +/- 13.7 months. Proportional hazards analysis showed that delivery rate was reduced by 2.0% per year of infertility. CONCLUSION(S): This study suggests that duration of infertility appears to be predictive of the likelihood of live delivery after spontaneous conception following an unsuccessful ICSI treatment.

Effect of repeated assisted reproductive technology cycles on ovarian response.

OBJECTIVE: To assess the effect of repeated assisted reproductive technology (ART) cycles on the ovarian response in patients treated with human menopausal gonadotropins and GnRH agonists. DESIGN: Retrospective analysis. SETTING: Tertiary referral center. PATIENT(S): Three thousand two hundred forty-nine patients who had completed at least two in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles (minimum two, maximum six cycles per patient). INTERVENTION(S): Nine thousand three hundred seventy-nine repeated IVF/ICSI cycles. MAIN OUTCOME MEASURE(S): Mean number of cumulus oocyte complexes (COC) retrieved per cycle, mean number of ampules used per attempt. RESULT(S): Repeated ART cycles did not exert a significant effect on the mean number of COC retrieved per attempt in contrast to maternal age, which was inversely related to the mean number of COC retrieved in all cycles performed. Across repeated ART attempts, an increase in the mean number of ampules used per cycle was observed. This was due to an effect of maternal age, which increased in line with the mean number of ampules used per cycle, as well as to an age-independent effect of repeated cycles. CONCLUSION(S): An age-independent deterioration of the ovarian response appears to occur across repeated ART cycles.

Cumulative delivery rates after ICSI in women aged >37 years.

BACKGROUND: Female patients aged >37 years have a poor prognosis after ICSI. To determine the cumulative delivery rates in these women by life-table analysis, 228 patients aged >37 years who had undergone a total of 437 ICSI cycles were analysed retrospectively. METHODS: Only cycles in which fresh ejaculated sperm was used, and in which at least one oocyte was micro-injected, were analysed. The main outcome measure was cumulative rate of deliveries. Any delivery after 25 weeks gestation was included in the study. RESULTS: In women aged 38-39 years, the real cumulative delivery rate after two cycles was 21%, while the expected delivery rate was 26%. In patients aged 40-43 years, the real and expected cumulative delivery rates were 12 and 17% respectively after three cycles, when they reached a plateau. There was only one delivery in the age group >43 years, which consisted of 26 patients with 66 cycles. In women aged >37 years, an expected cumulative delivery rate of 30% may be obtained at the end of the fourth cycle. Women aged >43 years do not have a realistic chance of achieving a delivery with their own oocytes. CONCLUSIONS: This life-table analysis provides a means by which to counsel couples about their chances of achieving a delivery by ICSI at an age >37 years.