Screening for blood born viruses in assisted reproduction: is annual testing necessary?

PURPOSE: Screening for blood born viruses is routinely performed before fertility treatment in assisted reproduction technology (ART) clinics worldwide. It involves testing for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), among others. Identifying patients with positive viral screening allows to refer them and their partners for appropriate counseling and treatment. The need for repeat viral screening and its required frequency have never been clearly established. In Israel, viral screening is mandatory and is repeated annually. Our aim was to determine the prevalence of HBV, HCV, and HIV seroconversion in patients with negative screening upon initiation of ART treatment. METHODS: A retrospective analysis of viral screening tests of all fertility patients in a single assisted conception unit between 1997 and 2015. RESULTS: During the study period, 2844 patients were treated at our clinic, out of whom 1945 patients met the inclusion criteria. The average length of treatment was 1.61 ± 0.81 years, during which female patients underwent screening tests 2.6 ± 0.9 times, and male patients 2.3 ± 1.2 times. No case of seroconversion to any of the three viruses was noted during the entire study period, resulting a seroconversion rate of 0%. CONCLUSIONS: Primary infection with HBV, HCV, or HIV is an extremely rare event among Israeli infertile patients, and the risk for seroconversion in this population is practically nil. Annual screening of both partners leads to substantial costs and appears to be futile. Our results question the current practice and support increasing the interval between screening tests in low-risk populations.

Human chorionic gonadotropin serum levels following ovulation triggering and IVF cycle outcome.

PURPOSE: The clinical significance of serum hCG levels after ovulation triggering was studied previously with conflicting results. Our aim was to study the correlation of hCG levels on the day after ovulation triggering using recombinant hCG (r-hCG) with treatment outcome. METHODS: A prospective observational study of all fresh IVF/ICSI cycles in a single medical center, between January 2015 and June 2016, was performed. hCG serum levels were obtained 10-12 h following ovulation triggering with 250 mcg r-hCG. Clinical and laboratory outcome parameters were compared between cycles with serum hCG above and below median level. A multivariate regression analysis was performed in order to study the association between hCG levels and live birth rate, after controlling for confounders. RESULTS: Overall, 326 cycles were included. Median serum hCG level was 91.35 IU/L. hCG levels were lower as age and BMI were higher (p = 0.004, p < 0.001, respectively). The study groups did not differ with regard to clinical pregnancy rate (p = 0.14), live birth rate (p = 0.09), fertilization rate (p = 0.45), or metaphase II oocyte rate (p = 0.68). On multivariate regression analysis, hCG level was not associated with live birth (aOR 0.99, 95% CI 0.98-1.005), after controlling for patient's age and BMI. CONCLUSIONS: hCG levels on the day after ovulation triggering with 250 mcg r-hCG are inversely correlated with patient age and BMI. However, they are not correlated with any clinical or laboratory outcome parameter. Therefore, testing for hCG levels after ovulation induction seems futile and cannot be recommended.

A previous caesarean section is not a risk factor for tubal abnormalities in the infertile population.

In this retrospective cohort study of 1716 cases of women undergoing infertility treatment between the years 1999-2012, we aimed to identify whether parturients with a previous surgical history are at a higher risk for tubal abnormalities as determined by hysterosalpingography (HSG) in this infertile population. Amongst the study population, tubal obstruction was identified on HSG in 15.8% of patients with no past history of an abdominal surgery and 16.3% of patients with a previous caesarean section (CS) delivery. These rates were significantly lower than those for women with a previous gynaecological surgery (34.7%) or abdominal surgery (27%) (p < .001 for all comparisons). Our results suggest that past history of CS poses no additional risk for tubal abnormality within the infertile population, whereas a history of other abdominal or gynaecological surgical procedures doubles this risk. Impact Statement What is already known on this subject? While numerous risk factors for tubal factor infertility have been established, to date, the relation between previous abdominal surgeries and the risk for tubal factor infertility remains inconclusive. What the results of this study add? In this study, we aimed to evaluate the correlation between previous CS history and the risk for having tubal factor infertility. Our results demonstrated that previous caesarean section delivery does not increase the risk for tubal factor infertility in the infertile population, whereas history of other abdominal or gynaecological surgical procedures doubles this risk. What the implications are of these findings for clinical practice and/or further research? Further research is needed for further evaluation of this association and its clinical implications.

Ovarian reserve following cesarean section with salpingectomy vs tubal ligation: a randomized trial.

BACKGROUND: Epithelial ovarian cancer is assumed to derive from the fallopian tube. Salpingectomy has been previously demonstrated to reduce the risk of ovarian cancer, and may be used as a means of sterilization. OBJECTIVE: We aimed to compare short-term ovarian reserve and operative complications in cases of salpingectomy and tubal ligation during cesarean section. STUDY DESIGN: Study patients who underwent elective cesarean section at our institution and requested sterilization were randomized to bilateral salpingectomy or tubal ligation. Prior to surgery, blood samples were obtained for antimüllerian hormone. Surgical course was noted, including overall time, complications, and postoperative hemoglobin. Repeat antimüllerian hormone samples were obtained from patients 6-8 weeks following surgery. RESULTS: In all, 46 patients were recruited for participation, of whom 33 completed a follow-up visit, and for whom repeat antimüllerian hormone levels were available. Patients in the salpingectomy group were slightly older (37.0 ± 3.9 vs 34.3 ± 4.1 years, P = .02). No differences were noted in patient parity, body mass index, or gestational age between the groups. Pregnancy and postdelivery antimüllerian hormone levels were not significantly different between the groups, with an average increase of 0.58 ± 0.98 vs 0.39 ± 0.41 ng/mL in the salpingectomy and tubal ligation groups, respectively (P = .45). Surgeries including salpingectomy were longer by an average 13 minutes (66.0 ± 20.5 vs 52.3 ± 15.8 minutes, P = .01). No difference was demonstrated between the groups regarding surgical complications and postoperative hemoglobin decrease. CONCLUSION: Sterilization by salpingectomy appears to be as safe as tubal ligation regarding operative complications and subsequent ovarian reserve. As salpingectomy offers the advantage of cancer risk reduction, it may be offered in the settings of elective preplanned surgeries.

Extension of the clomiphene citrate stair-step protocol to gonadotropin treatment in women with clomiphene resistant polycystic ovarian syndrome.

Our objective was to evaluate the safety and efficacy of direct initiation of gonadotropin ovarian stimulation without prior withdrawal bleeding in anovulatory clomiphene citrate (CC) resistant polycystic ovarian syndrome (PCOS) patients. Eighteen PCOS patients underwent ovulation induction with CC using a stair-step regimen. Patients who failed to respond to the maximal dose of CC initiated gonadotropin stimulation without inducing withdrawal bleeding, using the chronic low dose regimen. The primary outcome measure was the time to ovulation from the beginning of CC treatment until the day of ovulatory trigger. This was compared with the time to ovulation calculated according to the traditional approach, which includes inducing progesterone withdrawal bleeding between each CC dose increment and before gonadotropin therapy. The time to ovulation in the study group was 67.0 ± 6.8 days. The estimated time to ovulation according to the traditional approach was approximately 110 days. The clinical pregnancy rate was 44% (8/18), and all pregnancies were singletons. One patient miscarried; hence the live birth rate was 38.9% (7/18). Direct initiation of gonadotropin therapy without prior induction of withdrawal bleeding in clomiphene resistant PCOS patients results in considerable reduction of the time to ovulation and is both safe and efficacious.

Possible risk for cancer among children born following assisted reproductive technology in Israel.

BACKGROUND: Among children conceived by assisted reproductive technology (ART), increased risk of adverse birth outcomes has been observed, including multiple births, preterm births, and congenital malformations. Regarding cancer among ART-conceived children, findings are discrepant. METHODS: This is a historical cohort of 9,042 ART-conceived children and 211,763 spontaneously conceived (SC) children born from 1997 through 2004. The median duration of follow-up was 10.6 years (interquartile range 9.0-12.3) in the ART group and 9.3 years (interquartile range 8.0-10.6) in the SC group. The cohort database was linked with the Israel National Cancer Registry updated until December 31, 2011 using each child's personal identification number. RESULTS: Twenty-one cases of cancer were identified in the ART group (2.2 per 10,000 person-years), as compared to 361 cancer cases in the SC group (1.8 per 10,000 person-years). The relative risk (RR) for overall cancer in the ART group compared to the SC group adjusted for maternal characteristics was 1.18 (95% confidence interval [CI] 0.80-1.75). ART children had a significantly increased risk for specific cancers, although based on small number of cases, including two cases of retinoblastoma (RR 6.18, 95% CI 1.22-31.2), as well as four cases of renal tumors (RR 3.25, 95% CI 1.67-6.32). CONCLUSION: A statistically significant increased risk for two pediatric cancers was found. However, for overall types of cancer the risk estimate was elevated but not statistically significant. Further studies with larger sample size and longer follow-up time are warranted in order to either confirm or refute these findings.

Controlled ovarian stimulation using a long gonadotropin-releasing hormone antagonist protocol: a proof of concept and feasibility study.

BACKGROUND/AIMS: To evaluate the feasibility of a long protocol of controlled ovarian stimulation prior to in vitro fertilization (IVF) and embryo transfer with a gonadotropin-releasing hormone (GnRH) antagonist used for pituitary and ovarian suppression. METHODS: Thirty patients undergoing IVF/intracytoplasmic sperm injection were randomized into two groups. The control group (n = 16) received a standard flexible GnRH antagonist protocol. Ovarian stimulation consisted of 225 IU/day of recombinant follicle-stimulating hormone for 5 days, followed by 225 IU/day of human menopausal gonadotropin until human chorionic gonadotropin (hCG) administration. The study group (n = 14) received 0.25 mg of GnRH antagonist daily for 7 days, thereafter, upon confirmation of pituitary and ovarian suppression, ovarian stimulation was commenced with the same protocol as used in the control group. Hormone and follicle dynamics, as well as laboratory characteristics and cycle outcome, were compared for both groups. RESULTS: Both groups were comparable in baseline characteristics. Pituitary and ovarian suppression were effectively achieved in 12/14 patients in the study group. The duration of ovarian stimulation and gonadotropin consumption were similar in both groups, as was also the number and size of follicles on hCG day. CONCLUSION: The results of our study confirm the feasibility of a long GnRH antagonist protocol. This regimen could become another option to optimize GnRH antagonist protocols, and should thus be further explored.

Zygote intrafallopian transfer among patients with repeated implantation failure.

OBJECTIVE: To summarize the experience of a single center with laparoscopic zygote intrafallopian transfer (ZIFT) performed exclusively among patients with high-order repeated implantation failure (RIF) following in vitro fertilization-embryo transfer (IVF-ET). METHODS: A retrospective cohort study was performed at the Edith Wolfson Medical Center, a tertiary referral university hospital located in Holon, Israel. A group of 176 patients with 8.15±3.9 previously failed IVF-ET cycles underwent 280 ZIFT procedures between 1995 and 2010. The main outcome measure was the live birth rate per patient treated. RESULTS: In all, there were 274 fresh and 6 frozen ZIFT cycles recorded in the study cohort, resulting in 96 clinical pregnancies per attempt (34.3%) and 72 live births (25.7%). The live birth rate per patient was 39.8%. CONCLUSION: The use of ZIFT remains a powerful tool in the clinical management of selected patients with high-order RIF. This procedure should be kept in mind when all other measures fail among patients with at least 1 unobstructed fallopian tube.

The effect of delayed initiation of gonadotropin-releasing hormone antagonist in a flexible protocol on in vitro fertilization outcome.

OBJECTIVE: To determine the proportion of patients stimulated on a flexible GnRH antagonist regimen who meet the criteria for antagonist administration after stimulation day 6 (S6) and to compare their clinical characteristics and cycle outcome with those patients who start the antagonist on S6 or earlier. DESIGN: Retrospective study. SETTING: Tertiary university hospital. PATIENT(S): Patients undergoing IVF (n = 442) using a flexible GnRH antagonist protocol. INTERVENTION(S): Ovarian stimulation was performed using gonadotropins and GnRH antagonists. Group A (n = 323) patients met the criteria for antagonist administration (follicle size >12 mm, E2 >300 pg/mL) on S6 or earlier. Group B patients (n = 119) started the antagonist later. MAIN OUTCOME MEASURE(S): Implantation rate. RESULT(S): Comparable implantation (30.4% vs. 33.7%), clinical (47.4% vs. 52.9%), and ongoing pregnancy rates (41.2% vs. 47.9%) were observed in groups A and B, respectively. Group B patients had a significantly higher body mass index, longer stimulation, increased gonadotropins dosage, fewer oocytes and two pronuclei oocytes, fewer frozen embryos, and fewer cycles with embryo freezing. Patients with polycystic ovary syndrome were more likely to be in group B. CONCLUSION(S): A considerable proportion of patients on a flexible regimen begin GnRH antagonist administration later than S6. Despite different stimulation and laboratory characteristics, their reproductive outcome is not compromised as compared with patients with an earlier antagonist start.

Association of common thrombophilias and antiphospholipid antibodies with success rate of in vitro fertilisation.

Assisted reproductive technology (ART) is extensively used as a tool for pregnancy achievement in subfertile couples. Congenital and acquired thrombophilias have been suggested by some investigators to play a role in abnormal embryo implantation and placentation. The objective of this study was to assess the role of common thrombophilias in women with unexplained infertility undergoing in vitro fertilisation (IVF). We retrospectively analysed 594 women from a large healthcare maintenance organisation going through IVF and who had a thrombophilia workup, and compared them for prevalence of thrombophilia to two reference groups consisting of 637 fertile women from previous work and 17,337 women members of the same healthcare organisation with no history of venous thromboembolism. The mean age of the women at the first cycle of IVF was 30.9 years (SD: 4.1).The mean number of IVF cycles was 7.3 (SD: 5.0), and the mean fertility success rate per woman was 14.6% (SD: 19.0%). None of the common thrombophilias tested was found to be significantly associated with the number of IVF cycles or with lower fertility success rate. Rather, women who had APCR and /or factor V Leiden and lupus anticoagulant had significantly higher live birth rates (12.3% and 12.6%, respectively) in comparison to women who were tested negative (9.0% and 9.7%, respectively). Thus, hypercoagulability is not associated with failure to achieve pregnancy. These data suggest that neither screening for thrombophilia nor anticoagulant treatment is indicated in cases with unexplained reproductive failure.

Spontaneous ovulation versus HCG triggering for timing natural-cycle frozen-thawed embryo transfer: a randomized study.

In ovulatory patients, frozen-thawed embryo transfer (FET) is commonly performed during a natural cycle (NC). The objective was to compare serial monitoring until documentation of ovulation with human chorionic gonadotrophin (HCG) triggering, for timing NC-FET. Sixty women with regular menstrual cycles undergoing NC-FET were randomized into two groups: group A (n=30) had FET in a natural cycle after ovulation triggering with HCG; group B (n=30) had FET in a natural cycle after detection of spontaneous ovulation. The main outcome measure was the number of monitoring visits at the clinic per cycle. Secondary outcome measures included implantation rate, clinical pregnancy and live-birth rates. Both groups were similar in terms of demographic characteristics and reproductive history. Clinical and laboratory characteristics of fresh and frozen cycles and pregnancy and delivery rates were comparable for both groups. The number of monitoring visits in group A (3.2 ± 1.4) was significantly lower than in group B (4.7 ± 1.6) (P=0.002). In patients undergoing NC-FET, triggering ovulation by HCG can significantly reduce the number of visits necessary for cycle monitoring without an adverse effect on cycle outcome. Ovulation triggering can increase both patient convenience and cycle cost effectiveness.

Dehydroepiandrosterone supplementation increases baseline follicular phase progesterone levels.

The use of dehydroepiandrosterone (DHEA) supplementation in infertile patients with diminished ovarian reserve (DOR) has become increasingly popular. It has been our observation that serum progesterone levels during the follicular phase are often increased during controlled ovarian stimulation when DHEA is coadministered. Our aim was to compare progesterone levels during the follicular phase before and during DHEA supplementation in women with DOR undergoing in vitro fertilization (IVF). In a case-control study, we compared progesterone levels during the follicular phase in IVF cycles before and during DHEA supplementation in 15 women with DOR who received 75 mg of DHEA daily. Progesterone levels on stimulation day 5 (0.5 ± 0.29 ng/ml vs. 1.54 ± 0.49 ng/ml; p < 0.0001) and on the day of human chorionic gonadotropin administration (0.75 ± 0.31 ng/ml vs. 1.87 ± 0.49 ng/ml; p < 0.0001) were significantly higher during DHEA treatment. The number of retrieved and fertilized oocytes was similar in both the groups. DHEA administration during IVF cycles in women with DOR causes a significant elevation of progesterone levels without an apparent deleterious effect on cycle outcome.

What is the preferred method for timing natural cycle frozen-thawed embryo transfer?

Spontaneous ovulation during a natural menstrual cycle represents a simple and efficient method for synchronization between frozen embryos and the endometrium. The objective was to compare serial monitoring until documentation of ovulation, with human chorionic gonadotrophin (HCG) triggering, for timing frozen embryo transfer (FET) in natural cycles (NC). In a retrospective study, 112 women with regular menstrual cycles undergoing 132 NC-FET cycles were divided into two groups: group A (n = 61) patients had FET in an NC after ovulation triggering with HCG; group B (n = 71) patients had FET in an NC after spontaneous ovulation was detected. The main outcome measure was the number of monitoring visits at the clinic. Patients in both groups were similar in terms of demographic characteristics and reproductive history. Clinical and laboratory characteristics of fresh and frozen cycles were also found comparable for both groups, as were pregnancy and delivery rates. The number of monitoring visits in group A (3.46 +/- 1.8) was significantly lower than in group B (4.35 +/- 1.4) (P < 0.0001). In patients undergoing NC-FET, triggering ovulation by HCG can significantly reduce the number of visits necessary for cycle monitoring without an adverse effect on cycle outcome. Ovulation triggering can increase both patient convenience and cycle cost-effectiveness.

Combined jugular and subclavian vein thrombosis following assisted reproductive technology--new observation.

OBJECTIVE: To study the predilection of jugular and subclavian vein thrombosis in patients going through assisted reproductive technology (ART). This technology puts women at high risk of developing the ovarian hyperstimulation syndrome (OHSS) and thrombotic events. DESIGN: Study cases. SETTING: Large Academic Medical Center. PATIENT(S): Five women who developed jugular and subclavian vein thrombosis following ART were included in the study. INTERVENTION(S): The deep vein thrombosis was demonstrated by ultrasound Doppler or computerized tomography angiography. All women were interviewed and data obtained from outpatient and hospital medical charts. Magnetic resonance imaging and complete thrombophilic profile workup was performed in each woman. Open biopsy from the lesions was taken from one of the women. MAIN OUTCOME MEASURE(S): Correlation between mechanical branchial cysts filled with fluid during OHSS and jugular and subclavian vein thrombosis. RESULT(S): Five women developed jugular and subclavian vein thrombosis following ART. They were found to harbor clusters of rudimentary branchial cysts filled with fluid at the time of OHSS, which compressed the jugular and subclavian veins at their junction at the base of the neck. Four patients (80%) were found to be carriers of factor V Leiden. CONCLUSION(S): Predilection of jugular and subclavian vein thrombosis early in pregnancy is the result of mechanical compression mediated by rudimentary branchial cysts filled with fluid during OHSS, particularly in subjects who are carriers of factor V Leiden.

Pregnancies and live births following ICSI with testicular spermatozoa after repeated implantation failure using ejaculated spermatozoa.

The use of testicular spermatozoa for IVF/intracytoplasmic sperm injection (ICSI) is currently indicated exclusively for patients with azoospermia, since a favourable outcome is expected even when very few spermatozoa are present in the ejaculate. Here, a series of four couples with long-standing male factor infertility and multiple failed IVF/ICSI cycles are described. In all couples, the use of ejaculated spermatozoa for ICSI resulted in poor embryo quality and repeated implantation failure. Testicular sperm aspiration was performed in subsequent cycles, and testicular spermatozoa were used for ICSI. Embryo implantation and ongoing pregnancies/deliveries were achieved in all four couples. It is postulated that spermatozoa are subjected to post-testicular damage during sperm transport between the seminiferous tubules and epididymis, with the injection of damaged spermatozoa being the cause for repetitive IVF/ICSI failures. In selected patients, the use of testicular spermatozoa for IVF/ICSI should be considered, even when motile spermatozoa can be identified in the ejaculate.

Blastocyst culture and transfer: lessons from an unselected, difficult IVF population.

Blastocyst-stage transfer has yielded excellent results in good prognosis IVF patients, but its efficacy in the general IVF population has not been clearly demonstrated. The objective of this study was to compare cleavage-stage and blastocyst-stage transfer in a mixed, general IVF population. In a prospective, quasi-randomized study, 152 patients underwent 164 treatment cycles. Patients were allocated to cleavage-stage (group 1; n = 94) or blastocyst-stage (group 2; n = 70) transfer. Main outcome measures included implantation, clinical pregnancy and live birth rates. Implantation (11.2% versus 15.5%), clinical pregnancy (34% versus 21%) and live birth rates per transfer (21.3% versus 13.8%) and per started cycle (21.3% versus 11.4%) were all comparable for groups 1 and 2, respectively. Logistic regression analysis revealed that blastocyst culture and transfer reduced the odds for pregnancy in the general IVF population and defined a good prognosis group for blastocyst transfer. Introducing blastocyst culture and transfer to all IVF patients is not advantageous. Blastocyst transfer should be offered primarily to good prognosis patients, and this group should be specifically defined in each clinical set-up.

Timing intra-Fallopian transfer procedures.

With the gradual decline in the use of zygote intra-Fallopian transfer (ZIFT), current practice is to offer ZIFT almost exclusively to patients with repeated implantation failure (RIF). For practical reasons, the procedure is sometimes deferred by 1 day and embryo intra-Fallopian transfer (EIFT) is performed. The aim of the present study was to compare the reproductive outcome of ZIFT versus EIFT. In a retrospective analysis, 176 patients who failed in 7.65 +/- 3.7 previous IVF cycles underwent 200 ZIFT and 73 EIFT procedures. Implantation and live birth rates were compared for both groups. Patients in both groups were found comparable for demographic and clinical parameters. Similar numbers of oocytes were retrieved and fertilized in both groups, and 5.2 +/- 1.2 zygotes/embryos were transferred. Implantation and live birth rates (10.5 and 26.5% versus 10.9 and 24.7% for ZIFT and EIFT respectively) were comparable. It is concluded that tubal transfer of zygotes and day-2 cleavage stage embryos are equally effective.

Follicular growth and development under continuous gonadotropin-releasing hormone antagonist administration.

OBJECTIVE: Ovarian follicle and cyst formation have been recognized as an advance phenomenon associated with GnRH agonist administration. With the use of GnRH antagonists, pituitary suppression is immediate and no flare effect and follicle growth are expected. We describe two patients who developed a dominant follicle and presumably ovulated in response to hCG triggering under continuous sole administration of a GnRH antagonist. DESIGN: Case report. SETTING: An IVF unit at a university hospital. PATIENT(S): Two young healthy female patients undergoing IVF because of male-factor infertility. INTERVENTION(S): Continuous daily administration of a GnRH antagonist from menstruation with the aim of achieving ovarian suppression. MAIN OUTCOME MEASURE(S): Endocrine and ultrasound characteristics of follicular growth. RESULT(S): Both patients developed a dominant follicle under sole administration of a GnRH antagonist, accompanied by a gradual rise in serum estradiol and endometrial thickness which culminated in a spontaneous LH surge. Ovulation was triggered by hCG and mid-luteal progesterone levels were suggestive of ovulation. CONCLUSION(S): We describe for the first time the development of a dominant follicle and presumable ovulation under continuous administration of a GnRH antagonist. Serum gonadotropin concentrations indicate that the pituitary failed to suppress in both patients. The exact mechanism of this phenomenon remains to be elucidated.