BACKGROUND The morphology of an embryo has a limited predictive value for assessing viability and ongoing pregnancy, therefore new selection tools are needed to maintain success rates with ...single-embryo transfer (SET). In this study, we investigated if metabolomic profiling of biomarkers of embryo culture medium by near-infrared (NIR) spectroscopy has a correlation with ongoing pregnancy in SET. METHODS A total of 333 patients scheduled for in vitro fertilization (IVF) with SET were included in the study. Embryos were selected for transfer by morphological criteria on Days 2 and 3 of in vitro culture, and left over culture media samples were analyzed by NIR spectroscopy. RESULTS The NIR spectral analysis produced unique metabolomic profiles that correlated to an embryo's reproductive potential. Resulting relative viability scores between positive and negative pregnancy outcomes were statistically significant (P < 0.03). A logistic regression of factors correlated to pregnancy outcomes showed that maternal age, percent fragmentation and relative viability scores all demonstrated a relationship. The extent of the correlation was determined by accuracy computation, where the accuracy of assessing viable embryos on Day 3 by metabolomic profiling was 53.6% and the accuracy of the morphological selection was 38.5%. In addition, the positive predictive value of metabolomic profiling was 0.365 and the negative predictive value was 0.830. CONCLUSIONS NIR metabolomic profiling of spent embryo culture media was able to distinguish viable embryos from non-viable embryos for reproduction.
STUDY QUESTION
Does the type of medium used to culture fresh and frozen–thawed embryos influence neonatal birthweight after single embryo transfer (SET) in IVF?
SUMMARY ANSWER
A comparison of two ...commercially available culture media showed no significant influence on mean birthweight and mean birthweight adjusted for gestational age, gender and parity (z-scores) of singletons born after a fresh or frozen–thawed SET. Furthermore, we show that embryo freezing and thawing cycles may lead to a significantly higher mean birthweight.
WHAT IS KNOWN AND WHAT THIS PAPER ADDS
Animal studies have shown that culture media constituents are responsible for changes in birthweight of offspring. In human IVF, there is still little knowledge of the effect of medium type on birthweight. Until now, only a small number of commercially available culture media have been investigated (Vitrolife, Cook® Medical and IVF online medium). Our study adds new information: it has a larger population of singleton births compared with the previously published studies, it includes outcomes of other media types (HTF and Sage®), not previously analysed, and it includes data on frozen–thawed SETs.
DESIGN
This study was a retrospective analysis of birthweights of singleton newborns after fresh (Day 3) or frozen–thawed (Day 5) SET cycles, using embryos cultured in either of two different types of commercially available culture media, between 2008 and 2011.
PARTICIPANTS AND SETTING
Before January 2009, a single-step culture medium was used: human tubal fluid (HTF) with 4 mg/ml human serum albumin. From January 2009 onwards, a commercially available sequential medium was introduced: Sage®, Quinn's advantage protein plus medium. Singletons born after a fresh SET (99 embryos cultured in HTF and 259 in Sage®) and singletons born after a frozen–thawed SET (32 embryos cultured in HTF only, 41 in HTF and Sage® and 86 in Sage® only) were analysed. Only patients using autologous gametes without the use of a gestational carrier were considered. Also excluded were (vanishing) twins, triplets, babies with congenital or chromosomal abnormalities and babies born before 22 weeks of gestation.
MAIN RESULTS AND THE ROLE OF CHANCE
Analysis of 358 singletons born after a fresh SET and 159 singletons born after a frozen–thawed SET showed no significant difference between the HTF and Sage® groups in terms of birthweight. Gestational age, parity and gender of the baby were significantly related to birthweight in multiple linear regression analyses, and other possible confounding factors included maternal age, BMI and smoking, the number of blastomeres in the transferred embryo and the type of culture medium. Maternal age, BMI and smoking, gestational age at birth, gender of the baby and the percentage of firstborns did not differ significantly between the HTF and Sage® groups; however, among the fresh embryos, those cultured in Sage® had significantly more blastomeres at the time of embryo transfer compared with the embryos cultured in HTF. Birthweights adjusted for gestational age and gender or gestational age and parity (z-scores) were not significantly different between the HTF and Sage® groups for fresh or frozen–thawed SETs. Mean birthweight, as well as the mean birthweight among firstborns and the mean birthweights adjusted for gestational age and gender or parity (z-scores) were significantly higher in the cryopreservation group compared with the fresh embryo transfer group.
BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION
Our study is limited by its retrospective design and only two commercially available types of culture media were tested. More research is necessary to investigate the potential influence of culture media on gene expression.
GENERALIZABILITY TO OTHER POPULATIONS
Although our data do not indicate the major influences of the HTF and Sage® culture media on birthweight, our results cannot be extrapolated to other culture media types. Furthermore, there remains a potential influence of embryo culture environment on epigenetic variation not represented by birthweight differences but by more subtle features.
STUDY FUNDING/COMPETING INTEREST(S)
No external funding was obtained for this study.
BACKGROUND Obesity is increasing rapidly among women all over the world. Obesity is a known risk factor for subfertility due to anovulation, but it is unknown whether obesity also affects spontaneous ...pregnancy chances in subfertile, ovulatory women. METHODS We evaluated whether obesity affected the chance of a spontaneous pregnancy in a prospectively assembled cohort of 3029 consecutive subfertile couples. Women had to be ovulatory and had to have at least one patent tube, whereas men had to have a normal semen analysis. Time to spontaneous ongoing pregnancy within 12 months was the primary endpoint. RESULTS The probability of a spontaneous pregnancy declined linearly with a body mass index (BMI) over 29 kg/m2. Corrected for possible related factors, women with a high BMI had a 4% lower pregnancy rate per kg/m2 increase hazard ratio: 0.96 (95% CI 0.91–0.99). CONCLUSIONS These results indicate that obesity is associated with lower pregnancy rates in subfertile ovulatory women.
Abstract
STUDY QUESTION
Is pre-ovulatory endometrial thickness (EMT) in women with unexplained subfertility undergoing IUI with ovarian stimulation (OS) associated with pregnancy chances?
SUMMARY ...ANSWER
We found no evidence for an association between EMT and pregnancy chances.
WHAT IS KNOWN ALREADY
It has been suggested that OS with clomiphene citrate (CC) results in a lower EMT than with gonadotrophins or aromatase inhibitors, but the clinical consequences in terms of pregnancy are unclear.
STUDY DESIGN, SIZE, DURATION
We performed a systematic review and meta-analysis of studies comparing CC, gonadotrophins or aromatase inhibitors in an IUI program reporting on EMT and pregnancy rates in women with unexplained subfertility.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We searched MEDLINE, EMBASE and the non-MEDLINE subset of PubMed from inception to 28th June 2016 and cross-checked references of relevant articles. Outcome measures were clinical pregnancy rate and mean pre-ovulatory EMT. We calculated mean differences (MD) with 95% CIs with a fixed effect model, and in case of heterogeneity with an I2 > 50% a random effect model. We performed a meta-regression analysis to determine if stimulating drugs interacted with the estimated effect of EMT.
MAIN RESULTS AND THE ROLE OF CHANCE
Our search retrieved 1563 articles of which 23 were included, totaling 3846 women. There were 17 RCTs and 6 cohort studies. The average study quality was low and there was considerable to substantial statistical heterogeneity. Seven studies provided data on EMT in relation to pregnancy. There was no evidence of a difference in EMT between women who conceived and women that did not conceive (1525 women, MDrandom: 0.51 mm, 95% CI: −0.05 to 1.07). Women treated with CC had a significantly thinner EMT than women treated with gonadotrophins (two studies, MD: −0.33, 95% CI: −0.64 to −0.01). There was no evidence of a difference in EMT when comparing CC with letrozole (five studies, MDrandom: −0.84, 95% CI: −1.97 to 0.28). The combination of CC plus gonadotrophins resulted in a slightly thinner endometrium than letrozole (nine studies, MDrandom: −0.79, 95% CI: −1.37 to −0.20). Letrozole resulted in a thinner EMT than gonadotrophins (two studies, MDrandom: −1.31, 95% CI: −2.08 to −0.53).
LIMITATIONS, REASONS FOR CAUTION
The overall quality of the included studies was low to moderate. We found considerable to substantial heterogeneity in the comparisons, hampering firm conclusions.
WIDER IMPLICATIONS OF THE FINDINGS
We found no evidence for an association between EMT and pregnancy rates during IUI –OS. As a consequence, canceling IUI cycles because of a thin endometrial lining may negatively affect clinical care. Although we found some evidence for very small differences in EMT when comparing various drugs, we cannot make inferences on their effect on pregnancy chances since these differences may be coincidental.
STUDY FUNDING/COMPETING INTEREST(S)
None.
REGISTRATION NUMBER
N/A.
BACKGROUND: Prediction models for spontaneous pregnancy may be useful tools to select subfertile couples that have good fertility prospects and should therefore be counselled for expectant ...management. We assessed the accuracy of a recently published prediction model for spontaneous pregnancy in a large prospective validation study. METHODS: In 38 centres, we studied a consecutive cohort of subfertile couples, referred for an infertility work-up. Patients had a regular menstrual cycle, patent tubes and a total motile sperm count (TMC) >3 × 106. After the infertility work-up had been completed, we used a prediction model to calculate the chance of a spontaneous ongoing pregnancy (www.freya.nl/probability.php). The primary end-point was time until the occurrence of a spontaneous ongoing pregnancy within 1 year. The performance of the pregnancy prediction model was assessed with calibration, which is the comparison of predicted and observed ongoing pregnancy rates for groups of patients and discrimination. RESULTS: We included 3021 couples of whom 543 (18%) had a spontaneous ongoing pregnancy, 57 (2%) a non-successful pregnancy, 1316 (44%) started treatment, 825 (27%) neither started treatment nor became pregnant and 280 (9%) were lost to follow-up. Calibration of the prediction model was almost perfect. In the 977 couples (32%) with a calculated probability between 30 and 40%, the observed cumulative pregnancy rate at 12 months was 30%, and in 611 couples (20%) with a probability of ≥40%, this was 46%. The discriminative capacity was similar to the one in which the model was developed (c-statistic 0.59). CONCLUSIONS: As the chance of a spontaneous ongoing pregnancy among subfertile couples can be accurately calculated, this prediction model can be used as an essential tool for clinical decision-making and in counselling patients. The use of the prediction model may help to prevent unnecessary treatment.
STUDY QUESTION
Does the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 ...years and older?
SUMMARY ANSWER
Supplementation of LH during the second half of the follicular phase has no effect on pregnancy rates, implantation rates or on ovarian response in women of 35 years and older undergoing GnRH antagonist IVF/ICSI cycles.
WHAT IS KNOWN ALREADY
In IVF/ICSI stimulation protocols GnRH agonists or antagonists are administered to prevent a premature pituitary LH surge, which can have a detrimental effect on the IVF/ICSI procedure. In effect, GnRH analogues cause the levels of both gonadotrophins to drop. In order to allow follicle growth FSH is administered exogenously, whereas LH is usually not supplemented. Although GnRH analogues prevent LH surges, there is evidence that, particularly in older women, administration of GnRH analogues may cause endogenous LH levels to decrease excessively. Several studies have been performed to investigate whether the addition of recombinant LH (r-LH) to r-FSH improves cycle outcome. Only a few studies have analysed this issue in the GnRH antagonist protocol and the results of these trials obtained in older women (>35 years old) are conflicting.
STUDY DESIGN, SIZE, DURATION
A multicentre RCT was performed between 2004 and 2010 in 253 couples who were undergoing IVF or ICSI. Women were 35 years or older and received ovarian stimulation in a protocol with r-FSH (Gonal-F 225 IU/day) starting from cycle day 3 and GnRH antagonist (Cetrotide 0.25 mg/day) from stimulation day 6. Randomization took place on stimulation day 6 to receive both r-FSH and r-LH (Luveris 150 IU/day) or continue with FSH alone. Randomization for r-LH supplementation was performed centrally by serially numbered, opaque, sealed envelopes, stratified by centre.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Of 253 subjects randomized, 125 received both r-FSH and r-LH and 128 received r-FSH only. Patients were recruited from the Division of Reproductive Medicine of the Obstetrics and Gynaecology department of four hospitals in the Netherlands.
MAIN RESULTS AND THE ROLE OF CHANCE
There were no demographic or clinical differences between the groups. The intention-to-treat analysis revealed that of those receiving both r-FSH and r-LH, 35 (28.0%) had a clinical pregnancy, compared with 38 (29.7%) receiving only r-FSH (mean difference −1.5%; 95% confidence interval (CI) −9.4 to 12.7, P = 0.9). Ongoing pregnancy rates were 25 (20%) versus 28 (21.9%) (mean difference −1.9%; 95% CI −8.2 to 11.9, P = 0.9) and implantation rates 18.8 versus 20.7% (mean difference −1.9%; 95% CI −8.0 to 11.7, P = 0.6) in the ‘r-FSH and r-LH’ and ‘r-FSH only’ groups respectively.
LIMITATIONS, REASONS FOR CAUTION
A limitation of our study is its early closure. This was done because the interim analysis after randomization of 250 patients indicated no benefit in any aspect of the experiment.
WIDER IMPLICATIONS OF THE FINDINGS
Given previous data, including a Cochrane review, and our own results the evidence indicates that LH supplementation has no benefit on ongoing pregnancy rates in women of 35 years or older.
STUDY FUNDING/COMPETING INTEREST(S)
Merck Serono Netherlands, an affiliate of Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany has donated the r-LH (Luveris®). No conflict of interest to declare.
TRIAL REGISTRATION NUMBER
The trial was registered in the Dutch trial register (ISRCTN10841210).
Abstract
STUDY QUESTION
Does hysteroscopic proximal tubal occlusion by intratubal devices as a treatment for hydrosalpinges result in comparable ongoing pregnancy rates following IVF/ICSI when ...compared with laparoscopic salpingectomy?
SUMMARY ANSWER
Hysteroscopic proximal tubal occlusion by intratubal devices is inferior to laparoscopic salpingectomy in the treatment of hydrosalpinges in women undergoing IVF/ICSI with respect to ongoing pregnancy rates.
WHAT IS KNOWN ALREADY
It is known that women with hydrosalpinges undergoing IVF have poorer pregnancy outcomes compared with women with other forms of tubal infertility. In these women, both laparoscopic salpingectomy and laparoscopic proximal tubal ligation are known to improve IVF outcomes. At present, it is unclear whether a less-invasive hysteroscopic treatment with intratubal devices leads to similar ongoing pregnancy rates following IVF when compared with laparoscopic salpingectomy.
STUDY DESIGN, SIZE, DURATION
A two-centre, randomized, controlled, non-inferiority trial. Between October 2009 and December 2014 a total of 85 women were included in this study; of whom, 42 were randomized to hysteroscopic proximal occlusion by intratubal device placement and 43 were randomized to laparoscopic salpingectomy. Randomization was based on a computer-generated randomization list. The study was unblinded. The primary outcome was ongoing pregnancy rate, defined as a fetal heartbeat on ultrasound beyond 10-week gestation following one IVF/ICSI treatment (fresh and frozen–thawed embryo transfers).
PARTICIPANTS/MATERIALS, SETTING, METHODS
We studied women aged 18–41 years, with uni- or bilateral ultrasound visible hydrosalpinges who were scheduled for an IVF/ICSI treatment.
MAIN RESULTS AND THE ROLE OF CHANCE
The ongoing pregnancy rates per patient according to the intention-to-treat principle were 11/42 (26.2%) after hysteroscopic proximal occlusion by intratubal devices (intervention group) versus 24/43 (55.8%) after laparoscopic salpingectomy (control group) (P = 0.008) absolute difference: 26.1%; 95% confidence interval (CI): 0.5–51.7, relative risk (RR): 0.56; 95% CI: 0.31–1.03, P = 0.01. In the per protocol analysis, the ongoing pregnancy rate per patient following hysteroscopic proximal occlusion by intratubal devices was 9/27 (33.3%) compared with 19/32 (59.4%) following laparoscopic salpingectomy (P = 0.067) (absolute difference: 29.6%; 95% CI: 7.1 to 49.1, RR: 0.47; 95% CI: 0.27–0.83, P = 0.062).
LIMITATIONS, REASONS FOR CAUTION
Masking participants and investigators would be difficult due to the nature of both interventions. Since we had objective outcome measurements, we withheld sham procedures, leaving the study unblinded. Furthermore, our low sample size resulted in wide CIs. A larger sample size would result in a more accurate treatment effect; however, this was non-feasible for recruitment and inclusion.
WIDER IMPLICATIONS OF THE FINDINGS
In the treatment of hydrosalpinges prior to IVF/ICSI, hysteroscopic proximal occlusion by intratubal devices is inferior to laparoscopic salpingectomy.
STUDY FUNDING/COMPETING INTEREST(S)
The intratubal devices were received from Conceptus, Inc., San Carlos, CA, USA, which was acquired by Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA in 2013. Conceptus, Inc./Bayer HealthCare Pharmaceuticals, Inc. had no role in the study design, data collection and analyses, decision to publish or preparation of the manuscript. The study as a whole was funded by the SWOG (foundation for scientific investigation in obstetrics and gynaecology of the VU University Medical Centre, Amsterdam, the Netherlands). P.G.A.H. has received non-financial support from Conceptus, Inc. during the conduct of this study. He has received grants from Ferring B.V., Merck Serono and Abbott outside the submitted work. M.H.E. has received personal fees from Smith and Nephew and IQ Medical Ventures outside the submitted work.
TRIAL REGISTRATION NUMBER
The Dutch Trial Register: NTR 2073.
TRIAL REGISTRATION DATE
October 21, 2009.
DATE OF FIRST PATIENT'S ENROLMENT
October 26, 2009.
BACKGROUND: Advancing female age is associated with declining fertility potential due to decreasing numbers and quality of oocytes but also with a distinct increase in dizygotic twinning rates, a ...phenomenon that has never been explained. METHOD: An analysis of follicle development was made in 959 spontaneous ovulatory cycles of 507 women. RESULTS: Multiple ovarian follicular development (>1 follicle >14 mm) and, by implication, multiple rather than single ovulations occurred in 105 women whose mean age (36.1 versus 34.6 years) and mean basal FSH concentrations (10.3 versus 7.7 IU/l) were significantly greater than those with monofollicular development (P < 0.01). The prevalence of multifollicular development increased with age. CONCLUSIONS: Dizygotic twinning must be associated with the development of >1 large follicle, which we found to be a significantly more frequent occurrence in older women. It is hypothesized that the response of pituitary release of FSH to the decreased negative feedback induced by impending ovarian failure often ‘overshoots’, causing multiple follicular development. In the presence of two good-quality oocytes, a twin pregnancy may result.
BACKGROUND Clomiphene citrate (CC) response in anovulatory women is difficult to predict and patient-tailored treatment would benefit patient care and time-management. The objective of this study was ...to evaluate the role of the follicle-stimulating hormone receptor (FSHR) Ser680Ser-polymorphism as a predictor for CC response. METHODS In this retrospective study, 193 patients, diagnosed with polycystic ovary syndrome (PCOS) according to Rotterdam criteria and treated with ovulation induction, were included over a 5-year period in a university hospital in the Netherlands. Data on demographics, BMI, menstrual cycle, laboratory screening (including FSHR genotyping), transvaginal ultrasonography of ovaries and ovulation parameters were collected. Main outcome measures were response to CC and FSHR genotype. RESULTS The frequency distribution of the 680-polymorphism was 26% (Asn/Asn), 50% (Asn/Ser) and 24% (Ser/Ser). No significant differences in basal characteristics were found. Significantly more patients with Ser/Ser-polymorphism were resistant to CC (28%) compared with Asn/Ser (14%) and Asn/Asn group (15%), with an odds ratio for ovulation of 0.44 (95% CI, 0.21–0.97). Patients with higher FSH levels, higher age and lower BMI were significantly more likely to ovulate in univariate analysis. In a multivariate logistic regression model, corrected for age, BMI, mean ovarian, volume, hyperandrogenism, and amenorrhoea, only FSHR and basal FSH levels were predictive for ovulation. CONCLUSIONS Chance of resistance to CC is almost double in women with PCOS harbouring the Ser/Ser genotype.
Pregnancy rates among infertile women have been reported to increase after hysterosalpingography, but it is unclear whether the type of contrast medium used (oil-based or water-soluble contrast) ...influences this potential therapeutic effect.
We performed a multicenter, randomized trial in 27 hospitals in the Netherlands in which infertile women who were undergoing hysterosalpingography were randomly assigned to undergo this procedure with the use of oil-based or water-based contrast. Subsequently, couples received expectant management or the women underwent intrauterine insemination. The primary outcome was ongoing pregnancy within 6 months after randomization. Outcomes were analyzed according to the intention-to-treat principle.
A total of 1119 women were randomly assigned to hysterosalpingography with oil contrast (557 women) or water contrast (562 women). A total of 220 of 554 women in the oil group (39.7%) and 161 of 554 women in the water group (29.1%) had an ongoing pregnancy (rate ratio, 1.37; 95% confidence interval CI, 1.16 to 1.61; P<0.001), and 214 of 552 women in the oil group (38.8%) and 155 of 552 women in the water group (28.1%) had live births (rate ratio, 1.38; 95% CI, 1.17 to 1.64; P<0.001). Rates of adverse events were low and similar in the two groups.
Rates of ongoing pregnancy and live births were higher among women who underwent hysterosalpingography with oil contrast than among women who underwent this procedure with water contrast. (Netherlands Trial Register number, NTR3270 .).
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