Peter G.A. Hompes

Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial

BACKGROUND Intrauterine insemination with controlled ovarian hyperstimulation is commonly used as first-line treatment for couples with unexplained subfertility. Since such treatment increases the risk of multiple pregnancy, a couples chances of achieving an ongoing pregnancy without it should be considered to identify those most likely to benefit from treatment. We aimed to assess the incremental effectiveness of intrauterine insemination with controlled ovarian hyperstimulation compared with expectant management in couples with unexplained subfertility and an intermediate prognosis of a spontaneous ongoing pregnancy. METHODS 253 couples with unexplained subfertility and a 30-40% probability of a spontaneous ongoing pregnancy within 12 months were randomly assigned either intrauterine insemination with controlled ovarian hyperstimulation for 6 months or expectant management for 6 months. The primary endpoint of this hospital-based study was ongoing pregnancy within 6 months. Analysis was by intention to treat. This trial is registered with the Dutch Trial Register and as an International Standard Randomised Clinical Trial, number ISRCTN72675518. FINDINGS Of the 253 couples enrolled, 127 were assigned intrauterine insemination with controlled ovarian hyperstimulation and 126 expectant management. In the intervention group, 42 (33%) women conceived and 29 (23%) pregnancies were ongoing. In the expectant management group, 40 (32%) women conceived and 34 (27%) pregnancies were ongoing (relative risk 0.85, 95% CI 0.63-1.1). There was one twin pregnancy in each study group, and one woman in the intervention group conceived triplets. INTERPRETATION A large beneficial effect of intrauterine insemination with controlled ovarian hyperstimulation in couples with unexplained subfertility and an intermediate prognosis can be excluded. Expectant management for 6 months is therefore justified in these couples.

Metabolomic profiling by near-infrared spectroscopy as a tool to assess embryo viability: a novel, non-invasive method for embryo selection

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 embryos 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.

Prediction models in reproductive medicine: a critical appraisal†

BACKGROUND Prediction models have been developed in reproductive medicine to help assess the chances of a treatment-(in)dependent pregnancy. Careful evaluation is needed before these models can be implemented in clinical practice. METHODS We systematically searched the literature for papers reporting prediction models in reproductive medicine for three strategies: expectant management, intrauterine insemination (IUI) or in vitro fertilization (IVF). We evaluated which phases of development these models had passed, distinguishing between (i) model derivation, (ii) internal and/or external validation, and (iii) impact analysis. We summarized their performance at external validation in terms of discrimination and calibration. RESULTS We identified 36 papers reporting on 29 prediction models. There were 9 models for the prediction of treatment-independent pregnancy, 3 for the prediction of pregnancy after IUI and 17 for the prediction of pregnancy after IVF. All of the models had completed the phase of model derivation. For six models, the validity of the model was assessed only in the population in which it was developed (internal validation). For eight models, the validity was assessed in populations other than the one in which the model was developed (external validation), and only three of these showed good performance. One model had reached the phase of impact analysis. CONCLUSIONS Currently, there are three models with good predictive performance. These models can be used reliably as a guide for making decisions about fertility treatment, in patients similar to the development population. The effects of using these models in patient care have to be further investigated.

The influence of the type of embryo culture medium on neonatal birthweight after single embryo transfer in IVF

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(®), Quinns 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.

Role of semen analysis in subfertile couples

OBJECTIVE To evaluate the associations between the results of the male partners semen analysis (classified according to the World Health Organization [WHO] criteria) and fathering a child without any treatment. DESIGN Prospective multicenter cohort study. SETTING Twenty subfertility centers in The Netherlands. PATIENT(S) A total of 3,345 consecutive couples presenting for subfertility. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Associations between the results of the male partners semen analysis, classified according to the WHO criteria, and fathering a child without any treatment within a time horizon of 1 year. Subsequently, we redefined semen quality criteria and reevaluated the associations. RESULT(S) Follow-up data of 3,129 couples (94%) were available, of which 517 (17%) had a healthy pregnancy without treatment. The 1-year pregnancy rate in men with WHO normozoospermia did not differ significantly from that in men with WHO impaired semen (24% vs. 23%). In contrast, we observed lower chances of fathering a child for sperm concentrations <40 × 10(6)/mL, total sperm count <200 × 10(6), and sperm morphology <20% normal forms. With a multivariable regression model based on the redefined male semen subfertility criteria we were able to make a finer differentiation between subfertile men, with probabilities of fathering a child ranging from 7% to 41%. CONCLUSION(S) The current WHO criteria for semen quality do not discriminate between fertile and subfertile men. Our redefined and graded semen criteria have strong predictive value. If interpreted correctly, the fast and inexpensive semen analysis remains the gold standard for defining a mans role in subfertility.

Day 3 embryo selection by metabolomic profiling of culture medium with near-infrared spectroscopy as an adjunct to morphology: a randomized controlled trial

STUDY QUESTION Is the selection of a single Day 3 embryo by metabolomic profiling of culture medium with near-infrared (NIR) spectroscopy as an adjunct to morphology able to improve live birth rates in IVF, compared with embryo selection by morphology alone? SUMMARY ANSWER The live birth rate after embryo selection by NIR spectroscopy and morphology is not significantly different compared with the live birth rate after embryos were selected by morphology alone. WHAT IS KNOWN ALREADY The elevated incidence of pregnancy and neonatal problems associated with a high-twinning rate after IVF can only be successfully reduced by the transfer of one embryo. Current embryo assessment methods are unable to accurately predict the reproductive potential of an individual embryo. Today, a number of techniques are said to be more accurate at selecting the best embryo. One of these new technologies is metabolomic profiling of spent embryo culture media with the use of NIR spectroscopy. STUDY DESIGN, SIZE AND DURATION A double-blind, randomized controlled trial was conducted between 2009 and 2011, and included 417 couples undergoing IVF with a single embryo transfer. Randomization was performed centrally just before Ovum Pick-Up (OPU), using a computerized randomization program. Both patient and physician were unaware of the treatment allocation. To ensure blinding, the allocations were placed in consecutively numbered, opaque envelopes. Patients were randomized (1:1) into either the control group (embryo selection by morphology only) or the treatment group (embryo selection by morphology plus NIR spectroscopy of embryo culture medium). PARTICIPANTS/MATERIALS, SETTING AND METHODS At OPU, 208 patients were randomized to the morphology only group and 209 patients were randomized to the morphology plus viability score group. On Day 3, 163 patients in the control group and 146 patients in the treatment group met the inclusion criteria. The study was conducted in an academic hospital with IVF laboratory and three non-academic hospitals. MAIN RESULTS AND THE ROLE OF CHANCE Patient demographics and baseline characteristics were distributed equally over the two groups, except for embryo fragmentation, which was significantly higher in the treatment group. In the intention to treat analysis, the live birth rates were 31.7 and 26.8% for the control group and the treatment group, respectively (relative risk 0.84; 95% confidence interval 0.63-1.14, P=0.27). In the per protocol analysis, the live birth rates were 31.3 and 29.5% for the control group and the treatment group, respectively (relative risk 0.94; 95% confidence interval 0.67-1.32, P=0.73). For the treatment group, the embryological technicians independent choice (by morphology) of which embryo to transfer was recorded 138 times. In 75.4% (104 of 138) of the transfers, the embryo with the best morphology did not have the highest viability score. The live birth rate of these 104 transferred embryos was 30.8%. LIMITATIONS, REASONS FOR CAUTION A possible limitation of our study is the pre-selection of all embryos by morphology and dividing the cohort of available embryos into two groups: good quality embryos and poor quality embryos. As a consequence, we have probably selected for a better prognosis patient group. WIDER IMPLICATIONS OF THE FINDINGS To avoid the use of incompetent embryo selection tools at the expense of the patient, an evidence-based proof of clinical usefulness is essential before the implementation of new diagnostic tools in IVF laboratories. TRIAL REGISTRATION NUMBERS Dutch Trial Registry, registry number NTR1178.

Essure hysteroscopic tubal occlusion device for the treatment of hydrosalpinx prior to in vitro fertilization-embryo transfer in patients with a contraindication for laparoscopy

OBJECTIVE To investigate the success rate of proximal tubal occlusion with Essure devices in subfertile women with hydrosalpinges, and to observe the results of subsequent treatment with IVF. DESIGN Prospective, single-arm, clinical study. SETTING University hospital and teaching hospital. PATIENT(S) Ten women with uni- or bilateral hydrosalpinges prior to IVF. In all patients laparoscopy was felt to be contraindicated. INTERVENTION(S) Hysteroscopic placement of Essure devices in an office setting. MAIN OUTCOME MEASURE(S) Placement rate, successful proximal tubal occlusion, and pregnancy rate after IVF. RESULT(S) All patients had successful placement of the Essure devices without any complications. Proximal tubal occlusion was confirmed by hysterosalpingography in 9 out of 10 patients. A 40% ongoing pregnancy rate was achieved with 20% life births after one IVF cycle and/or frozen embryo transfer. CONCLUSION(S) Proximal occlusion of hydrosalpinges with Essure devices before IVF is a successful treatment for patients with a contraindication for salpingectomy.

Accuracy of diagnostic laparoscopy in the infertility work-up before intrauterine insemination

OBJECTIVE To evaluate the accuracy of diagnostic laparoscopy after normal hysterosalpingography (HSG) and before intrauterine insemination (IUI) with respect to laparoscopic findings leading to a change of treatment decisions in couples with male subfertility, cervical hostility, or idiopathic infertility. DESIGN Retrospective chart review. SETTING University medical centre. PATIENT(S) Infertility patients who had undergone diagnostic laparoscopy after a normal HSG and before IUI in a period of 5 years. INTERVENTION(S) Diagnostic laparoscopy in infertility work-up before IUI. MAIN OUTCOME MEASURE(S) Prevalence of laparoscopic findings leading to change in treatment decision. RESULT(S) Of 495 patients, 21 (4%) had severe abnormalities that resulted in a change of treatment to in vitro fertilization or open surgery. In 103 patients (21%) abnormalities, endometriosis (stages I and II), and adhesions were directly treated by laparoscopic intervention, followed by IUI treatment. If surgery to remove early stage endometriosis does not improve pregnancy rates, then the laparoscopic yield would be 40 out of 495 (8.1%). CONCLUSION(S) Diagnostic laparoscopy altered treatment decisions in an unexpectedly high number of patients before IUI. This suggests that laparoscopy may be of considerable value, provided the change in treatment is effective. Further prospective studies are required to assess whether the diagnostic use of laparoscopy is cost effective and whether interventions as result of laparoscopic findings are effective in improving pregnancy rates.

Contemporary Pharmacological Manipulation in Assisted Reproduction

Follicle-stimulating hormone (FSH) treatment to induce follicular development in anovulating women and multiple follicular development for assisted conception has been incorporated in almost all reproductive treatment cycles in the form of either urinary, purified urinary or recombinant preparations. Besides improved tolerance and theoretically lower chances of infection by prions, the latter may be more effective in terms of clinical pregnancy rates, FSH requirement and cost effectiveness. The low-dose, step-up protocol to induce monofollicular development, which is applied worldwide, has to compete with the equally effective but health economically beneficial step-down protocol. The long protocol using recombinant FSH 150 IU/day is advocated when using gonadotropin-releasing hormone (GnRH) agonists in in vitro fertilisation (IVF) or intracytoplasmatic sperm injection treatment. However, the current paradigmatic hyperstimulation came under scrutiny after the introduction of the GnRH antagonists, which allow milder and more convenient approaches with acceptable cancellation and pregnancy rates but lower requirements for FSH. Risk of ovarian hyperstimulation syndrome (OHSS) can be further eliminated if recombinant luteinising hormone (rLH) or GnRH agonists are used to trigger oocyte maturation and ovulation; the latter require pituitary responsiveness and are therefore excluded in agonist protocols.FSH and LH are both required for appropriate folliculo- and steroidogenesis. In hypogonadotropic women, the addition of LH (human menopausal gonadotropin, human chorionic gonadotropin or rLH) is therefore obligate to achieve appropriate follicular growth and pregnancy. The role of LH in ovulation induction is still a matter of debate, although in GnRH agonistic protocols there seems to be a ’‘therapeutic window’; levels that are too high or too low have detrimental effects on IVF outcome.To broaden the pharmaceutical armoury, recent efforts have been directed towards the development of novel GnRH antagonists and FSH preparations with optimal pharmacokinetic, pharmacodynamic and safety profiles. Alternative strategies with fewer adverse effects and higher benefit/cost ratios are under development. However, before the GnRH agonist is abandoned for the antagonist as standard therapy, the cause of the observed possible lower pregnancy rates with the latter need to be clarified. In addition, prospective studies investigating possible direct effects of GnRH analogues, optimal dose-finding studies and treatment regimens under different conditions, with or without pharmacological coadministration and for different indications, should be performed to optimise the efficacy and tailor treatment strategies to individual needs.

Adenomyosis has no adverse effects on IVF/ICSI outcomes in women with endometriosis treated with long-term pituitary down-regulation before IVF/ICSI☆

OBJECTIVES To establish the effect of adenomyosis on IVF/ICSI outcomes in infertile patients with endometriosis who were pretreated with long-term (>/=3 months) GnRH-agonist prior to IVF/ICSI. STUDY DESIGN Retrospective study in 74 infertile patients with surgically proven endometriosis who were treated with IVF/ICSI between January 2002 and March 2007. The diagnosis of adenomyosis was based on transvaginal ultrasound criteria. All patients were pretreated with long-term (>or=3 months) GnRH-agonist prior to IVF/ICSI. RESULTS 90.4% of the patients were diagnosed with endometriosis rASRM stages III-IV. Adenomyosis was demonstrated in 27% of them and was predominantly located in the posterior wall of the uterus. The following IVF/ICSI outcomes were found: a mean duration of GnRH-agonist use prior to IVF/ICSI of 5.35 months (3-26); a mean dosage of FSH used of 208IU (75-450); the mean number of oocytes retrieved was 8.73 (1-30); the mean number of embryos obtained was 3.86 (0-16); the mean number of embryos transferred was 1.6; a mean fertilization rate of 43.6%; a mean implantation rate of 26.3%; a mean miscarriage rate of 24.3%; and a clinical pregnancy rate (fetal heart activity on ultrasound beyond 12 weeks of gestation) of 31.7%. No significant differences were found for any of the IVF/ICSI outcomes between women with and without adenomyosis. CONCLUSIONS Adenomyosis had no adverse effects on IVF/ICSI outcomes in infertile women with proven endometriosis who were pretreated with long-term GnRH-agonist.