STUDY QUESTION

What is the potential physiopathological role of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in recurrent miscarriage (RM), characterized by at least three consecutive pregnancy losses.

SUMMARY ANSWER

The levels of serum TRAIL immediately after miscarriage in RM patients are significantly elevated with respect to that in first-trimester normal pregnant women, and recombinant TRAIL inhibits the adhesion and migration of HTR8 trophoblastic cells in vitro.

WHAT IS KNOWN ALREADY

Both TRAIL and its trans-membrane receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3 and TRAIL-R4) have been documented in the placenta, but their physiopathological role is incompletely understood.

STUDY DESIGN, SIZE, DURATION

The study populations consisted of RM patients (n = 80) and first-trimester normal pregnant women (n = 80). Blood samples were obtained within 24 h after abortion (RM) or at gestational 12-week (normal pregnant women). As additional controls, third-trimester normal pregnant women (n = 28) were examined before (within 72 h) and after (within 24 h) partum.

PARTICIPANTS/MATERIALS, SETTING, METHODS

The concentrations of TRAIL were analysed in serum samples by ELISA. In parallel, the effect of soluble recombinant TRAIL (0.1–1000 ng/ml) was analysed on the survival of primary extravillus trophoblasts (EVTs) and on the survival, proliferation, adhesion and migration of trophoblastic HTR8 cells.

MAIN RESULTS AND THE ROLE OF CHANCE

The circulating levels of TRAIL in RM women (median: 52.5 pg/ml; mean and SD: 55.5 ± 24.4 pg/ml) were significantly higher with respect to first-trimester normal pregnant women (median: 44.9 pg/ml; mean and SD: 47 ± 15.1 pg/ml) and third-trimester normal pregnant women, as assessed before (median: 45.1 pg/ml; mean and SD: 46 ± 12.4 pg/ml) and after partum (median: 35.4 pg/ml; mean and SD: 38 + 17.5 pg/ml). Both primary EVT and HTR8 cells expressed detectable levels of TRAIL death receptors, but exposure to soluble recombinant TRAIL did not induce cell death of trophoblastic cells. On the other hand, TRAIL dose-dependently inhibited the adhesion of HTR8 cells to decidual endothelial cells (DEC) as well as the migration of HTR8 in transwell assays using either fibronectin or DEC.

LIMITATIONS, REASONS FOR CAUTION

Although this study suggests that TRAIL might have a pathogenic role in RM by inhibiting both the adhesion and migration capabilities of first trimester trophoblastic cells, there is a possibility that the elevated serum levels of TRAIL in RM are not cause but rather the result of RM.

WIDER IMPLICATIONS OF THE FINDINGS

Our current findings together with data of other authors suggest that circulating TRAIL should be further analysed as a potential important biomarker in different physiopathological settings.

STUDY FUNDING/COMPETING INTEREST(S)

This study was funded by FIRB projects (RBAP11Z4Z9_002 to Giorgio Zauli and RBAP10447J_002 to Paola Secchiero). The authors have no competing interests to declare.

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Recommendation and review posted by G. Smith

STUDY QUESTION

What is the methylation status of the Nanog and Oct4 promoters in human gametes and ICSI embryos and is abnormal reprogramming of their methylation associated with developmental failure of ICSI embryos?

SUMMARY ANSWER

Developmental failure of human ICSI embryos is associated with high methylation of the Oct4 promoter.

WHAT IS KNOWN ALREADY

Nanog and Oct4 genes play critical roles in the establishment and maintenance of pluripotency during normal early embryonic development, and both are negatively regulated through the methylation of their promoters.

STUDY DESIGN, SIZE AND DURATION

We analysed the methylation profile of Nanog and Oct4 promoters in 5 control sperm from normally fertile men, 70 metaphase II oocytes, 21 4-cell control ICSI embryos, 7 control blastocysts and 45 ICSI embryos arrested at 2- to 8-cell stage following prolonged culture.

PARTICIPANTS, MATERIALS, SETTING AND METHODS

Embryos and gametes were donated for research by patients from the Department of Reproductive Medicine at the Hôpital Femme Mère Enfant (Bron, France) and the Clinique du Tonkin (Villeurbanne, France) after giving their informed consent.

MAIN RESULTS

For both promoters, high methylation was observed in sperm cells. Although, in general, the promoters were unmethylated in oocytes, the methylation of some alleles was observed, particularly in oocytes from women with known infertility. Both gene promoters were hypomethylated in control blastocyst ICM (inner cell mass) and in control 2–8-cells embryos obtained from 6 out of 8 couples. However, they appeared highly methylated in embryos obtained from the other two couples. In most arrested ICSI embryos, the Nanog promoter was unmethylated while the Oct4 promoter was highly methylated. High methylation of the Oct4 promoter was significantly more pronounced in embryos from couples where a male factor was the only known cause of infertility. When the embryos were heterozygous for a G/A single nucleotide polymorphism, both alleles could be methylated, each likely representing a paternally inherited or a maternally inherited copy.

LIMITATIONS AND REASONS FOR CAUTION

The study was done on a limited number of oocytes and embryos and the gametes of the couples were not available.

WIDER IMPLICATIONS OF THE FINDINGS

These results provide new insight regarding the roles of epigenetic abnormalities in early developmental failure in humans.

STUDY FUNDING/COMPETING INTEREST(S)

No external funding was obtained for this study. There was no competing interest.

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Recommendation and review posted by G. Smith

BACKGROUND

Current non-invasive diagnostic methods for endometriosis lack sensitivity and specificity. In search for new diagnostic biomarkers for ovarian endometriosis, we used a hypothesis-generating targeted metabolomics approach.

METHODS

In a case–control study, we collected plasma of study participants and analysed their metabolic profiles. We selected a group of 40 patients with ovarian endometriosis who underwent laparoscopic surgery and a control group of 52 healthy women who underwent sterilization at the University Clinical Centre Ljubljana, Slovenia. Over 140 targeted analytes included glycerophospholipids, sphingolipids and acylcarnitines. The analytes were quantified by electrospray ionization tandem mass spectrometry. For assessing the strength of association between the metabolite or metabolite ratios and the disease, we used crude and adjusted odds ratios. A stepwise logistic regression procedure was used for selecting the best combination of biomarkers.

RESULTS

Eight lipid metabolites were identified as endometriosis-associated biomarkers due to elevated levels in patients compared with controls. A model containing hydroxysphingomyelin SMOH C16:1 and the ratio between phosphatidylcholine PCaa C36:2 to ether-phospholipid PCae C34:2, adjusted for the effect of age and the BMI, resulted in a sensitivity of 90.0%, a specificity of 84.3% and a ratio of the positive likelihood ratio to the negative likelihood ratio of 48.3.

CONCLUSIONS

Our results suggest that endometriosis is associated with elevated levels of sphingomyelins and phosphatidylcholines, which might contribute to the suppression of apoptosis and affect lipid-associated signalling pathways. Our findings suggest novel potential routes for therapy by specifically blocking highly up-regulated isoforms of phosphpolipase A2 and lysophosphatidylcholine acyltransferase 4.

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http://humrep.oxfordjournals.org/rss/current.xml

Recommendation and review posted by G. Smith

BACKGROUND

Dizygotic twin pregnancies after IVF treatment are the result of multiple embryos transferred into the uterine cavity, followed by successful double implantation. Factors that increase the chance of multiple implantation after IVF are relatively unknown. The present study aimed to investigate whether features of body composition, such as maternal height, weight and body mass index (BMI) are associated with an increased chance of dizygotic twinning after IVF with double embryo transfer (DET).

METHODS

This study was conducted using data from a large Dutch nationwide cohort that comprised 19 861 women who had IVF or ICSI treatment between 1983 and 1995 (OMEGA study). First ‘fresh’ IVF and ICSI cycles with DET resulting in a delivery of a singleton or twin (living as well as stillborn) were selected. A multivariable logistic regression analysis was performed, with the delivery of a singleton or twin as the dependent variable and height, weight, BMI, maternal age, number of retrieved oocytes, use of alcohol, smoking, highest level of education and parity as independent variables.

RESULTS

Of the 6598 women who completed their first IVF or ICSI cycle, 2375 had DET, resulting in 496 deliveries of 371 singletons and 125 twins. Multivariable regression analysis revealed that tall women (>1.74 cm) and women with a high number of retrieved oocytes (>8) had an increased chance of dizygotic twinning [OR: 1.8 (95% CI: 1.0–3.4) and OR: 2.2 (95% CI: 1.3–3.8), respectively].

CONCLUSIONS

Our data demonstrate that tall stature and increased number of retrieved oocytes independently increase the chance of dizygotic twinning after IVF with DET.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

Recommendation and review posted by G. Smith

STUDY QUESTION

What is the validity of the Templeton model (TM) in predicting live birth (LB) for a couple starting an IVF/ICSI cycle?

SUMMARY ANSWER

A centre-specific model based on the original predictors of the TM may reach a sufficient level of accuracy to be used in every day practice, with a few simple adaptations.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

The TM seems the best predictive model of LB in IVF. However, previous validations of the TM suggest a lack of discrimination and calibration which means that it is not used in regular practice. We confirm this finding, and argue that such results are predictable, and essentially due to a strong centre effect. We provide evidence that the TM constitutes a useful reference reflecting a high proportion of the patient-mix effect since the parameters of the model remain invariant among centres, but also across various cultures, countries and types of hospitals. The only difference was the intercept value, interpreted as the measurement of the global performance of one centre, in particular, for a population of reference.

STUDY DESIGN

The validity of the TM was tested by a retrospective analysis all IVF/ICSI cycles (n = 12 901) in our centre since 2000.

PARTICIPANTS, SETTING AND METHODS

All IVF/ICSI cycles were included in the analysis. The model discrimination was evaluated by C-statistics, calculated as the area under the curve of an ROC curve. The TM was then adjusted for our data and additional variables were assessed.

MAIN RESULTS AND THE ROLE OF CHANCE

Poor calibration and discrimination (C = 0.64) was observed in conformity with previous external validations. Fitting the TM to our centre constituted the first substantial improvement in prediction accuracy of discrimination (C = 0.69) and calibration. We identified an important linear time trend effect and the added value of three other predictors (FSH, smoking habits and BMI) that significantly improved the model (C = 0.71).

BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION

Bias due to missing data handling was assessed through sensitivity analyses.

GENERALIZABILITY TO OTHER POPULATIONS

Neither the TM nor any other models based on some centres are directly applicable to other centres. However, the TM constitutes a useful basis to build an accurate centre-specific model.

STUDY FUNDING/COMPETING INTEREST(S)

There were no commercial relationships (i.e. consultancies, patent-licensing agreements) that might pose a conflict of interest in connection with the submitted manuscript. The objective of this research was not directed toward any treatment effects.

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Recommendation and review posted by G. Smith

BACKGROUND

Tubal patency tests are routinely performed in the diagnostic work-up of subfertile patients, but it is unknown whether these diagnostic tests add value beyond the information obtained by medical history taking and findings at physical examination. We used individual patient data meta-analysis to assess this question.

METHODS

We approached authors of primary studies for data sets containing information on patient characteristics and results from tubal patency tests, such as Chlamydia antibody test (CAT), hysterosalpingography (HSG) and laparoscopy. We used logistic regression to create models that predict tubal pathology from medical history and physical examination alone, as well as models in which the results of tubal patency tests are integrated in the patient characteristics model. Laparoscopy was considered to be the reference test.

RESULTS

We obtained data from four studies reporting on 4883 women. The duration of subfertility, number of previous pregnancies and a history of previous pelvic inflammatory disease (PID), pelvic surgery or Chlamydia infection qualified for the patient characteristics model. This model showed an area under the receiver operating characteristic curve (AUC) of 0.63 [95% confidence interval (CI) 0.61–0.65]. For any tubal pathology, the addition of HSG significantly improved the predictive performance to an AUC of 0.74 (95% CI 0.73–0.76) (P < 0.001). For bilateral tubal pathology, the addition of both CAT and HSG increased the predictive performance to an AUC of 0.76 (95% CI 0.74–0.79).

CONCLUSIONS

In the work-up for subfertile couples, the combination of patient characteristics with CAT and HSG results gives the best diagnostic performance for the diagnosis of bilateral tubal pathology.

Source:
http://humrep.oxfordjournals.org/rss/current.xml

Recommendation and review posted by G. Smith