Background

Pre-eclampsia affects 2–7% of all pregnant women and is a major cause of maternal and fetal morbidity and mortality. The etiology of pre-eclampsia is still unknown but it is well documented that impaired placentation is a major contributor to its development. One of the placenta-specific proteins is placental protein 13 (PP13). Lower first trimester levels of maternal serum PP13 and its encoding placental mRNA are associated with the development of both early and late-onset severe pre-eclampsia. In cases where this protein is mutated, the frequency of pre-eclampsia is higher.

Methods

19 out of 68 studies on PP13, published between January 2006 and September 2012, were used to evaluate the value of maternal blood PP13 as a marker of pre-eclampsia.

Results

A meta-analysis presented in this review shows that low serum levels of PP13 in the first trimester of pregnancy can predict the development of pre-eclampsia later in pregnancy. Although some functions of this protein have been assessed in in vitro experiments, the in vivo functions of PP13 are still unknown, especially when circulating in the maternal bloodstream. A recent pilot study has shown that in gravid rats PP13 causes significant vasodilatation, reduced blood pressure and increased maternal uterine artery remodeling.

Conclusion

Reviewing these effects of PP13, the authors propose the use of PP13 as a new drug candidate. Replenishing PP13 in those women with low serum levels early in pregnancy may help prepare their vasculature for pregnancy. This novel pharmacological approach to combat pre-eclampsia is presented as a new direction to transfer from individualized risk to personalized prevention.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/4/391?rss=1

Human Reproduction and Development
A time lapse video showing you where babies come from. Learn you some.

By: SavannaSci

Read the original:
Human Reproduction and Development - Video

BACKGROUND

Most intrauterine contraception (IUC) placements do not require pain relief. However, small proportions of nulliparous (~17%) and parous (~11%) women experience substantial pain that needs to be proactively managed. This review critically evaluates the evidence for pain management strategies, formulates evidence-based recommendations and identifies data gaps and areas for further research.

METHODS

A PubMed literature search was undertaken. Relevant articles on management of pain associated with IUC insertion, published in English between 1980 and November 2012, were identified using the following search terms: ‘intrauterine contraception’, ‘insertion’ and ‘pain’. RCTs were included; further relevant articles were also identified and included as appropriate.

RESULTS

Seventeen studies were identified and included: 12 RCTs and one non-randomized study of pre-insertion oral analgesia, cervical priming and local anaesthesia; one systematic review and one RCT on post-insertion analgesia and two non-randomized studies on non-pharmacological interventions. There was no conclusive evidence that any prophylactic pharmacological intervention reduces pain associated with IUC insertion. However, most of the regimens studied were adopted from hysteroscopy or abortion and effectiveness in specific subsets of women has not been studied adequately. A systematic review found non-steroidal anti-inflammatory agents (NSAID) to be effective in reactively treating post-insertion pain, but no benefit was found with prophylactic use.

CONCLUSIONS

No prophylactic pharmacological intervention has been adequately evaluated to support routine use for pain reduction during or after IUC insertion. Women's anxiety about the procedure may contribute to higher levels of perceived pain, which highlights the importance of counselling, and creating a trustworthy, unhurried and professional atmosphere in which the experience of the provider also has a major role; a situation frequently referred to as ‘verbal anaesthesia’.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/4/419?rss=1

BACKGROUND

The recruitment of immune cells by chemokines and the regulation of endometrial cell apoptosis are critical aspects of endometriosis biology. Here, we review the local (paracrine) and systemic hormone (endocrine) modulation of these two specific, but highly related phenomena.

METHODS

We searched Pubmed for items published in English between September 1991 and September 2011 and selected the studies evaluating the effects of hormones on chemokines or apoptosis in normal human endometrium and endometriosis.

RESULTS

Estradiol has proinflammatory and antiapoptotic effects in endometrial cells, and these effects appear to be exacerbated in women with endometriosis. In these women, physiological estradiol concentrations are able to induce an enhanced inflammatory response mediated by local chemokine production and to reinforce mechanisms of cell survival mediated by extracellular signal-regulated kinases and Bcl-2. The main effect of progestogens is to inhibit interleukin-8 and other chemokines in stromal cells from both eutopic and ectopic endometrium. Progesterone is also effective in inducing apoptosis in endometrial and endometriotic cells through the inhibition of Bcl-2 and nuclear factor-B.

CONCLUSIONS

Estrogens and progestogens modulate chemotaxis and apoptosis in human endometrium and endometriotic cells and tissues. These endocrine and paracrine pathways are perturbed in women with endometriosis, contributing to inflammatory responses, abnormal tissue remodeling, therapeutic refractoriness and disease persistence. Ultimately, they promote adhesion formation and the clinical symptoms of pelvic pain and infertility. A more detailed understanding of the molecular mechanisms involved will offer new opportunities for novel pharmacological strategies to diagnose and treat endometriosis.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/4/406?rss=1

Human reproduction - fertilisation animation by year 7 learners

By: henrycordy

Link:
Human reproduction - fertilisation animation by year 7 learners - Video

This Task Force document revisits the debate about the ethics of sex selection for non-medical reasons in the light of relevant new technological developments. First, as a result of improvement of the Microsort® flow cytometry method, there is now a proven technique for preconception sex selection that can be combined both with IVF and IUI. Secondly, the scenario where new approaches that are currently being developed for preimplantation genetic screening (PGS) may lead to such screening becoming a routine part of all IVF treatment. In that scenario professionals will more often be confronted with parental requests for transfer of an embryo of a specific sex. Thirdly, the recent development of non-invasive prenatal testing based on cell-free fetal DNA in maternal plasma allows for easy and safe sex determination in the early stages of pregnancy. While stressing the new urgency that these developments give to the debate, the Task Force did not come to a unanimous position with regard to the acceptability of sex selection for non-medical reasons in the context of assisted reproduction. Whereas some think maintaining the current ban is the best approach, others are in favour of allowing sex selection for non-medical reasons under conditions that take account of societal concerns about the possible impact of the practice. By presenting these positions, the document reflects the different views about this issue that also exist in the field. Specific recommendations include the need for a wider delineation of accepted ‘medical reasons’ than in terms of avoiding a serious sex-linked disorder, and for a clarification of the legal position with regard to answering parental requests for ‘additional sex selection’ in the context of medically indicated preimplantation genetic diagnosis, or routine PGS.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1448?rss=1

STUDY QUESTION

Does vasectomy impact microRNA (miRNA) expression in the epididymis and seminal microvesicles (SMVs) in a non-reversible manner?

SUMMARY ANSWER

The miRNA signature in the epididymis and SMVs is altered by vasectomy and only partially restored after vasovasostomy surgery.

WHAT IS KNOWN ALREADY

Vasectomy modifies the epididymal transcriptome and triggers non-reversible changes that affect sperm function. Some vasovasostomized men experience a reduced fertility outcome.

STUDY DESIGN, SIZE, DURATION

Human epididymides provided by three control donors and three vasectomized donors were collected under artificial circulation through Transplant Quebec (Quebec, QC, Canada). Semen from three normal, three vasectomized and five vasovasostomized donors was provided by the andrology clinic.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Epididymides and semen were collected from donors between 26 and 50 years of age with no known pathologies that could potentially affect reproductive function. After RNA extraction, epididymal miRNA profiles were determined by microarray (Affimetrix), compared by ANOVA and confirmed by real-time PCR. The correlation between miRNA and gene expression profiles was investigated by an integrated genomic approach. miRNA signature from purified SMVs was established by microarray.

MAIN RESULTS AND THE ROLE OF CHANCE

Vasectomy significantly modified the expression of epididymal miRNAs, which were mainly correlated with mRNAs for transcription factors. Vasectomy also impacted the detection of 118 of the miRNAs found in SMVs from normal donors, including miRNAs of epididymal origin contained in epididymosomes. Among seminal miRNAs changes, 52 were reversible according to the expression levels of miRNA in the semen samples from vasovasostomized donors, while 66 were non-reversible.

LIMITATIONS, REASONS FOR CAUTION

Identification of miRNAs responsive to vasectomy was determined with a limited number of samples due to the low number of human specimen samples available.

WIDER IMPLICATIONS OF THE FINDINGS

According to the critical role played by miRNAs in all biological systems, we believe that miRNA changes occurring upstream and downstream of the vasectomy site may be related to the reduced fertility outcome reported following surgically successful vasectomy reversal. This study may provide new tools for predicting vasovasostomy success and open avenues for the identification of the molecular players involved in male infertility.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by a grant obtained by R.S. from the Canadian Institutes for Health Research (CIHR). The authors have no conflicts of interest to declare.

TRIAL REGISTRATION NUMBER

Not applicable.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1455?rss=1

STUDY QUESTION

Is fertility preservation feasible after the onset of puberty in adolescents with Klinefelter syndrome (KS)?

SUMMARY ANSWER

Fertility preservation counseling should be an integral part of the care of XXY adolescents. Frozen ejaculated or testicular spermatozoa and even frozen immature germ cells can give them the potential to conceive their genetic progeny. However, no biological or clinical parameters were predictive of mature or immature germ cell retrieval.

WHAT IS KNOWN ALREADY

KS is the commonest sex chromosome disorder observed in azoospermic infertile males. Testicular sperm extraction success decreases with age and after testosterone therapy. Arguably, spermatozoa should be retrieved from KS males at the onset of puberty and before testosterone therapy to increase the chance of success.

STUDY DESIGN, SIZE, DURATION

A retrospective study was performed in eight KS adolescents, aged between 15 and 17 years, who were referred for counseling about their future fertility to the center CECOS (Centre d'Etude et de Conservation des Oeufs et du Sperme humain) at Rouen University Hospital between October 2008 and December 2011.

PARTICIPANTS/MATERIALS, SETTING, METHODS

The patients were first seen with their parents and then separately. It was proposed to them that they should provide a semen sample, if this was azoospermic, two other semen samples spaced by 3 months were collected. If azoospermia was confirmed, a bilateral testicular biopsy was proposed for sperm retrieval and testicular tissue preservation. Each adolescent met the psychologist before undergoing testicular biopsy. Paraffin-embedded testicular tissue was evaluated after staining with hematoxylin–eosin and saffron and immunostaining using vimentin, anti-Müllerian hormone, androgen receptor and MAGE-A4 antibodies. Sertoli cell maturity, germ cell identification and lamina propria alteration were assessed on seminiferous tubules.

MAIN RESULTS AND THE ROLE OF CHANCE

KS adolescents were not deeply concerned about their future fertility and only became involved in the process of fertility preservation after at least three medical consultations. The parents agreed immediately that fertility preservation should be attempted. Seven non-mosaic XXY adolescents presented with azoospermia and one XXY/XY adolescent had oligozoospermia. Increased plasma levels of FSH and LH as well as bilateral testicular hypotrophy were observed in all patients. The XXY/XY adolescent banked four semen samples before testosterone replacement therapy. Two patients refused testicular biopsy. Five patients accepted a bilateral testicular biopsy. Spermatozoa were retrieved in one patient, elongated spermatids and spermatocytes I in a second patient.

LIMITATIONS, REASONS FOR CAUTION

The number of patients enrolled in our study was low because the diagnosis of KS is only rarely made before or at the onset of puberty. Most XXY males are diagnosed in adulthood within the context of male infertility.

WIDER IMPLICATIONS OF THE FINDINGS

Spermatozoa can be retrieved in semen sample and in testicular tissue of adolescent Klinefelter patients. Furthermore, the testis may also harbor spermatogonia and incompletely differentiated germ cells. However, the physician should discuss with the patient and his parents over a period of several months before collecting a semen sample and performing bilateral testicular biopsy. Fertility preservation might best be proposed to adolescent Klinefelter patients just after the onset of puberty when it is possible to collect a semen sample and when the patient is able to consider alternative options to achieve fatherhood and also to accept the failure of spermatozoa or immature germ cell retrieval.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by Rouen University Hospital and grant from the University of Rouen dedicated to the research team ‘Gametogenesis and gamete quality’. The authors have no conflicts of interest to declare.

TRIAL REGISTRATION NUMBER

Not applicable.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1468?rss=1

STUDY QUESTION

Does preconceptionally started low-dose aspirin prevent hypertensive pregnancy complications and preterm delivery in IVF patients?

SUMMARY ANSWER

The current data do not support the use of preconceptionally started low-dose aspirin treatment for the prevention of hypertensive pregnancy complications and preterm delivery in IVF women.

WHAT IS KNOWN ALREADY

Studies starting low-dose aspirin treatment as prevention in the second trimester of pregnancy found no or only moderate reductions in the relative risk of developing pre-eclampsia. Low-dose aspirin was possibly started too late, that is after the first episode of trophoblast invasion.

STUDY DESIGN, SIZE, DURATION

We performed a meta-analysis with individual patient data (IPD), in which four authors could provide IPD on a total of 268 pregnancies (n = 131 treated with aspirin, n = 137 placebo). Data on hypertensive pregnancy complications and preterm delivery were collected.

PARTICIPANTS/MATERIALS, SETTING, METHODS

All separate databases were merged into a summary database. Treatment effect of aspirin on the incidence of hypertensive pregnancy complications (n = 187) and preterm delivery (n = 180) were estimated with odds ratios (OR) and 95% confidence intervals (95% CI) using multivariable logistic regression.

MAIN RESULTS AND THE ROLE OF CHANCE

There were significantly fewer twin pregnancies in the aspirin group (OR 0.55 95% CI 0.30–0.98), but no significant differences for hypertensive pregnancy complications and preterm delivery: for singletons OR 0.62 (95% CI 0.22–1.7) and OR 0.52 (95% CI 0.16–1.7), respectively, as well as for twin pregnancies OR 1.2 (95% CI 0.35–4.4) and OR 1.6 (95% CI 0.51–5.0), respectively.

LIMITATIONS, REASONS FOR CAUTION

We have to bear in mind that the included studies showed clinical heterogeneity; there was variation in the duration of low-dose aspirin therapy and degree of hypertension between the different studies. Although we combined IPD from four studies, we have to realize that the studies were not powered for the outcome of the current IPD meta-analysis.

WIDER IMPLICATIONS OF THE FINDINGS

Based on the current meta-analysis with IPD we found no confirmation for the hypothesis that preconceptionally started low-dose aspirin reduces the incidence of hypertensive pregnancy complications or preterm delivery in IVF women. Larger studies are warranted.

STUDY FUNDING/COMPETING INTEREST(S)

None.

TRIAL REGISTRATION NUMBER

not applicable.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1480?rss=1

STUDY QUESTION

Are there any differences in the location and distance to the internal cervical ostium of the implantation site of the intrauterine gestation sacs, early pregnancy symptoms and pregnancy outcome at 12 weeks gestation between women with and without a previous Caesarean section (CS)?

SUMMARY ANSWER

The presence of a CS scar affects the site of implantation, and the distance between implantation site and the scar is related to the risk of spontaneous abortion.

WHAT IS KNOWN ALREADY?

Little is known about the impact of a CS scar on implantation other than the risk of Caesarean scar pregnancy (CSP). Furthermore, there is a paucity of information on how the proximity of implantation to the scar impacts on pregnancy outcome in the first trimester.

STUDY DESIGN, SIZE, AND DURATION

A prospective cohort study conducted over 15 months in the early pregnancy unit of a London Teaching Hospital. Three hundred and eighty women underwent a transvaginal scan at 6–11 weeks of gestation. A total of 170 women had undergone ≥1 CS, and 210 women had no history of CS.

PARTICIPANTS/MATERIALS, SETTING, METHODS

The 380 women were recruited as consecutive non-selected cases. The relationship between the implanted sac and the CS scar was assessed by quantifiable measures and by subjective impression. Logistic regression analysis was used to determine the influence of the presence of a CS scar on pregnancy outcome. The final outcome of the study was the viability of the pregnancy at 12 weeks.

MAIN RESULTS AND THE ROLE OF CHANCE

Implantation was most frequently posterior (53%) in the CS group and fundal in the non-CS group (42%). Gestation sac implantation was 8.7 mm lower in the CS group (95% confidence interval (CI) 6.7–10.7, P < 0.0001). Presenting complaints differed in women with and without a previous CS (P = 0.0009). More frequent vaginal bleeding [73 versus 55%, difference –18, 95% CI (–27 to –8%] yet no clearly increased spontaneous abortion rates were noted in the CS group compared with the non-CS group (adjusted odds ratio = 1.1, 95% CI 0.6–1.9, P = 0.74). Subjective impression showed that in eight cases the implantation site crossed the scar, seven of which resulted in spontaneous abortion, while the remaining case survived to term complicated by placenta praevia and post-partum haemorrhage. The subjective impression of the examiner was supported by the measurements of distance between implantation site and CS scar.

LIMITATIONS, REASONS FOR CAUTION

A weakness of the study is the lack of a reference technique to verify the location of implantation.

WIDER IMPLICATIONS OF THE FINDINGS

This study adds further support to the hypothesis that the presence of a CS on the uterus impacts on the implantation site of a future pregnancy. The possibility that the CS scar has an impact on the risk of spontaneous abortion should be further studied. Caution must be exercised when implantation occurs near to, and crosses, a CS scar as this is not always associated with the diagnosis of CSP. A potential limitation of the study is that we did not examine scar dimensions and morphology.

STUDY FUNDING/COMPETING INTEREST(S)

The authors have no competing interests to declare. The study was not supported by an external grant.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1489?rss=1

STUDY QUESTION

Does embryo biopsy inherent to preimplantation genetic screening (PGS) affect neurological, cognitive and behavioural development of 4-year-old children?

SUMMARY ANSWER

PGS does not seem to affect neurological, cognitive and behavioural development of 4-year-old singletons; however, our data suggest that it may be associated with altered neurodevelopment in twins.

WHAT IS KNOWN ALREADY

Evidence concerning the safety of PGS on neurodevelopmental outcome in offspring is scarce. The present study provides information on neurodevelopmental, cognitive and behavioural outcome of 4-year-old PGS offspring.

STUDY DESIGN, SIZE, DURATION

A prospective, assessor-blinded follow-up study of children born to women who participated in a multi-centre RCT on the effect of IVF with or without PGS.

PARTICIPANTS/MATERIALS, SETTING, METHODS

At 4 years, 49 children (31 singletons, 9 sets of twins) born following IVF with PGS and 64 children (42 singletons, 11 sets of twins) born following IVF without PGS (controls) were assessed (post-natal attrition 18%). Neurological development was evaluated with the standardized, age-specific and sensitive neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the rate of adverse neurological outcome. Primary outcome was the fluency score, as fluency of movements is easily reduced by subtle dysfunction of the brain. Cognitive development was evaluated with the Kaufman Assessment Battery for Children; behavioural development was evaluated with the Child Behavior Checklist. The effect of PGS was analysed with a mixed effects model.

MAIN RESULTS AND THE ROLE OF CHANCE

Based on the intention to treat analysis, neurodevelopmental outcome of PGS children was similar to that of controls. However, additional analyses indicated that PGS affected neurodevelopmental outcome of twins in a different way than that of singletons. The fluency score of singletons born following PGS was similar to that of control singletons [mean values, 95% confidence intervals (CIs): 12.2 (11.5;12.8) and 12.2 (11.6;12.8)], respectively, P = 0.977) that was also true for the other neurodevelopmental parameters. The fluency score of PGS twins was significantly lower than that of control twins [mean values, 95% CIs: 10.6 (9.8;11.3) and 12.3 (11.5;13.1)], respectively, P = 0.001); the same was true for the NOS. In addition, PGS in twins was associated with a higher sequential intelligence quotient score. On the other hand, other neurodevelopmental parameters were similar for PGS twins and control twins. Post hoc sample size calculation for the primary outcome parameter, the fluency score, indicated that the study groups, including the subgroups of singletons and twins, were adequately powered.

LIMITATIONS, REASONS FOR CAUTION

We assessed singletons and twins who contributed to the generalizability of the study. A limitation of our study is the relative small size of our study groups and the selective dropout in both groups (dropouts PGS group: higher gestational age; control group: less well-educated parents). These preclude the conclusion that PGS per se is not associated with neurodevelopmental, cognitive and behavioural problems in singletons and the conclusion that PGS is associated with altered neurodevelopmental outcome in twins.

WIDER IMPLICATIONS OF THE FINDINGS

The need for careful long-term monitoring of children born following embryo biopsy remains, as it is still applied in the form of PGD and it is still unknown whether embryo biopsy affects long-term neurodevelopmental outcome.

STUDY FUNDING/COMPETING INTEREST(S)

The RCT was financially supported by the Organization for Health Research and Development (ZonMw), The Netherlands (grant number 945-03-013). The follow-up at 4 years was financially supported by the University Medical Center Groningen (grant number: 754510), the Cornelia Foundation, the Junior Scientific Master Class and the Postgraduate School of Behavioural and Cognitive Neurosciences, Groningen, The Netherlands. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. There are no conflicts of interest.

TRIAL REGISTRATION NUMBER

ISRCTN76355836.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1508?rss=1

STUDY QUESTION

What are the effects of the eotaxin group of chemokines (CCL11, CCL24 and CCL26) on extravillous trophoblast (EVT) functions important during uterine decidual vessel remodelling?

SUMMARY ANSWER

CCL11, CCL24 and CCL26 can regulate EVT migration, invasion and adhesion, highlighting a potential regulatory role for these chemokines during uterine decidual spiral arteriole remodelling in the first trimester of human pregnancy.

WHAT IS KNOWN ALREADY

A successful human pregnancy depends on adequate remodelling of the uterine decidual spiral arterioles, a process carried out by EVT which invade from the placenta. The invasion by EVT into the maternal uterine decidual vessels is regulated by the interaction of many factors including members of the chemokine subfamily of cytokines.

STUDY DESIGN, SIZE, DURATION

This study used the HTR8/SVneo cell line as a model for invasive EVT. All experiments were repeated on at least three separate occasions.

PARTICIPANTS/MATERIALS, SETTING, METHODS

The effect of recombinant human CCL11, CCL24 and CCL26 on EVT migration and invasive potential was measured using the xCELLigence real-time system, wound-healing and Matrigel invasion assays, zymography to measure MMP activity and reverse zymography to measure TIMP activity. A commercially available adhesion assay was used to assess EVT adhesion to extracellular matrix proteins.

MAIN RESULTS AND THE ROLE OF CHANCE

All the three eotaxins were found to significantly stimulate migration of the EVT-derived cell line HTR8/SVneo (P < 0.05) with no significant changes in cell number following treatment with each chemokine (P > 0.05). All the three eotaxins significantly increased HTR8/SVneo invasion (P < 0.05) and MMP2 activity (P < 0.05) without any effects on TIMP2 activity (P > 0.05). All the three eotaxins significantly increased HTR8/SVneo cell binding to collagen IV (P < 0.05) and fibronectin (P < 0.05).

LIMITATIONS, REASONS FOR CAUTION

This work has been conducted in vitro with a commonly used cell line model of EVT, HTR8/SVneo.

WIDER IMPLICATIONS OF THE FINDINGS

This study is the first to comprehensively examine the effects of the eotaxin group of chemokines on EVT functions and demonstrates that all the three eotaxins have the ability to regulate EVT functions critical to their role in vessel remodelling. This identifies a new role for the eotaxin group of chemokines during placentation.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by a grant from the Heart Foundation, Australia (G10M 5185). There are no competing interests and the authors have no conflicts of interest to declare.

TRIAL REGISTRATION NUMBER

N/A.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1497?rss=1

STUDY QUESTION

Does the human embryo growth rate affect the outcome of vitrified–warmed blastocyst transfer?

SUMMARY ANSWER

Following vitrification, the incidence of abnormal spindle morphology was increased and the implantation competence was decreased in growth-retarded embryos compared with normally developing embryos.

WHAT IS KNOWN ALREADY

Various types of spindle abnormality occur in human cleavage- and blastocyst-stage embryos. However, the incidence of abnormal spindle morphology in growth-retarded blastocysts is not known. Furthermore, there is conflicting data about the implantation potential of such blastocysts.

STUDY DESIGN, SIZE, DURATION

This was a retrospective cohort study including 878 single vitrified–warmed blastocyst transfers between 9 January 2010 and 10 July 2012, and an experimental study using 121 vitrified–warmed blastocysts donated to research. A comparison on the implantation potential and spindle shape of vitrified–warmed blastocysts was made between normally developing and growth-retarded blastocysts.

PARTICIPANTS/MATERIALS, SETTING, METHODS

In the clinical study, we compared the implantation rates of vitrified–warmed embryos that developed to the blastocyst stage on Day 5 after insemination (normally developing embryos) with those that required culture to Day 6 (growth-retarded embryo). In the experimental study, donated vitrified–warmed blastocysts were immunostained with an anti-α-tubulin antibody to visualize microtubules, an anti--tubulin antibody to image centrosomes and Hoechst 33342 or 4,6-diamidino-2-phenylindole to visualize DNA. Confocal image analysis captured a z-series stack of 0.5-µm-thick optical sections encompassing the entire blastocyst. Only spindles with fusiform poles and with chromosomes aligned at the equator were classified as normal.

MAIN RESULTS AND THE ROLE OF CHANCE

The implantation rate of growth-retarded embryos (47%, n = 270) was significantly lower (P < 0.05) than that of normally developing embryos (57%, n = 608). A total of 533 spindles were analyzed in Day 5 and 6 vitrified–warmed blastocysts. The incidence of abnormal spindles in the growth-retarded embryos (47%, n = 274) was significantly higher (P < 0.01) than in the normally developing embryos (30%, n = 259).

LIMITATIONS, REASONS FOR CAUTION

Further studies are required to clarify the link between an increase in abnormal spindle formation and a decrease in embryonic implantation potential.

WIDER IMPLICATIONS OF THE FINDINGS

This study provided new insights into the possible implications of abnormalities in spindle formation in growth-retarded human blastocysts.

STUDY FUNDING/COMPETING INTEREST(S)

Part of this work was supported by a grant from the Japan Society for the Promotion of Science (JPS-RFTF 23 580 397 to S.H.). No other competing interests are declared.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1528?rss=1

STUDY QUESTION

Is the attachment of biofunctionalized polysilicon barcodes to the outer surface of the zona pellucida an effective approach for the direct tagging and identification of cultured embryos?

SUMMARY ANSWER

The results achieved provide a proof of concept for a direct embryo tagging system using biofunctionalized polysilicon barcodes, which could help to minimize the risk of mismatching errors (mix-ups) in human assisted reproduction technologies.

WHAT IS KNOWN ALREADY

Even though the occurrence of mix-ups is rare, several cases have been reported in fertility clinics around the world. Measures to prevent the risk of mix-ups in human assisted reproduction technologies are therefore required.

STUDY DESIGN, SIZE, DURATION

Mouse embryos were tagged with 10 barcodes and the effectiveness of the tagging system was tested during fresh in vitro culture (n=140) and after embryo cryopreservation (n = 84). Finally, the full-term development of tagged embryos was evaluated (n =105).

PARTICIPANTS/MATERIALS, SETTING, METHODS

Mouse pronuclear embryos were individually rolled over wheat germ agglutinin-biofunctionalized polysilicon barcodes to distribute them uniformly around the ZONA PELLUCIDA surface. Embryo viability and retention of barcodes were determined during 96 h of culture. The identification of tagged embryos was performed every 24 h in an inverted microscope and without embryo manipulation to simulate an automatic reading procedure. Full-term development of the tagged embryos was assessed after their transfer to pseudo-pregnant females. To test the validity of the embryo tagging system after a cryopreservation process, tagged embryos were frozen at the 2-cell stage using a slow freezing protocol, and followed in culture for 72 h after thawing.

MAIN RESULTS AND THE ROLE OF CHANCE

Neither the in vitro or in vivo development of tagged embryos was adversely affected. The tagging system also proved effective during an embryo cryopreservation process. Global identification rates higher than 96 and 92% in fresh and frozen-thawed tagged embryos, respectively, were obtained when simulating an automatic barcode reading system, although these rates could be increased to 100% by simply rotating the embryos during the reading process.

LIMITATIONS, REASONS FOR CAUTION

The direct embryo tagging developed here has exclusively been tested in mouse embryos. Its effectiveness in other species, such as the human, is currently being tested.

WIDER IMPLICATIONS OF THE FINDINGS

The direct embryo tagging system developed here, once tested in human embryos, could provide fertility clinics with a novel tool to reduce the risk of mix-ups in human assisted reproduction technologies.

STUDY FUNDING/COMPETING INTEREST(S)

This study was supported by Spanish Ministry of Education and Science (TEC2011-29140-C03) and by the Generalitat de Catalunya (2009SGR-00282). The authors do not have any competing interest.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1519?rss=1

STUDY QUESTION

Does heparin ablate the advantageous effects of cyclic adenosine mono-phosphate (cAMP) modulators during pre-in vitro maturation (IVM) and have a deleterious effect in standard oocyte IVM?

SUMMARY ANSWER

Heparin interrupts energy metabolism and meiotic progression and adversely affects subsequent development of oocytes under conditions of elevated cAMP levels in cumulus-oocyte complexes (COCs) after pre-IVM treatment with forskolin.

WHAT IS KNOWN ALREADY

In animal IVM studies, artificial regulation of meiotic resumption by cAMP-elevating agents improves subsequent oocyte developmental competence. Heparin has no effect on spontaneous, FSH- or epidermal growth factor (EGF)-stimulated meiotic maturation.

STUDY DESIGN, SIZE, DURATION

An in vitro cross-sectional study was conducted using immature mouse and human COCs. Depending on individual experimental design, COCs were treated during pre-IVM with or without heparin, in the presence or absence of forskolin and/or 3-isobutyl-1-methylxanthine (IBMX), and then COC function was assessed by various means.

PARTICIPANTS/MATERIALS, SETTINGS, METHODS

Forty-two women with polycystic ovaries (PCOs) or polycystic ovarian syndrome (PCOS) donated COCs after oocyte retrieval in a non-hCG-triggered IVM cycle. COCs were collected in pre-IVM treatments and then cultured for 40 h and meiotic progression was assessed. COCs from 21- to 24-day-old female CBA F1 mice were collected 46 h after stimulation with equine chorionic gonadotrophin. Following treatments, COCs were checked for meiotic progression. Effects on mouse oocyte metabolism were measured by assessing oocyte mitochondrial membrane potential using JC-1 staining and oocyte ATP content. Post-IVM mouse oocyte developmental competence was assessed by in vitro fertilization and embryo production. Blastocyst quality was evaluated by differential staining of inner cell mass (ICM) and trophectoderm (TE) layers.

MAIN RESULTS AND THE ROLE OF CHANCE

In the absence of heparin in pre-IVM culture, the addition of cAMP modulators did not affect human oocyte MII competence after 40 h. In standard IVM, heparin supplementation in pre-IVM did not affect MII competence; however, when heparin was combined with cAMP modulators, MII competence was significantly reduced from 65 to 15% (P < 0.05). In mouse experiments, heparin alone in pre-IVM significantly delayed germinal vesicle breakdown (GVBD) so that fewer GVBDs were observed at 0 and 1 h of IVM (P < 0.05), but not by 2 or 3 h of IVM. Combined treatment with IBMX and forskolin in the pre-IVM medium produced a large delay in GVBD such that no COCs exhibited GVBD in the first 1 h of IVM, and the addition of heparin in pre-IVM further significantly delayed the progression of GVBD (P < 0.05), in a dose-dependent manner (P < 0.01). Combined IBMX and forskolin treatment of mouse COCs during pre-IVM significantly increased mitochondrial membrane potential and ATP production in the oocyte at the end of pre-IVM (P < 0.05), and significantly improved fertilization, embryo development and quality (P < 0.05). However, heparin abolished the IBMX + forskolin-stimulated increase in mitochondrial membrane potential and ATP production (P < 0.05), and adversely affected embryonic cleavage, development rates and embryo quality (P < 0.05). This latter adverse combinational effect was negated when mouse COCs were collected in heparin and IBMX for 15 min, washed and then cultured for 45 min in IBMX and forskolin without heparin.

LIMITATION, REASONS FOR CAUTION

Experiments in mice found that heparin ablation of the advantageous effects of cAMP modulators during pre-IVM was associated with altered oocyte metabolism, but the mechanism by which heparin affects metabolism remains unclear.

WIDER IMPLICATIONS OF THE FINDINGS

This study has revealed a novel and unexpected interaction between heparin and cAMP modulators in pre-IVM in immature mouse and human oocytes, and established a means to collect oocytes using heparin while modulating oocyte cAMP to improve developmental potential.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by Cook Medical with the Cook Medical Adelaide Fellowship awarded to H.-t.Z, and Cook Medical collaborative research grants awarded to the University of Adelaide and UZ Brussel. This work was also supported by an Australian National Health and Medical Research Council (NHMRC) Project Grant awarded to R.B.G. and J.S. (APP1007551), NHMRC Senior Research Fellowships (APP1023210, APP627007), the National Natural Science Foundation of China (30901605, 81000248), the Fundamental Research Funds for the Central Universities (10ykpy02) and by the Belgian Institute for the Promotion of Innovation in Science and Industry (IWT-070719).

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1536?rss=1

STUDY QUESTIONS

What are the symptoms of uterine perforation caused by modern copper intrauterine devices (Cu-IUDs) and the levonorgestrel-releasing intrauterine system (LNG-IUS); how is perforation detected and what are the findings in abdominal surgery?

SUMMARY ANSWER

Symptoms are mostly mild and ~30% of women are asymptomatic. Surgical findings are mainly minimal; no visceral complications were found in this study. However, adhesions as well as pregnancies seem to be more common among women using Cu-IUDs.

WHAT IS KNOWN ALREADY

Prior studies and case reports have suggested that uterine perforation by modern IUDs/IUSs is rarely serious.

STUDY DESIGN, SIZE, DURATION

A retrospective study of 75 patients (54 LNG-IUS and 21 Cu-IUD) treated surgically for uterine perforation between 1996 and 2009.

PARTICIPANTS/MATERIALS, SETTING, METHODS

The patients treated for uterine perforation by an IUD/IUS at clinics of the Helsinki and Uusimaa Hospital District were identified using the National Care Register for Health Institutions in Finland. The clinical data were collected from individual patient records.

MAIN RESULTS AND THE ROLE OF CHANCE

The majority of patients (n = 53; 71%) had mild symptoms of abnormal bleeding or abdominal pain or both, in combination with missing IUD/IUS threads. Asymptomatic patients (n = 22; 29%) were examined because of missing threads or pregnancy. Failure to remove the IUD/IUS by pulling visible threads was the reason for referral in seven women (9%) requesting removal of the device. Eleven women (15%) were pregnant. Misplaced IUDs/IUSs were localized by a combination of vaginal ultrasonography (US) and X-ray, hysteroscopy or curettage. Only after this were patients treated by means of laparoscopy. The majority (n = 44; 65%) of the 68 intra-abdominal devices were located in the omentum, the remaining 24 (35%) around the uterus. Partial perforation or myometrial embedding was diagnosed in all seven cases (9%) with visible threads, but unsuccessful removal by pulling. During laparoscopy, filmy adhesions were found in 21 patients (30%). Pregnancy (33 versus 7%, P = 0.009) and intra-abdominal adhesions (58 versus 20%, P = 0.002) were significantly more common in the Cu-IUD group. Infections were rare; one non-specific acute abdominal infection, later found to be unrelated to the IUD, led to laparoscopy and in four cases the IUD was surrounded by pus, but there were no symptoms of infection.

LIMITATIONS, REASONS FOR CAUTION

The study setting revealed only surgically treated symptomatic patients and asymptomatic women attending regular follow-up. Women not treated, but only followed or not attending follow-up, were not identified, excluding the possibility to analyse missed undiagnosed perforations, or conservative follow-up as a treatment option.

WIDER IMPLICATIONS OF THE FINDINGS

As surgical findings are minimal, asymptomatic women may need no treatment at all. An alternative form of contraception is, however, important as pregnancies do occur. If a woman plans a pregnancy, a misplaced LNG-IUS should be removed, as it may act as a contraceptive.

STUDY FUNDING/COMPETING INTEREST(S)

Helsinki University Central Hospital research funds. O.H. has lectured and designed educational events with Bayer AG and MSD, and serves occasionally on scientific advisory boards for these companies. S.S. has lectured in educational events organized by MSD Finland (part of Merck & Co. Inc.) and served on the advisory board for contraception of this company. The other authors have no conflicts of interest to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1546?rss=1

STUDY QUESTION

Is there a global consensus on the management of endometriosis that considers the views of women with endometriosis?

SUMMARY ANSWER

It was possible to produce an international consensus statement on the current management of endometriosis through engagement of representatives of national and international, medical and non-medical societies with an interest in endometriosis.

WHAT IS KNOWN ALREADY

Management of endometriosis anywhere in the world has been based partially on evidence-based practices and partially on unsubstantiated therapies and approaches. Several guidelines have been developed by a number of national and international bodies, yet areas of controversy and uncertainty remain, not least due to a paucity of firm evidence.

STUDY DESIGN, SIZE, DURATION

A consensus meeting, in conjunction with a pre- and post-meeting process, was undertaken.

PARTICIPANTS/MATERIALS, SETTING, METHODS

A consensus meeting was held on 8 September 2011, in conjunction with the 11th World Congress on Endometriosis in Montpellier, France. A rigorous pre- and post-meeting process, involving 56 representatives of 34 national and international, medical and non-medical organizations from a range of disciplines, led to this consensus statement.

MAIN RESULTS AND THE ROLE OF CHANCE

A total of 69 consensus statements were developed. Seven statements had unanimous consensus; however, none of the statements were made without expression of a caveat about the strength of the statement or the statement itself. Only two statements failed to achieve majority consensus. The statements covered global considerations, the role of endometriosis organizations, support groups, centres or networks of expertise, the impact of endometriosis throughout a woman's life course, and a full range of treatment options for pain, infertility and other symptoms related to endometriosis.

LIMITATIONS, REASONS FOR CAUTION

This consensus process differed from that of formal guideline development. A different group of international experts from those participating in this process would likely have yielded subtly different consensus statements.

WIDER IMPLICATIONS OF THE FINDINGS

This is the first time that a large, global, consortium, representing 34 major stake-holding organizations from five continents, has convened to systematically evaluate the best available current evidence on the management of endometriosis, and to reach consensus. In addition to 18 international medical organizations, representatives from 16 national endometriosis organizations were involved, including lay support groups, thus generating input from women who suffer from endometriosis.

STUDY FUNDING/COMPETING INTEREST(S)

The World Endometriosis Society commissioned and hosted the consensus meeting. Financial support for participants to attend the meeting was provided by the organizations that they represented. There was no other specific funding for this consensus process. Full disclosures of all participants are presented herein.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1552?rss=1

STUDY QUESTION

What are the diagnostic benefits of using ultrasound in patients with a clinical suspicion of acute salpingitis and signs of pelvic inflammatory disease (PID)?

SUMMARY ANSWER

In patients with a clinical suspicion of acute salpingitis, the absence of bilateral adnexal masses at ultrasound decreases the odds of mild-to-severe acute salpingitis about five times, while the presence of bilateral adnexal masses increases the odds about five times.

WHAT IS KNOWN ALREADY

PID is difficult to diagnose because the symptoms are often subtle and mild. The diagnosis is usually based on clinical findings, and these are unspecific. The sensitivity and specificity of ultrasound with regard to salpingitis have been reported in one study (n = 30) of appropriate design, where most patients had severe salpingitis (i.e. pyosalpinx) or tubo-ovarian abscess.

STUDY DESIGN, SIZE, DURATION

This diagnostic test study included 52 patients fulfilling the clinical criteria of PID. Patients were recruited between October 1999 and August 2008.

PARTICIPANTS/MATERIALS, SETTING, METHODS

The patients underwent a standardized transvaginal gray scale and Doppler ultrasound examination by one experienced sonologist (index test) before diagnostic laparoscopy by a laparoscopist blinded to the ultrasound results. The final diagnosis was determined by laparoscopy, histology of the endometrium and other histology where relevant (reference standard).

MAIN RESULTS AND THE ROLE OF CHANCE

Of the 52 patients, 23 (44%) had a final diagnosis unrelated to genital infection, while the other 29 had cervicitis (n = 3), endometritis (n = 9) or salpingitis (n = 17; mild n = 4, moderate n = 8, severe, i.e. pyosalpinx n = 5). Bilateral adnexal masses and bilateral masses lying adjacent to the ovary were seen more often on ultrasound in patients with salpingitis than with other diagnoses (bilateral adnexal masses: 82 versus 17%, i.e. 14/17 versus 6/35, P = 0.000, positive likelihood ratio 4.8, negative likelihood ratio 0.22; bilateral masses adjacent to ovary: 65 versus 17%, i.e.11/17 versus 6/35, P = 0.001, positive likelihood ratio 3.8, negative likelihood ratio 0.42). In cases of salpingitis, the masses lying adjacent to the ovaries were on average 2–3 cm in diameter, solid (n = 14), unilocular cystic (n = 4), multilocular cystic (n = 3) or multilocular solid (n = 1), with thick walls and well vascularized at colour Doppler. In no case were the cogwheel sign or incomplete septae seen. All 13 cases of moderate or severe salpingitis were diagnosed with ultrasound (detection rate 100%, 95% confidence interval 78–100%) compared with 1 of 4 cases of mild salpingitis. Three of six cases of appendicitis, and two of two ovarian cysts were correctly diagnosed with ultrasound, and one case of adnexal torsion was suspected and then verified at laparoscopy.

LIMITATIONS, REASONS FOR CAUTION

The sample size is small. This is explained by difficulties with patient recruitment. There are few cases of mild salpingitis, which means that we cannot estimate with any precision the ability of ultrasound to detect very early salpingitis. The proportion of cases with salpingitis of different grade affects the sensitivity and specificity of ultrasound, and the sensitivity and specificity that we report here are applicable only to patient populations similar to ours.

WIDER IMPLICATIONS OF THE FINDINGS

The information provided by transvaginal ultrasound is likely to be of help when deciding whether or not to proceed with diagnostic laparoscopy in patients with symptoms and signs suggesting PID and, if laparoscopy is not performed, to select treatment and plan follow-up.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by funds administered by Malmö University Hospital and two Swedish governmental grants (ALF-medel and Landstingsfinansierad Regional Forskning). The authors have no conflict of interest.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1569?rss=1

STUDY QUESTION

What are the anatomic variants (and their frequencies) of double uterus, obstructed hemivagina and ipsilateral renal agenesis?

SUMMARY ANSWER

Most cases examined (72.4%) were of the classic anatomic variant of the Herlyn-Werner-Wunderlich syndrome (with didelphys uterus, obstructed hemivagina and ipsilateral renal agenesis) but the 27.6% of cases are of a rare variant of the syndrome (with uterus septum or cervical agenesis), showing relevant clinical and surgical implications.

WHAT IS KNOWN ALREADY

The extreme variability of anatomic structures involved in this syndrome (both uterus, cervico-vaginal and renal anomalies) is well known, even if a complete and uniform analysis of all its heterogeneous presentations in a large series is lacking.

STUDY DESIGN, SIZE, DURATION

This is a retrospective study with 87 patients referred to our third level referral center between 1981 and 2011.

PARTICIPANTS/MATERIALS, SETTING, METHODS

We analyzed the laparoscopic and chart records of 87 women, who referred to our institute with double uterus, unilateral cervico-vaginal obstruction and ipsilateral renal anomalies.

MAIN RESULTS

Sixty-three of 87 patients had the more classic variant of didelphys uterus with obstructed hemivagina; 10/87 patients had septate bicollis uterus with obstructed hemivagina; 9/87 patients had bicornuate bicollis uterus with obstructed hemivagina; 4/87 patients had didelphys uterus with unilateral cervical atresia; 1/87 patients had bicornuate uterus with one septate cervix and unilateral obstructed hemivagina.

LIMITATIONS

This is a retrospective study with a long enrolling period (30 years).

WIDER IMPLICATIONS OF THE FINDINGS

New insights in the anatomic variants of this rare syndrome with their relevant surgical implications.

STUDY FUNDING/COMPETING INTEREST

No specific funding was obtained for this study. None of the authors have any competing interests to declare.

TRIAL REGISTRATION NUMBER

N/A.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1580?rss=1

STUDY QUESTION

What is the relative importance of the six dimensions of quality of care according to different stakeholders and can a quality indicator set address all six quality dimensions and incorporate the views from professionals working in different disciplines and from patients?

SUMMARY ANSWER

Safety, effectiveness and patient centeredness were the most important quality dimensions. All six quality dimensions can be assessed with a set of 24 quality indicators, which is face valid and acceptable according to both professionals from different disciplines and patients.

WHAT IS KNOWN ALREADY

To our knowledge, no study has weighted the relative importance of all quality dimensions to infertility care. Additionally, there are very few infertility care-specific quality indicators and no quality indicator set covers all six quality dimensions and incorporated the views of professionals and patients.

STUDY DESIGN, SIZE AND DURATION

A three-round iterative Delphi survey including patients and professionals from four different fields, conducted in two European countries over the course of 2011 and 2012.

PARTICIPANTS/MATERIALS, SETTINGS AND METHODS

Dutch and Belgian gynaecologists, embryologists, counsellors, nurses/midwifes and patients took part (n = 43 in round 1 and finally 30 in round 3). Respondents ranked the six quality dimensions twice for importance and their agreement was evaluated. Furthermore, in round 1, respondents gave suggestions, which were subsequently uniformly formulated as quality indicators. In rounds 2 and 3, respondents rated the quality indicators for preparedness to measure and for importance (relation to quality and prioritization for benchmarking). Providing feedback allowed selecting indicators based on consensus between stakeholder groups. Measurable indicators, important to all stakeholder groups, were selected for each quality dimension.

MAIN RESULTS

All stakeholder groups and most individuals agreed that safety, effectiveness and patient centeredness were the most important quality dimensions. A total of 498 suggestions led to the development of 298 indicators. Professionals were sufficiently prepared to measure 204 of these indicators. Based on importance, 52 (7–15 per dimension; round 2) and finally 24 (4 per dimension; round 3) quality indicators were selected.

LIMITATIONS, REASONS FOR CAUTION

The final quality indicator set does not cover the entire care process, but rather takes a ‘sample’ of each quality dimension. Although the quality indicators are face valid and acceptable, their psychometric characteristics need to be tested by further research.

WIDER IMPLICATIONS OF THE FINDINGS

Quality management should focus on safety, effectiveness and patient centeredness of care. Clinics can use the quality indicator set to assess all quality dimensions of their care.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/6/1584?rss=1