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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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

BACKGROUND

Previous research suggests the removal of uterine leiomyomata may improve ability to conceive. Most of this previous research was conducted in infertility clinics. We investigated the association between leiomyoma characteristics on time to pregnancy among women enrolled from the general population.

METHODS

We enrolled a cohort study of women in early pregnancy. Participants retrospectively reported their time to conception. Leiomyomata characteristics were determined by first-trimester ultrasound. We used discrete time hazard models to estimate the effects of uterine leiomyomata on time to pregnancy.

RESULTS

In this population of 3000 women, 11% (324) with one or more leiomyomata, we found no association between leiomyomata presence, type, location, segment or size on time to pregnancy.

CONCLUSIONS

These results suggest that leiomyomata have little effect on time to pregnancy in this cohort of women. The study excluded women who had been treated for infertility, and this may have resulted in underestimation of the association. However, differences between our study and previous studies in specialty clinics may be, in part, attributable to differences between our community-recruited population of women and women receiving fertility care, as well as difference in leiomyomata size or type in women having myomectomies to treat infertility.

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

STUDY QUESTION

Do heterosexual parents of young children following oocyte donation (OD) and sperm donation (SD) tell or intend to tell their offspring about the way he/she was conceived?

SUMMARY ANSWER

Following successful treatment with oocytes or sperm from identity-release donors in Sweden, almost all heterosexual couples intend to tell their offspring about the way he/she was conceived and some start the information-sharing process very early.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

Although the Swedish legislation on identity-release gamete donors has been in effect since 1985, there is a discrepancy between the behaviour of donor-insemination parents and the legal intention that offspring be informed about their genetic origin. The present study contributes data on a relatively large sample of oocyte and sperm recipient couples' intended compliance with the Swedish legislation.

DESIGN AND DATA COLLECTION METHOD

The present study constitutes a follow-up assessment of heterosexual couples who had given birth to a child following treatment with donated oocytes. Data collection was performed during 2007–2011; participants individually completed a questionnaire when the child was between 1 and 4 years of age.

PARTICIPANTS AND SETTING

The present study is part of the Swedish Study on Gamete Donation, a prospective longitudinal cohort study including all fertility clinics performing gamete donation in Sweden. For children conceived via OD, 107 individuals (including 52 couples and 3 individuals) agreed to participate (73% response). For children conceived via SD, the response rate was 70% (n = 122 individuals, including 59 couples and 4 individuals). Mean age of participants was 34 years (SD 4.4) and they reported a high level of education.

MAIN RESULTS

The majority of participants (78%) planned to tell the child about the donation, 16% had already started the information-sharing process and 6% planned not to tell their child about the donation or were undecided. Many were unsure about a suitable time to start the disclosure process and desired more information about strategies and tools for information sharing. Agreement on disclosure to offspring within the couple was related to the quality of the partner relationship.

BIAS AND GENERALIZABILITY

There is a risk of selection bias, with gamete recipients preferring secrecy and non-disclosure declining study participation. The results may be regarded as partly generalizable to heterosexual couples with young children following treatment with gametes from legislatively mandated identity-release donors in an established donor programme.

STUDY FUNDING/COMPETING INTERESTS

Study funding by Merck Serono, The Swedish Research Council and The Family Planning Fund in Uppsala. No conflicts of interest to declare.

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BACKGROUND

This study aimed to prospectively examine families created using surrogacy over a 10-year period in the UK with respect to intending parents' and children's relationship with the surrogate mother, parents' decisions over disclosure and children's understanding of the nature of their conception.

METHODS

Semi-structured interviews were administered by trained researchers to intending mothers, intending fathers and children on four occasions over a 10-year period. Forty-two families (19 with a genetic surrogate mother) participated when the child was 1-year old and by age 10 years, 33 families remained in the study. Data were collected on the frequency of contact with the surrogate mother, relationship with the surrogate, disclosure of surrogacy to the child and the child's understanding of their surrogacy birth.

RESULTS

Frequency of contact between surrogacy families and their surrogate mother decreased over time, particularly for families whose surrogate was a previously unknown genetic carrier (P < 0.001) (i.e. where they had met through a third party and the surrogate mother's egg was used to conceive the child). Most families reported harmonious relationships with their surrogate mother. At age 10 years, 19 (90%) children who had been informed of the nature of their conception had a good understanding of this and 13 of the 14 children who were in contact with their surrogate reported that they liked her.

CONCLUSIONS

Surrogacy families maintained good relationships with the surrogate mother over time. Children felt positive about their surrogate mother and their surrogacy birth. The sample size of this study was small and further, larger investigations are needed before firm conclusions can be drawn.

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

STUDY QUESTION

Is thymic stromal lymphopoietin (TSLP) involved in the pathophysiology of endometriosis?

SUMMARY ANSWER

TSLP is up-regulated by interleukin (IL)-1β and may be involved in the development of endometriosis.

WHAT IS KNOWN ALREADY

Endometriosis is a chronic inflammatory disease in which the Th2 immune response is activated and has been suggested to promote the disease. TSLP is a master cytokine that drive Th2 immune response.

STUDY DESIGN, SIZE, DURATION

A laboratory study.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Primary cultures of endometrioma stromal cells (ESCs) were treated with IL-1β, a typical inflammatory cytokine associated with endometriosis. Gene expression of TSLP in ESCs and secretion of TSLP protein from ESCs were studied using quantitative PCR and a specific ELISA. Interferon (IFN), a typical Th1 cytokine, and IL-4, a typical Th2 cytokine, were added to the culture to evaluate their effect on the IL-1β-induced secretion of TSLP. Inhibitors of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK and stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK) were added to the culture to examine intracellular signals involved in IL-1β-induced TSLP secretion. The expression of TSLP in endometrioma tissue was examined by immunohistochemistry. The concentration of TSLP in the serum and peritoneal fluid (PF) of women with or without endometriosis was measured with a specific ELISA.

MAIN RESULTS AND THE ROLE OF CHANCE

IL-1β stimulated the expression of TSLP mRNA and secretion of TSLP protein from ESCs. IL-4 enhanced the IL-1β-induced TSLP secretion from ESCs, while IFN reduced it. Inhibitors of p42/44 MAPK, p38 MAPK and SAPK/JNK suppressed the IL-1β-induced secretion of TSLP from ESCs. Positive immunostaining of TSLP was observed in the stroma of endometrioma tissue. TSLP concentrations in the serum and PF were both higher in women with endometriosis compared with those without endometriosis.

LIMITATIONS, REASONS FOR CAUTION

The present study was only in vitro. The samples used for culture were endometrioma tissues, not including other types of endometriosis. Therefore, the present findings should be interpreted with caution.

WIDER IMPLICATIONS OF THE FINDINGS

This study provided new insights in the Th2 immune response-related mechanism in endometriosis.

STUDY FUNDING

This study is partly supported by grants from the Ministry of Health, Labour and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology. The authors have no conflicts of interest to declare.

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

STUDY QUESTION

Which is the role of microRNAs (miRNAs) related to several angiogenesis regulators such as VEGF-A (Vascular endothelial growth factor-A) and TSP-1 (Thrombospondin-1) in endometrial cancer?

SUMMARY ANSWER

A dysregulated expression of miRNAs related to angiogenesis and an increase in the VEGF-A levels were observed in endometrial cancer in comparison with control. The different expression of miRNAs could modulate the expression of angiogenic and antiangiogenic factors, which may play an important role in the pathogenesis of endometrial cancer.

WHAT IS KNOWN ALREADY

Dysregulated miRNA expression has been previously evaluated in endometrial adenocarcinoma. To the best of our knowledge, there are no studies on the relationship between angiogenic factors and miRNAs in endometrial cancer.

STUDY DESIGN, SIZE, DURATION

Case–control study: 41 patients with histologically proven endometrioid endometrial cancer and 56 women without endometrial cancer.

PARTICIPANTS/MATERIALS, SETTING, METHODS

RNAs isolated from tissue samples were analyzed using the GeneChip miRNA 2.0 Array platform (Affymetrix). TaqMan qRT–PCR was used to assess the expression of the selected miRNAs related to angiogenesis (miR-15b, -16, -17-5p, -20a, -21, -125a, -200b, -210, -214*, -221, -222 and -424), and VEGF-A and TSP-1 mRNAs were assessed by qRT–PCR using SYBR Green. Protein levels were quantified by ELISAs.

MAIN RESULTS AND THE ROLE OF CHANCE

Compared with the miRNAs in the control endometrium, eight miRNAs (miR-15b, -17-5p, -20a, -125a, -214*, -221, -222 and -424) were significantly down-regulated and two miRNAs (miR-200b and -210) were significantly up-regulated in the cancerous endometrium. A significant increase in VEGF-A mRNA and protein expression and in TSP-1 protein levels (P <0.01) was observed in endometrial cancer. Moreover, significant inverse correlations between VEGF-A protein levels and miR-20a, -125a, -214*, -221, -222 and -424 were detected. In contrast, a positive correlation was observed between VEGF-A and miR-200b and -210. Furthermore, stage IB endometrial cancer was associated with a higher VEGF-A protein/mRNA ratio and lower miR-214*, -221 and -222 expression in comparison with stage IA.

LIMITATIONS, REASONS FOR CAUTION

Future functional studies (e.g. miRNA inhibition or ectopic overexpression) in cell culture models are needed to confirm the VEGF targeting by the miRNAs found in the present study.

WIDER IMPLICATIONS OF THE FINDINGS

The findings of the present study have potential implications for diagnostics and therapeutics of endometrial carcinoma.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by research grants from the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (Instituto de Salud Carlos III, Fondo de Investigación Sanitaria, PI080185, PI0110091) and Red RECAVA (RD06/0014/0004), by Consellería de Sanidad (AP-141/11) and Consellería de Educación (PROMETEO/2011/027), Generalitat Valenciana, by Beca Fibrinolisis 2009 and Becario 2010, 2011 from Fundación Española de Trombosis y Hemostasia and by the Fundación Investigación Hospital La Fe, Spain. None of the authors have any conflicts of interest.

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

NEW YORK, Sept. 12, 2012 /PRNewswire/ --BRCA1/2 gene mutations, widely associated with breast and ovarian cancer risks in women, are, in principle, lethal to human embryos, according to new research conducted by three teams of researchers from the Center for Human Reproduction (CHR) in New York City, the Medical University Vienna in Vienna, Austria, and the Medical University Graz, Graz, Austria. BRCA1/2-positive embryos will only survive when also carrying a specific FMR1 gene genotype.

In a paper just published in the prestigious online medical journal PLoS ONE(1), the researchers examined the distribution of FMR1 genotypes and sub-genotypes amongst women with BRCA1/2 mutations and in a control population of infertile women. Unexpectedly, almost all the 99 carriers of BRCA1/2 mutations demonstrated a specific FMR1 genotype, the so-called "low" FMR1 allele, defined by less than 26 CGG triple nucleotides. In contrast, over 300 controls presented with a normal distribution of FMR1 genotypes and sub-genotypes.

The authors note that the most likely explanation for such a skewed distribution of FMR1 in BRCA1/2 mutation carriers is embryo lethality of BRCA1/2 in humans; only embryos carrying the "low" FMR1 allele are "rescued" from this embryo-lethality.

"We were very surprised by these results," says David H. Barad, MD, MS, Director of Clinical ART and Senior Scientist at CHR, a senior author of the study. "Since approximately 25% of all women have low FMR1 genotypes, this observation, if confirmed, can greatly impact current cancer screening methods for BRCA1/2-associated cancers in women, and greatly reduce costs."

"These findings also potentially explain the long-unexplained 'BRCA-paradox,'" notes Norbert Gleicher, MD, Medical Director and Chief Scientist of CHR, and another senior author of the study. "BRCA-paradox" refers to the fact that BRCA1/2 mutations are anti-proliferative in embryonic tissue but proliferative in cancer tissues. Dr. Gleicher continues: "Confirmed, these findings could mean that 'low' FMR1 alleles desuppress the antiproliferative activity of BRCA1/2 in both tissues, in embryonic tissues allowing the embryo to survive, while in cancers having the negative effect of allowing cancer to proliferate. This, of course, could open major therapeutic options for improving embryo growth and inhibiting cancer growth."

An Appellate Court recently reaffirmed Myriad Genetics' BRCA1/2 patent. Because of unusually high testing costs for BRCA1/2(ca. $3,000), breast cancer screening and ovarian cancer screening are currently recommended only for women with strong family histories of breast and ovarian cancers. This study suggests the possibility that much less costly FMR1 testing may be able to, at least partially, replace BRCA1/2 testing as a primary screening test. The FMR1 test application utilized in this research is pending U.S. patents, and has been licensed to Women's Laboratory Corporation, LLC, NY, NY.

(1) Weghofer et al, BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: Explanation for the "BRCA paradox"? PLoS ONE 2012; http://dx.plos.org/10.1371/journal.pone.0044753

Drs. Barad and Gleicher are available for further comments in New York City. Dr. Weghofer, Associate Professor of Obstetrics & Gynecology at Vienna University, Visiting Associate Scientist at CHR and another senior author of the paper, is available for further comments from Vienna, Austria.

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BRCA1/2 Mutation and FMR1 Gene Study Has Potential Implications for Cancer Screening and Treatment

Chinese University doctors have discovered that infertile women lack the necessary genetic process in their uterus which makes them unable to conceive even if they use in-vitro fertilization.

The new cause of implantation failure does not only solve one of the long-standing mysteries of human reproduction but also sheds new light on the cause of miscarriages and low success rate of test-tube baby techniques.

It also opens a new way for diagnosing infertility and contraception - or even an anti-pill that will reverse infertility, said Chan Hsiao-chang, Li Ka Shing professor of physiology and director of Epithelial Cell Biology Research Centre at the university.

The ground-breaking study, published in last month's issue of Nature Medicine, came ahead of the grand opening ceremony yesterday of the Lo Kwee- Seong Integrated Biomedical Sciences Building, as the university stakes its claim to be the leader in biomedical research in the SAR.

Chan said for pregnancy to occur, women need to have an epithelial sodium channel in their uterus as an initial starting point. Without that channel, women cannot have the embryo implanted in their womb.

The next step we propose is to have an infertility diagnostic tool. The other one could be the target for contraception by targeting the channel to prevent pregnancy, she said.

Director of the School of Biomedical Sciences professor Chan Wai-yee said the discovery of this sodium channel could also be used to find an anti- contraceptive pill for women to conceive.

Patents have been filed for the discovery but the university still has to find interested companies to take it further. However, the center will focus on cutting-edge technologies to study cancer and inflammation, neuro-degeneration and reproduction, thanks to a HK$150 million donation by Vitasoy founder Lo Kwee-seong, Chan Wai-yee said.

Dean of Medicine Fok Tai-fai said: Corporate support of research is important. There is nothing unethical in itself unless there is ulterior motive. (The Standard)

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Why Some Women Fail To Give Birth

Public release date: 29-Aug-2012 [ | E-mail | Share ]

Contact: Emma Mason wordmason@mac.com European Society of Human Reproduction and Embryology

One of the largest studies to look at the effect of induced abortions on a subsequent first birth has found that women who have had three or more abortions have a higher risk of some adverse birth outcomes, such as delivering a baby prematurely and with a low birth weight.

The research, which is published online in Europe's leading reproductive medicine journal Human Reproduction [1] today (Thursday), found that among 300,858 Finnish mothers, 31,083 (10.3%) had had one induced abortion between 1996-2008, 4,417 (1.5%) had two, and 942 (0.3%) had three or more induced abortions before a first birth (excluding twins and triplets). Those who had had three or more induced abortions had a small, but statistically significant increased risk of having a baby with very low birth weight (less than 1500g), low birth weight (less than 2500g), or of a preterm birth (before 37 weeks), or very preterm birth (before 28 weeks), compared to women who had had no abortions. There was a slightly increased risk of a very preterm birth for women who had had two induced abortions.

Dr Reija Klemetti, an associate professor and senior researcher in public health at the National Institute for Health and Welfare in Helsinki, Finland, who led the research, said: "Our results suggest that induced abortions before the first birth, particularly three or more abortions, are associated with a marginally increased risk during the first birth. However, the increased risk is very small, particularly after only one or even two abortions, and women should not be alarmed by our findings."

Most of the induced abortions (88%) were surgically performed and nearly all (91%) were performed before 12 weeks gestation. The researchers adjusted their findings to take account of various factors that could affect birth outcomes, such as social background, marital status, age, smoking, previous ectopic pregnancies and miscarriages. Multiple births (twins and triplets) were excluded.

The risk of having a baby born very preterm appeared to increase slightly with each induced abortion, but only the risk from two abortions or more was statistically significant.

"To put these risks into perspective, for every 1000 women, three who have had no abortion will have a baby born under 28 weeks," said Dr Klemetti. "This rises to four women among those who have had one abortion, six women who have had two abortions, and 11 women who have had three or more."

Among women who had had three or more abortions, there was a statistically significant increased risk of a third (35%) of having a baby born preterm (before 37 weeks), a two-fold (225%) increased risk of very low birth weight, and a two-fifths (43%) increased risk of low birth weight.

The study also showed a small increased risk of a baby's death around the time of birth. However, the numbers for this finding were very low (1498 births or five per 1000 babies) and so should be treated with caution. In addition, the authors say they might not have been able to fully adjust for all the factors that could affect this result and perinatal deaths are sensitive to social factors such as poverty.

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Increased risk of prematurity and low birth weight in babies born after 3 or more abortions

Rep. Todd Akin's fame -- more accurately, his infamy -- now reaches all the way to the Congo.

There, Eve Ensler, the award-winning American author of "The Vagina Monologues" and herself a survivor of rape, wrote an open letter castigating last week's suggestion by the Republican congressman that when a woman is a victim of "legitimate rape," her body has means of preventing pregnancy. As it happens, Ensler is in the Congo working to help some of the thousands of women raped in the fighting there. She called Akin's words "ignorant."

Nor is hers the only voice of international opprobrium. Criticism of the Missouri lawmaker has rung from such far points as London ("shamefully inaccurate"), Belfast ("profoundly offensive") and Paris ("medieval"). A writer in Australia dubbed Akin a "boofhead" -- apparently, not a compliment. All this, plus domestic denunciation, including sharp criticisms from his own party.

Akin, make no mistake, richly earned every ounce of contempt that now rains upon his head. What he told KTVI-TV, the Fox affiliate in. St. Louis, manages to combine repulsiveness ("Legitimate rape?" As opposed, one supposes, to the rapes where "she brought it on herself"?) and remarkable ignorance (Does he really think the uterus is equipped with a force field?) into one appallingly malodorous ball of stupid. Naturally, given his grasp of biology, Akin sits on the House Science Committee.

Yes, you read right. You can't make this stuff up.

Still, this is not about one congressman's need for sensitivity training and remedial science. Akin is hardly unique, after all. To the contrary, he is just the latest vivid example of conservatism's unrelenting hostility toward women's reproductive rights -- as in a Texas judge who just upheld the state's ban on Planned Parenthood.

Indeed, even as this controversy was simmering, the GOP unveiled a proposed platform plank calling for a constitutional amendment that would ban abortion with no exceptions for cases of rape or incest. It's a plank Akin himself could have written.

But he is emblematic of more than hard-core opposition to abortion. In him, one also senses the juvenile discomfort with which some male conservatives are afflicted at the merest suggestion of female sexuality.

Think then-Attorney General John Ashcroft, piously covering the breasts of the "Spirit of Justice" statue at the Department of Justice. Think then-Rep. Tom Coburn decrying the "full-frontal nudity" of a movie broadcast on network television -- the movie being "Schindler's List," the nudes being doomed European Jews. Think Republicans banning Rep. Lisa Brown from speaking in the Michigan State House for using the word "vagina" -- as opposed, perhaps, to "lady parts," "third base" or "tunnel of love." Think Rush Limbaugh calling Sandra Fluke a slut because she has, presumably, on occasion had sex.

It's the kind of behavior one associates with a locker room full of adolescent boys, waiting for their faces to clear up and their voices to change. But these are men. Worse, they are men who are judged competent to make, interpret or influence laws impacting the most intimate decisions a woman can make.

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The GOP and women: Akin's ignorance is hardly unique

When a viable sperm penetrates a viable egg inside a woman's reproductive tract, the result is a fertilized egg that can then implant in the uterus. That fact of life is consistent regardless of how that sperm and egg met up, including whether or not the sperm was ejaculated during rape.

That may be news to Rep. Todd Akin from Missouri who told a local television station, in explaining his stance that abortion should not be allowed even in the case of rape: "If it's a legitimate rape, the female body has ways to try to shut that whole thing down."

NEWS: Boy or Girl? Mother Can Control Outcome

"Physiologically, if the sperm is in the vagina, a pregnancy can occur, regardless of the circumstances of how that sperm got there," said Dr. Melisa Holmes, an ob-gyn and founder of Girlology, an organization that promotes healthy sexuality and communication in families.

And though the anti-abortion Republican says he "misspoke," Holmes says that Akin's remark also suggests that some rapes are not "legitimate," and this continues a harmful misconception about violence against women.

"A rape is a rape, and a woman has the same physical and emotional consequences whether she's raped by a stranger in a dark alley or someone she's known for five years," Holmes told LiveScience. "That's one of those misperceptions that gets perpetuated and unfortunately affects women in a bad way -- 'Were you really raped, or were you at fault for part of it?'"

NEWS: Moderate Drinking and Miscarriage Linked

Perhaps Akin is correct in thinking it's not the easiest of tasks to get pregnant; that's why men don't ejaculate just one sperm and instead release nearly 100 million sperm. (Men who have fewer than 20 million sperm per milliliter of semen may have difficulty conceiving, according to a WebMD article.) That's because few sperm survive the grueling journey from the vagina to the fallopian tubes where they can meet up with an egg. Even for those that make it, only the healthiest will penetrate, and fertilize, the egg. (11 Odd Facts About the Pregnant Body)

Still, of the 6.7 million pregnancies in the United States every year, about half are unintended, according to the Guttmacher Institute.

The chance of getting pregnant from one event of unprotected sexual intercourse is 5 percent on average, according to the Rape, Abuse & Incest National Network (RAINN).

Original post:
Akin and Pregnancy: Yes, It Can Happen to Rape Victims

BACKGROUND

This 12th European IVF-monitoring (EIM) report presents the results of treatments involving assisted reproductive technology (ART) initiated in Europe during 2008.

METHODS

From 36 countries (3 more compared with 2007), 1051 clinics reported 532 260 treatment cycles including: IVF (124 539), ICSI (280 552), frozen embryo replacements (FER, 97 120), egg donation (ED, 13 609), in vitro maturation (IVM, 562), preimplantation genetic diagnosis/screening (PGD/PGS, 2875) and frozen oocyte replacements (FOR, 4080). Overall, this represents a 7.9% increase in the activity since 2007, which is mainly related to an increase in cycles from almost all registers and only partially to the new countries entering EIM (Estonia, Kazakhstan, Moldova and Romania, 5480 cycles in total). European data on intrauterine insemination using husband/partner's (IUI-H) and donor (IUI-D) semen were reported from 27 and 21 countries, respectively. A total of 144 509 IUI-H (+1.5%) and 24 960 IUI-D (–4.3%) cycles were included.

RESULTS

In 19 countries where all clinics reported to the ART register, a total of 350 143 ART cycles were performed in a population of 369.8 million, corresponding to 947 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 28.5 and 32.5%, respectively, and for ICSI the corresponding rates were 28.7 and 31.9%. In FER cycles, the pregnancy rate per thawing was 19.3%. The delivery rate after IUI was 9.1% for IUI-H and 13.8% for IUI-D. In IVF and ICSI cycles, one, two, three and four or more embryos were transferred in 22.4, 53.2, 22.3 and 2.1%, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (combined) were 78.3, 20.7 and 1.0%, respectively, resulting in a total multiple delivery rate of 21.7%, compared with 22.3% in 2007, 20.8% in 2006 and 21.8% in 2005. In FER cycles, the multiple delivery rate was 13.7% (13.4% twins and 0.3% triplets). In women undergoing IUI, twin and triplet deliveries occurred in 10.6% and 0.7% with IUI-H and in 9.4 and 0.3% with IUI-D, respectively.

CONCLUSIONS

In comparison with previous years, there was an increase in the reported number of ART cycles in Europe. For the first time in 5 years, the pregnancy rates failed to show a year-on-year increase. Compared with 2007, the number of transfers of multiple embryos (3+) and a multiple delivery rate showed a marginal decline.

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STUDY QUESTION

Does elevated temperature-induced cystic fibrosis transmembrane conductance regulator (CFTR) down-regulation in Sertoli cells in cryptorchid testis disrupt testicular tight junctions (TJs) through the nuclear factor kappa B (NF-B)/cyclooxygenase-2 (COX-2)/prostaglandin E₂ (PGE₂) pathway?

SUMMARY ANSWER

Our results suggest that CFTR may be involved in regulating testicular TJs and the blood-testis barrier (BTB) through its negative regulation of the NF-B/COX-2/PGE₂ pathway in Sertoli cells, a defect of which may result in the spermatogenesis defect in cryptorchidism.

WHAT IS KNOWN ALREADY

Cryptorchidism, or undescended testes, is known to result in defective spermatogenesis. Although an elevated testicular temperature is regarded as an important factor affecting spermatogenesis in cryptorchidism, the exact mechanism remains elusive. It is known that the expression of functional CFTR is temperature sensitive. Our previous study has demonstrated that CFTR negatively regulates NF-B/COX-2/PGE₂ in bronchial epithelial cells. Disruption of TJs by COX-2/PGE₂ has been found in tumour cells.

STUDY DESIGN AND METHODS

Expression of CFTR, NF-B, COX-2 and TJ proteins was examined in the testes of a surgical-induced cryptorchidism mouse model and a testicular hyperthermia mouse model, as well as in control or CFTR-inhibited/knocked down primary rat Sertoli cells. PGE₂ production was measured by ELISA. Sertoli cell barrier function was determined by transepethelial resistance (TER) measurements in rat Sertoli cell primary cultures. BTB integrity in the cryptorchidism model was monitored by examining tracker dye injected into seminiferous tubules.

MAIN RESULTS

Down-regulation of CFTR accompanied by activation of NF-B, up-regulation of COX-2 and down-regulation of TJ proteins, including ZO-1 and occludin, was observed in a cryptorchidism mouse model. BTB leakage revealed impaired BTB integrity in cryptorchid testes, confirming the destruction of TJs. The inverse correlation of CFTR and COX-2 was further confirmed in a mouse testis hyperthermia model and CFTR knockout mouse model. Culturing primary Sertoli cells at 37°C, which mimics the pathological condition of cryptorchidism, led to a significant decrease in CFTR and increase in COX-2 expression and PGE₂ production compared with the culture at the physiological 32°C. Inhibition or knockdown of CFTR led to increased COX-2 but decreased ZO-1 and occludin expression in Sertoli cells, which could be mimicked by PGE₂, but reversed by NF-B or COX-2 inhibitor, suggesting that the regulation of TJs by CFTR is mediated by a NF-B/COX-2/PGE₂ pathway. Inhibition of CFTR or administration of PGE₂ significantly decreased Sertoli cell TER.

LIMITATIONS

This study has tested only the CFTR/NF-B/COX-2/PGE₂ pathway in mouse testes in vivo and in rat Sertoli cells in vitro, and thus, it has some limitations. Further investigations in other species, especially humans, are needed.

WIDER IMPLICATIONS OF THE FINDINGS

Our study may shed more light on one of the aspects of the complicated underlying mechanisms of defective spermatogenesis induced by cryptorchidism.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by the National Basic Research Program of China (2012 CB944900), Natural Sciences Foundation of China (30870933), Li Ka Shing Institute of Health Sciences, the Focused Investment Scheme of the Chinese University of Hong Kong and Morningside Foundation. The authors declare no conflict of interest.

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BACKGROUND

Fetal cells (microchimerism) are acquired by women during pregnancy. Fetal microchimerism persists decades later and includes cells with pluripotent capacity. Persistent microchimerism has the capacity for both beneficial and detrimental maternal health consequences. Both miscarriage and termination of pregnancy can result in fetal microchimerism. We sought to determine whether cellular fetal microchimerism is acquired during management of pregnancy loss and further explored factors that could influence fetal cell transfer, including viability of fetal tissue, surgical versus medical management and gestational age.

METHODS

Pregnant women (n= 150 samples from 75 women) with singleton pregnancies undergoing a TOP (n= 63) or treatment for embryonic or fetal demise (miscarriage, n= 12) were enrolled. Mononuclear cells were isolated from blood samples drawn before, and 30 min after, treatment. Fetal cellular microchimerism concentrations were determined using quantitative PCR for a Y chromosome-specific sequence, expressed as genome equivalents of fetal DNA per 100 000 maternal cell equivalents (gEq/10⁵). Detection rate ratios were determined according to clinical characteristics.

RESULTS

Cellular fetal microchimerism was found more often in post- compared with pretreatment samples, 24 versus 5% (P= 0.004) and at higher concentrations, 0–36 versus 0–0.7 gEq/10⁵ (P< 0.001). Likelihood of microchimerism was higher in surgical than medical management, detection rate ratio 24.7 (P= 0.02). The detection rate ratio for TOP versus miscarriage was 16.7 for known male fetuses (P= 0.02). Microchimerism did not vary with gestational age.

CONCLUSIONS

Significant fetal cell transfer occurs during miscarriage and TOP. Exploratory analyses support relationships between obstetric clinical factors and acquisition of fetal cellular microchimerism; however, our limited sample size precludes definitive analysis of these relationships, and confirmation is needed. In addition, the long-term persistence and potential consequences of fetal microchimerism on maternal health merit further investigation.

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BACKGROUND

Dendritic cells (DCs), which are biased toward a tolerogenic profile, play a pivotal role in tissue-remodeling processes and angiogenesis at the maternal–fetal interface. Here, we analyzed the effect of trophoblast cells on the functional profile of DCs to gain insight on the tolerogenic mechanisms underlying the human placental–maternal dialog at early stages of gestation.

METHODS

DCs were differentiated from peripheral blood monocytes obtained from fertile women (n = 21), in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor during 5 days in culture. Then, DCs were cultured with trophoblast cells (Swan-71 cell line obtained from normal cytotrophoblast, at 7 weeks) for 24 h and for an additional 24 h in the absence or presence of lipopolysaccharide (LPS) from Escherichia coli. DCs were recovered and used for flow cytometry, enzyme-linked immunosorbent assay, RT–PCR and suppression and migration assays.

RESULTS

Trophoblast cells significantly prevented the increase in CD83 expression induced by LPS without affecting the expression of CD86, CD40 and human leukocyte antigen-DR (P < 0.05). Trophoblast cells signifinatly decreased the production of IL-12p70 and tumor necrosis factor-α, while it increased the production of IL-10 (P < 0.05). No changes were observed in the production of IL-6 and monocyte chemotactic protein-1. The culture of DCs with trophoblast cells, also suppressed the stimulation of the allogeneic response triggered by LPS (P < 0.05). Conditioned DCs were able to increase the frequency of CD4 + CD25 + Foxp3 cells and this effect was accompanied by an increase in indoleamine 2, 3-dioxygenase expression in DCs (P < 0.05).

CONCLUSIONS

The interaction of DCs with trophoblast cells promotes the differentiation of DCs into cells with a predominantly tolerogenic profile that could contribute to a tolerogenic microenvironment at the maternal–fetal interface.

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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.

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STUDY QUESTION

Do different human ART culture protocols prepare embryos differently for post-implantation development?

SUMMARY ANSWER

The type of ART culture protocol results in distinct cellular and molecular phenotypes in vitro at the blastocyst stage as well as subsequently during in vivo development.

WHAT IS KNOWN ALREADY

It has been reported that ART culture medium affects human development as measured by gestation rates and birthweights. However, due to individual variation across ART patients, it is not possible as yet to pinpoint a cause–effect relationship between choice of culture medium and developmental outcome.

STUDY DESIGN, SIZE, DURATION

In a prospective study, 13 human ART culture protocols were compared two at a time against in vivo and in vitro controls. Superovulated mouse oocytes were fertilized in vivo using outbred and inbred mating schemes. Zygotes were cultured in medium or in the oviduct and scored for developmental parameters 96h later. Blastocysts were either analyzed or transferred into fosters to measure implantation rates and fetal development. In total, 5735 fertilized mouse oocytes, 1732 blastocysts, 605 fetuses and 178 newborns were examined during the course of the study (December 2010–December 2011).

PARTICIPANTS/MATERIALS, SETTING, METHODS

Mice of the B6C3F1, C57Bl/6 and CD1 strains were used as oocyte donors, sperm donors and recipients for embryo transfer, respectively. In vivo fertilized B6C3F1 oocytes were allowed to cleave in 13 human ART culture protocols compared with mouse oviduct and optimized mouse medium (KSOM(aa)). Cell lineage composition of resultant blastocysts was analyzed by immunostaining and confocal microscopy (trophectoderm, Cdx2; primitive ectoderm, Nanog; primitive endoderm, Sox17), global gene expression by microarray analysis, and rates of development to midgestation and to term.

MAIN RESULTS AND THE ROLE OF CHANCE

Mouse zygotes show profound variation in blastocyst (49.9–91.9%) and fetal (15.7–62.0%) development rates across the 13 ART culture protocols tested (R²= 0.337). Two opposite protocols, human tubal fluid/multiblast (high fetal rate) and ISM1/ISM2 (low fetal rate), were analyzed in depth using outbred and inbred fertilization schemes. Resultant blastocysts show imbalances of cell lineage composition; culture medium-specific deviation of gene expression (38 genes, ≥4-fold) compared with the in vivo pattern; and produce different litter sizes (P ≤ 0.0076) after transfer into fosters. Confounding effects of subfertility, life style and genetic heterogeneity are reduced to a minimum in the mouse model compared with ART patients.

LIMITATIONS, REASONS FOR CAUTION

This is an animal model study. Mouse embryo responses to human ART media are not transferable 1-to-1 to human development due to structural and physiologic differences between oocytes of the two species.

WIDER IMPLICATIONS OF THE FINDINGS

Our data promote awareness that human ART culture media affect embryo development. Effects reported here in the mouse may apply also in human, because no ART medium presently available on the market has been optimized for human embryo development. The mouse embryo assay (MEA), which requires ART media to support at least 80% blastocyst formation, is in need of reform and should be extended to include post-implantation development.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by the Deutsche Forschungsgemeinschaft (BO 2540/4-1 to M.B. and SCHL 394/9 to S.S.) and by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (no. 63-258 to S.L.G.). No competing interests.

TRIAL REGISTRATION NUMBER

Not applicable.

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BACKGROUND

More than half of recurrent pregnancy loss (RPL) remains unexplained. We hypothesized that women with a history of unexplained RPL (URPL) have low venous reserve.

METHODS

Case–control study in 12 women with a history of URPL, 11 healthy nulliparous controls and 12 primiparous controls with a history of uncomplicated pregnancy. To quantify venous reserve, we measured plasma volume (PV, ml/m²) and venous compliance in forearm and calf (VC_arm, VC_calf, (ml/dl)/mmHg) during the follicular phase of the menstrual cycle. Mean arterial blood pressure (mmHg) was measured by oscillometry. Arterial demand was evaluated by cardiac index (CI, (l/min)/m²).

RESULTS

Baseline characteristics were comparable between groups. All groups had similar CI. Women with a history of RPL had 14% and 9% lower mean PV compared with nulliparous and primiparous controls (P < 0.01 and P = 0.04, respectively). In women with URPL, the mean VC_arm was 25% and 32% lower compared with nulliparous and primiparous controls (P = 0.04 and P < 0.01, respectively), while the mean VC_calf was 29 and 22% lower compared with the two control groups (P < 0.01 and P = 0.03, respectively).

CONCLUSIONS

Women with URPL have lower venous reserves when compared with controls at comparable arterial demand. Interventions that increase venous reserve may improve pregnancy outcome.

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BACKGROUND

The precise assessment of embryo viability is an extremely important factor for the optimization of IVF treatments. In order to assess embryo viability, several embryo scoring systems have been developed. However, they rely mostly on a subjective visual analysis of embryo morphological features and thus are subject to inter- and intra-observer variation. In this paper, we propose a method for image segmentation (the dividing of an image into its meaningful constituent regions) and classification of human blastocyst images with the aim of automating embryo grading.

METHODS

The delineation of the boundaries (segmentation) of the zona pellucida, trophectoderm (TE) and inner cell mass (ICM) were performed using advanced image analysis techniques (level set, phase congruency and fitting of ellipse methods). The fractal dimension and mean thickness of TE and ICM image texture descriptors (texture spectrum and grey-level run lengths) were calculated to characterize the main morphological features of the blastocyst with the aim of automatic grading using Support Vector Machine classifiers.

RESULTS

The fractal dimension calculated from the delineated TE boundary provided a good indication of cell number (presented a 0.81 Pearson correlation coefficient with the number of cells), a feature closely associated with blastocyst quality. The classifiers showed different accuracy levels for each grade. They presented accuracy ranges from 0.67 to 0.92 for the embryo development classification, 0.67–0.82 for the ICM classification and 0.53–0.92 for the TE classification. The value 0.92 was the highest accuracy achieved in the tests with 73 blastocysts.

CONCLUSIONS

Semi-automatic grading of human blastocysts by a computer is feasible and may offer a more precise comparison of embryos, reducing subjectivity and allowing embryos with apparently identical morphological scores to be distinguished.

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