STUDY QUESTION

Is there an association between chorionic villous vascularization, ultrasound findings and corresponding chromosome results in early miscarriage specimens from a cohort of recurrent pregnancy loss patients?

SUMMARY ANSWER

We did not find a significant difference in vascularization scores of chorionic villi between embryonic, yolk sac or empty sac miscarriages, or between euploid and noneuploid miscarriages.

WHAT IS KNOWN ALREADY

At least half of first trimester miscarriages are due to embryopathogenesis associated with chromosome errors and/or major congenital anomalies, resulting in an empty sac, a yolk sac or an embryonic miscarriage. Absent and decreased chorionic villous vascularization is usually present in these pregnancies.

STUDY DESIGN, SIZE, DURATION

For this retrospective study, 60 hematoxylin and eosin slides of miscarriage tissue of less than 10 weeks gestational age were collected from an academic institution. All patients were seen in consultation between July 2004 and October 2009.

PARTICIPANTS, SETTING, METHODS

Chorionic villous vascularization was determined using a previously published classification. The results were validated and compared with the ultrasound findings and corresponding chromosome results.

MAIN RESULTS AND THE ROLE OF CHANCE

There were 53 embryonic miscarriages, 5 yolk sac miscarriages and 2 empty sac miscarriages. Chromosome results were obtained in 59 of the 60 miscarriages; 37.3% were euploid and 62.7% were noneuploid. Validation of the vascularization score between observers was reasonable to good (Kappa 0.47–0.76), and 59% of the cases were classified as avascular. The vascularization score did not differ between euploid or noneuploid miscarriages, or between embryonic, yolk sac or empty sac miscarriages. Avascular villi were seen more frequently in miscarriages trisomic for chromosome 16, when compared with miscarriages with other trisomies (6 out of 7 versus 8 out of 22, P = 0.04).

LIMITATIONS, REASONS FOR CAUTION

Unfortunately, the number of samples in the study was limited.

WIDER IMPLICATIONS OF THE FINDINGS

Avascular villi may indicate abnormal early placentation as a part of embryopathogenesis. Further study is warranted to determine whether a genetic cause can be found to explain these results.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/916?rss=1

STUDY QUESTION

Are the fetal outcomes of singleton pregnancies that result from cleavage stage embryo transfer (ET) different from the outcomes from Day 5/6 blastocyst stage ET?

SUMMARY ANSWER

There was a significantly higher risk of preterm birth (<37 weeks) in singletons after extended embryo culture (Day 5/6) compared with cleavage stage (Day 3) transfer.

WHAT IS KNOWN ALREADY

Two recent studies, from Sweden and the USA, reported an increased risk of preterm birth in singleton pregnancies after Day 5/6 ET compared with Day 3 ET. The US study also showed increased early preterm births and the Swedish study showed increased fetal malformations in this group.

STUDY DESIGN, SIZE AND DURATION

A retrospective cohort study was performed. Data were collected from the Canadian ART Register database for all singleton births after fresh IVF/ICSI ET cycles (2001–2009).

PARTICIPANTS/MATERIALS, SETTING, METHODS

A total of 12 712 singleton births were included. Of these, 9506 resulted from a Day 3 ET and 3206 resulted from a blastocyst (Day 5/6) ET.

MAIN RESULTS AND THE ROLE OF CHANCE

Preterm birth rate <37 weeks (unadjusted by potential confounding factors) was higher with Day 5/6 versus Day 3 transfers (17.2 versus 14.1%, P < 0.001). Using logistic regression analysis to adjust for confounding factors, preterm birth rate <37 weeks was the only outcome significantly increased after Day 5/6 compared with Day 3 transfer (odds ratio 1.32, 95% confidence interval 1.17–1.49). The following confounding factors were adjusted for: year of treatment (2001–2009), maternal age (continuous), parity (0 versus ≥1 birth), diagnosis category, number of oocytes retrieved [≤20 versus >20 (high responder group)], insemination method (IVF versus ICSI), number of embryos transferred (1, 2 or ≥3) and the presence of a vanishing twin (≥1 fetal heart on the initial ultrasonographic examination).

LIMITATIONS, REASONS FOR CAUTION

Post-natal follow-up studies will be required to determine if this difference we observed translates into adverse long-term effects on these offspring. The rate of early preterm births (<32 weeks) was higher in Day 5/6 versus Day 3, but the low number of cases in this category did not have the power to show a difference (3.0 versus 2.7%, P = 0.34).

WIDER IMPLICATIONS OF THE FINDINGS

We found a significantly higher risk of preterm birth (<37 weeks) in singletons after extended embryo culture (Day 5/6) compared with cleavage stage (Day 3) transfer, even when adjusting for confounding factors. Our findings are in agreement with the previous two studies; however, we did not show a difference in the very preterm deliveries (unlike the US study) or in fetal malformations (as in the Swedish study). We hypothesize that there may be a deleterious effect of prolonged in vitro embryo culture on subsequent placentation. Longer term follow-up studies will be required to determine if prolonged in vitro culture to the blastocyst stage has an adverse effect on the long-term health of offspring when compared with shorter cleavage stage culture.

STUDY FUNDING/COMPETING INTEREST(S)

None.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/924?rss=1

STUDY QUESTION

Is the relative telomere length in cumulus cells associated with embryo quality and the subject's age?

SUMMARY ANSWER

The relative telomere length in cumulus cells at the time of oocyte collection may be a new potential biomarker for selecting highly competent oocytes and good quality embryos.

WHAT IS KNOWN ALREADY

Telomeres play central roles in aging and in determining cell fate. In mammalian ovarian follicles, maturing oocytes are nurtured and supported by surrounding somatic cells, the mural granulosa and cumulus cells.

STUDY DESIGN, SIZE, DURATION

A total of 350 oocyte–cumulus complex samples were collected from 80 IVF cycles prospectively recruited for this study at the Lee Women's Hospital, Taichung, Taiwan.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Cumulus cells were manually separated from the oocyte–cumulus complex under a microscope. DNA was extracted from cumulus cells and assessed for telomere length by real-time quantitative PCR. We analyzed telomere length relative to a single copy marker gene (36B4) to evaluate the effect of the real reproductive age of cumulus cells on oocyte and embryo development.

MAIN RESULTS AND THE ROLE OF CHANCE

The relative telomere length was longer in cumulus cells from mature oocytes compared with cumulus cells from immature oocytes, and in cumulus cells from good-quality embryos compared with cumulus cells from poor-quality embryos. The cut-off value of the T/S ratio between good and poor-quality embryos on embryonic Day 3 was 4.235.

LIMITATIONS, REASONS FOR CAUTION

Only a limited number of cumulus cells were measured for each oocyte and the corresponding embryo.

WIDER IMPLICATIONS OF THE FINDINGS

The relative telomere length in cumulus cells at the time of oocyte collection is predictive of highly competent oocytes and good-quality embryos but may not be sufficiently discriminating to be clinically useful.

STUDY FUNDING/COMPETING INTEREST(S)

National Science Council, Taiwan (NSC 97-2314-B-040-018). The authors have no conflicts of interest to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/929?rss=1

STUDY QUESTION

Which inflammation biomarkers detected in the vaginal fluid are most informative for identifying preterm delivery (PTD) risk?

SUMMARY ANSWER

Elevated interleukin (IL)-6 at mid-trimester was associated with increased odds of spontaneous PTD at <35 weeks and with PTD plus histologic chorioamnionitis (HCA), and had the greatest sensitivity for detecting these two PTD subtypes.

WHAT IS KNOWN ALREADY

Maternal and/or fetal inflammation play a role in some preterm deliveries, therefore inflammation biomarkers might help to identify women at greater risk.

STUDY DESIGN, SIZE, DURATION

We examined 1115 women from the Pregnancy Outcomes and Community Health Study, a cohort study conducted from September 1998 through June 2004, for whom data were available on mid-pregnancy inflammatory biomarkers.

PARTICIPANTS/MATERIALS, SETTING, METHODS

At enrollment at 16–27 weeks gestation, vaginal fluid samples were collected from a swab and 15 eluted biomarkers were measured using the Meso Scale Discovery multiplex electrochemiluminescence platform. Associations of biomarkers with PTD were examined, according to clinical circumstance, week at delivery and presence/absence of HCA. Weighted logistic regression was used to determine odds ratios (OR) and 95% confidence intervals (CI) adjusted for race. Sensitivity and specificity were compared between individual and multiple biomarkers, identified by a bootstrapping method.

MAIN RESULTS AND THE ROLE OF CHANCE

Elevated IL-6 (>75th percentile) displayed the strongest association with spontaneous PTD <35 weeks (OR 2.3; CI 1.3–4.0) and PTD with HCA (OR 2.8; CI 1.4–6.0). The sensitivity of IL-6 to detect spontaneous PTD <35 weeks or PTD with HCA was 0.43 and 0.51, respectively, while specificity was 0.74 and 0.75, respectively. IL-6 plus IL1β, IL-6r, tumor necrosis factor-alpha or granulocyte-macrophage colony-stimulating factor increased specificity (range 0.84–0.88), but decreased sensitivity (range 0.28–0.34) to detect both PTD subtypes. Results were similar when a combination of IL-6 and bacterial vaginosis (BV) was explored. Thus, the use of multiple biomarkers did not detect PTD subtypes with a greater sensitivity than IL-6 alone, and IL-6 is a specific but non-sensitive marker for the detection of spontaneous PTD.

LIMITATIONS, REASONS FOR CAUTION

Our ability to find small effect size associations between PTD and inflammation biomarkers (OR <2.0) might have been limited by the modest number of less common PTD subtypes in our population (e.g. spontaneous delivery <35 weeks, PTD accompanied by HCA) and by relatively higher variability for some cytokines, for example tumor necrosis factor-α, IL-12p70, IL-10 and granulocyte-macrophage colony-stimulating factor, that are less stable and commonly undetectable or detectable at low levels in human vaginal secretions.

WIDER IMPLICATIONS OF THE FINDINGS

Larger studies are needed to further explore a role of inflammation biomarkers in combination with other risk factors, including specific BV-associated organisms, for the prediction of PTD subtypes.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by the National Institute of Child Health and Human Development, National Institute of Nursing, March of Dimes Foundation, Thrasher Research Foundation and Centers for Disease Control and Prevention. The authors have no conflicts of interest.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/942?rss=1

STUDY QUESTION

What proportion of pregnancies are a result of ovum transmigration after salpingectomy for ectopic pregnancy?

SUMMARY ANSWER

Approximately one-third of spontaneously conceived pregnancies are a result of pick-up of the ovum from the ovary contralateral to the remaining tube in women with a history of salpingectomy.

WHAT IS KNOWN ALREADY

The corpus luteum has been found contralateral to tubal ectopic pregnancies in 32% of reported cases. The rate of contralateral ovum pick-up in intrauterine pregnancies is not known.

STUDY DESIGN, SIZE, DURATION

We conducted a retrospective cohort study of clinical and ultrasound records collected over a 12-year period 1999–2010. Ten per cent of cases identified were excluded from the final analysis due to incomplete data or bilateral corpora lutea.

PARTICIPANTS/MATERIALS, SETTINGS, METHODS

Included were 842 pregnancies in 707 women with a history of unilateral salpingectomy for ectopic pregnancy and subsequent spontaneous pregnancy. The study was set in the Early Pregnancy Unit of a large UK inner city teaching hospital. The outcome measure was the side of the corpus luteum in relation to the side of the remaining tube.

MAIN RESULTS AND THE ROLE OF CHANCE

The corpus luteum was located in the ovary contralateral to the remaining tube in 266/842 pregnancies (31.6%; 95% CI 28.5–34.8%). There was no significant difference in this proportion between intrauterine and ectopic pregnancies [246/769 (32.0%) versus 21/73 (28.8%), P = 0.60].

LIMITATIONS, REASONS FOR CAUTION

This was a retrospective study and so did not address the conception rate according to the laterality of ovulation.

WIDER IMPLICATIONS OF THE FINDINGS

Our findings were very similar to the frequency of ectopic pregnancies found contralateral to the corpus luteum described in previous studies. Ovum pick-up from the cul-de-sac probably occurs reasonably frequently and is unlikely to have a causative role in the pathogenesis of ectopic pregnancy. It is not known how often this phenomenon occurs in women with intact Fallopian tubes.

STUDY FUNDING/COMPETING INTEREST(S)

No specific funding was obtained. The authors have no conflicts of interest to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/937?rss=1

Controlled ovarian stimulation (COS) in women with estrogen receptor (ER)-positive breast cancer is potentially harmful because of the increase in serum estrogen levels. During COS for cryopreservation of oocytes or embryos, these women may receive high doses of tamoxifen (60 mg) to modulate the ER and prevent extra growth of estrogen responsive tumours during COS. However, it is unknown whether adequate serum concentrations of endoxifen, the most important metabolite of tamoxifen, can be reached. The aim of this study is to evaluate whether the tamoxifen dose used in a tamoxifen–COS combined schedule for women with ER-positive breast cancer is high enough to reach endoxifen levels that are considered therapeutically effective to inhibit breast cancer growth. The four women with ER-positive breast cancer who underwent COS for cryopreservation of oocytes were prospectively studied at the Academic Medical Centre, Amsterdam, the Netherlands. Throughout COS, blood samples were collected and tamoxifen and endoxifen levels were determined by a validated high-performance liquid chromatography tandem mass spectrometry assay. The four women with ER-positive breast cancer underwent a total of five COS cycles, while additionally using tamoxifen 60 mg daily. The tamoxifen and endoxifen levels showed a large variability between the women, with endoxifen levels during the whole period of ovarian stimulation varying between 3.96 and 41.0 ng/ml. The average number of vitrified oocytes was 11 (5–14). Therapeutically effective endoxifen serum levels can be reached when tamoxifen is used to counteract estrogen levels during COS for fertility preservation, but not in all women. Large variations of tamoxifen and endoxifen levels between the women were observed.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/953?rss=1

STUDY QUESTION

What are the age-specific incident rates of clinically recorded fertility problems in women aged 15–49 years and how do they vary by socioeconomic group and geographic area.

SUMMARY ANSWER

The incident rate of recorded fertility problems was highest in women age 30–34 years: about 1% of women per annum. Overall rates did not vary by socioeconomic group; however, age-specific rates varied substantially by socioeconomic deprivation quintile; among younger women, deprivation was associated with higher infertility rates.

WHAT IS KNOWN ALREADY AND WHAT THIS PAPER ADDS

The rates of infertility in the UK range from 2 to 26%. Infertility definitions and denominators vary widely, and most current evidence is based on questionnaire studies that are subject to recall, reporting and selection bias. The current paper presents population-based estimates of clinically recorded fertility problems in women of reproductive age and the variation by age and socioeconomic deprivation quintile across different regions of the UK, using a nationally representative cohort of women that is larger than any previous study. Although infertility overall does not vary by socioeconomic status, consultation for fertility problems is closely related to socioeconomic patterns of women's age at first conception, demonstrating that many couples have pre-existing, rather than specifically age-related, infertility.

STUDY DESIGN, SIZE, DURATION

This cohort study used data from The Health Improvement Network, a computerized primary care database of anonymized patient records from general practices across the UK, with prospective health records on over 1.7 million women between 1990 and 2010.

PARTICIPANTS/MATERIALS, SETTING AND METHODS

Our cohort included 1 776 746 women of reproductive age (age 15–49 years) who contributed one or more years of active general practice registration. We estimated rates of new clinically recorded fertility problems in these women using medical records and medications exclusively used to treat infertility. We assessed variation in age-specific incidence by socioeconomic deprivation quintile and geographic area using Poisson regression.

MAIN RESULTS AND THE ROLE OF CHANCE

The rate of incident recorded fertility problems was highest in women in the 30–34 year age group (10.9 per 1000 person-years), which equates to approximately 1% of women per annum in this age group. Lowest rates were in women in the 15–19 and 45–49 year age groups (0.7 and 0.4 per 1000 person-years, respectively). Overall rates did not vary by socioeconomic group, measured using quintiles of the Townsend index. Age-specific rates, however, varied substantially with socioeconomic deprivation quintile (P-value for interaction < 0.0001) such that up to age 25, women with more deprivation had more recorded fertility problems [rate ratio (RR) comparing most to least deprived 5.6, 95% confidence interval (CI) 4.4–7.2 at 15–20 years of age]. This reversed from age 25 to 39, when women with more deprivation had fewer recorded fertility problems (RR 0.6 95% CI 0.5–0.6 at age 30–34). After age 40, there was no socioeconomic gradient in absolute rates.

LIMITATIONS, REASONS FOR CAUTION

This is by far the largest population-based study to estimate clinically recorded fertility problems in women and the first in the UK to assess variation across such a broad age group from 15 to 49 years. Our data, however, did not capture women who experience difficulty in conceiving, but do not consult their general practitioner (GP) regarding fertility problems.

WIDER IMPLICATIONS OF THE FINDINGS

Compared with existing estimates, our measures of the extent and distribution of recorded fertility problems in primary care are more useful for GPs, primary care trusts and policy makers for the planning and delivery of fertility services. We have shown a high burden of infertility with little geographic variation; however, the significant burden in young, more deprived women needs recognition in light of age restrictions for treatment availability for infertility in the UK. Not only does treatment access need to be universal and more equitably allocated across socioeconomic groups, but also more resources are required to reduce fertility problems by targeting modifiable risk factors.

STUDY FUNDING/COMPETING INTEREST(S)

There was no direct source of funding for this research work. N.N.D. completed the work as part of an M.Sc., which was funded by Developing Solutions Scholarship provided by the International Office, University of Nottingham. J.W. is supported by a University of Nottingham/National Institute for Health Research (NIHR) Senior Clinical Research Fellowship.

TRIAL REGISTRATION NUMBER

Not applicable.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/960?rss=1

STUDY QUESTION

Could the protamine-1 to protamine-2 mRNA ratio serve as a biomarker to estimate the fertilizing capacity of sperm from men taking part in an IVF/ICSI programme?

SUMMARY ANSWER

The protamine mRNA ratio clearly discriminates between fertile and subfertile men and sperm with a normal protamine mRNA ratio exhibit a higher fertilizing capacity in IVF/ICSI.

WHAT IS KNOWN ALREADY

Aberrant sperm protamine ratios are associated with male factor infertility and mRNA ratio is comparable with protein ratio (due to transcriptional stop in elongating spermatids).

STUDY DESIGN, SIZE, DURATION

The study population was drawn from subfertile men, whose female partners participated in IVF or ICSI programmes between September 2010 and February 2012. Normozoospermic healthy volunteers served as controls. Sperm cells were lysed, mRNA extracted, reverse transcribed and subjected to real-time quantitative PCR using specific primer pairs for protamine-1 and protamine-2. Relative protamine-1 and protamine-2 mRNA levels were analysed with the Mann–Whitney U-test (two-tailed).

PARTICIPANTS/MATERIALS, SETTING, METHODS

Quantitative RT–PCR for protamines 1 and 2 has been performed in ejaculates from 32 normozoospermic volunteers (control, University Clinic Giessen, Germany) and 306 patients, whose female partners took part in an IVF (n = 76; University Clinic Hamburg, Germany and Shanghai Jiaotong University, China) or an ICSI (n = 230; University Clinic Munich, Germany and Kinderwunschzentrum Wiesbaden, Germany) programme.

MAIN RESULTS AND THE ROLE OF CHANCE

The sperm protamine mRNA ratio in normozoospermic men (0.98 ± 0.3) differed significantly from that of ICSI patients (Munich 0.81 ± 0.1; Wiesbaden 0.78 ± 0.2; P < 0.001), while processed samples obtained from IVF patients revealed a normal protamine mRNA ratio (Hamburg 1.0 ± 0.07; Shanghai 1.0 ± 0.54). Normal protamine mRNA ratios were associated with a significantly higher total motile sperm count and a significantly higher percentage of progressively motile sperm. Sperm with a normal protamine mRNA ratio revealed a higher fertilization capacity (fc) in both IVF (53.6% of patients with fc > 80%; P = 0.017) and ICSI (65.1% of patients with fc > 70%; P = 0.028).

LIMITATIONS, REASONS FOR CAUTION

The protamine mRNA ratio in an individual sperm cell used for ICSI may be different from the overall value obtained from a semen aliquot.

WIDER IMPLICATIONS OF THE FINDINGS

Data are in line with current literature and suggest the protamine mRNA ratio as a diagnostic marker to estimate the fertilizing capacity of sperm.

STUDY FUNDING

The German Research Foundation (DFG) to K.S., W.W. and A.P. (STE 892/9-2), as well as to A.S. and H.C.O. (SP721/1-3).

COMPETING INTEREST(S)

None.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/969?rss=1

STUDY QUESTION

What are the dropout rates in lifestyle intervention programs (LIPs) for overweight and obese infertile women and can intervention- or patient-related baseline factors associated with dropout be identified in these women?

SUMMARY ANSWER

The median dropout rate was 24% in overweight and obese infertile women who participated in a LIP; clinical useful intervention or patient-related factors associated with dropout could not be identified.

WHAT IS KNOWN ALREADY

Overweight and obese infertile women might improve their chance of conception when they improve their lifestyle and lose weight. Dropout from LIPs reduces the chance of losing considerable weight and is therefore considered to be an important limiting factor of the success of LIPs.

STUDY DESIGN, SIZE, DURATION

This systematic review included 15 studies published between January 1980 and December 2012.

PARTICIPANTS/MATERIALS, SETTING, METHODS

The included studies investigated the effect of LIPs for overweight and obese infertile women with infertility. From these studies, dropout rates and intervention- and patient-related baseline factors associated with dropout, as well as weight loss and pregnancy rates, were recorded.

MAIN RESULTS AND THE ROLE OF CHANCE

There were 15 studies identified, of which 10 reported dropout rates. The median dropout rate was 24% (range: 0–31%). Four studies reported baseline characteristics of women who dropped out, but modifiable predictors of dropout could not be identified. Weight loss and pregnancy rates were lower in women who dropped out than in women who completed the LIPs.

LIMITATIONS, REASONS FOR CAUTION

There were limited numbers of studies investigating patient-related factors associated with dropout. The heterogeneity in the studies precluded us from drawing firm conclusions on the relation between the type of intervention and dropout.

WIDER IMPLICATIONS OF THE FINDINGS

Dropout from LIPs is a major drawback because it predisposes to less weight loss and lower pregnancy rates. Identification of predictors of dropout is needed to identify overweight and obese infertile women who are prone for dropout. These women might benefit from extra support and monitoring, to potentially increasing adherence rates, weight loss and pregnancy chances.

STUDY FUNDING/COMPETING INTEREST(S)

M.A.Q.M. was supported by a research grant from the Dutch Organization for Health Research and Development (ZonMw). The department of obstetrics and gynaecology received research grants from Merck Sharpe and Dohme BV, feering pharmaceuticals, Merck Serono, the Netherlands.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/979?rss=1

STUDY QUESTION

What value can patients add to the development of guideline-based quality indicators for patient-centredness in fertility care?

SUMMARY ANSWER

Infertile patients mainly select different indicators and value different dimensions of patient-centredness (e.g. information and communication and access to care) than professionals (e.g. coordination and integration of care) during an indicator development process.

WHAT IS KNOWN ALREADY

Patient-centredness is an important dimension for the quality of fertility care. However, this dimension is not adequately evaluated by professionals, due to a lack of quality indicators. Furthermore, it is suggested that patients select different indicators for patient-centredness than professionals, although exact differences are unknown.

STUDY DESIGN, SIZE AND DURATION

The RAND-modified Delphi method (a two-step systematic consensus method) was used to develop two sets of quality indicators for patient-centredness. Similarities and differences in the indicators as well as in aspects of patient-centredness between patients' and professionals' sets of indicators were analysed descriptively.

PARTICIPANTS, SETTING, METHODS

The development of quality indicators for patient-centredness was based on the national multidisciplinary Network Guideline on infertility. Two panels participated: one patients' panel (n = 19) and one multidisciplinary professionals' panel (n = 15).

MAIN RESULTS AND THE ROLE OF CHANCE

From 119 formulated potential indicators of patient-centredness, the patients' panel selected a representative set of 16, while the professionals' panel selected 18. Five indicators were included in both sets. These regarded the need to perform IUI at least 6 days a week; report on treatment outcomes and complications; report on results of semen analyses in a standardized way; counsel infertile couples about the positive effects on their chance of pregnancy of the elimination of a harmful lifestyle and provide information on the negative consequences for achieving a pregnancy in case of a high BMI. Both patients and professionals put highest value on potential indicators of information and communication in fertility care. Patients also emphasized accessibility of care, whereas professionals emphasized coordination and integration as important quality measures for patient-centredness in fertility care.

LIMITATIONS, REASONS FOR CAUTION

First, the total number of developed indicators in the final set is relatively large (n = 29), which could be a first potential limitation in its use for accreditation and quality monitoring. Secondly, although panel members were asked to take reliability into account during the selection procedure, the indicators still need an evaluation of the measurability and the intra- and inter-observer reliability.

WIDER IMPLICATIONS OF THE FINDINGS

The final guideline-based indicator set consisting of 29 indicators represents a balanced set that is based on the expertise of all stakeholders, including patients. A next step should be the application of this set in a future practice test to assess the feasibility in daily practice. In our opinion, most quality indicators for patient-centredness could be used for monitoring and improving the quality of fertility care internationally, occasionally by a more broad interpretation (e.g. by replacing the general practitioners with other healthcare professionals engaged in the care process).

STUDY FUNDING/COMPETING INTEREST(S)

This study was supported by a research grant (number 150020015) from the Dutch Organisation for Health Research and Development (ZonMw) in a research programme on broadening and acceleration in multidisciplinary guideline development. The authors have no conflicts of interest to declare.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/987?rss=1

STUDY QUESTION

Is anxiety focused on the pregnancy outcome, known to be particularly salient in women conceiving through assisted reproductive technology (ART), related to difficult infant temperament?

SUMMARY ANSWER

While trait anxiety predicts infant temperament, pregnancy-focused anxiety is not associated with more difficult infant temperament.

WHAT IS KNOWN ALREADY

A large body of research has provided convincing evidence that fetal exposure to maternal anxiety and stress in pregnancy has adverse consequences for child neurodevelopmental, behavioural and cognitive development, and that pregnancy-specific anxiety (concerns related to the pregnancy outcome and birth) may be of particular significance. Women conceiving through ART are of particular interest in this regard. Research over more than 20 years has consistently demonstrated that while they do not differ from spontaneously conceiving (SC) women with respect to general (state and trait) anxiety, they typically report higher pregnancy-specific anxiety. While research suggests normal behavioural and developmental outcomes for children conceived through ART, there is some evidence of more unsettled infant behaviour during the first post-natal year.

STUDY DESIGN, SIZE, DURATION

The longitudinal cohort design followed 562 nulliparous women over a 7-month period, during the third trimester of pregnancy and at 4 months after birth.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Approximately equal numbers of nulliparous women conceiving through ART (n = 250) and spontaneously (SC: n = 262) were recruited through ART clinics and nearby hospitals in Melbourne and Sydney, Australia. Participants completed three anxiety measures (state, trait, pregnancy specific) at time 1 in the third trimester of pregnancy and a measure of infant temperament at time 2, 4 months after birth. At time 1, relevant socio-demographic, pregnancy (maternal age, smoking, alcohol, medications, medical complications) information was recorded and at time 2, information regarding childbirth (gestation, infant birthweight, mode of delivery) and post-natal (concurrent mood) variables was recorded and controlled for in analyses.

MAIN RESULTS AND THE ROLE OF CHANCE

In the third trimester of pregnancy, women conceiving through ART reported lower state and trait anxiety, but higher pregnancy-focused anxiety than their SC counterparts (all Ps < 0.05). Hierarchical regression analyses including mode of conception, all anxiety variables and relevant covariates indicated that while trait anxiety in pregnancy predicted more difficult infant temperament (P < 0.001), pregnancy specific and state anxiety did not. Mode of conception predicted infant temperament; with ART women reporting less difficult infant temperament (P < 0.001) than their SC counterparts.

LIMITATIONS, REASONS FOR CAUTION

The major limitations in the study are the reliance on a self-report measure of infant temperament and the fact that the study did not assess quality of caregiving which may moderate the effect of pregnancy anxiety on infant temperament.

WIDER IMPLICATIONS OF THE FINDINGS

This study is the first to our knowledge to prospectively examine the impact of gestational stress (pregnancy anxiety) on infant temperament in women conceiving through ART. Findings confirm existing research indicating that trait anxiety in pregnancy is associated with difficult infant temperament and suggest that pregnancy-specific anxiety (measured in the third trimester) is not implicated. These findings are reassuring for women conceiving through ART whose pregnancies may be characterized by particularly intense concerns about the wellbeing of a long sought after baby.

STUDY FUNDING/COMPETING INTEREST(S)

The study was funded by a grant from the Australian Research Council (ARC) and in kind and financial contributions from IVF Australia and Melbourne.

TRIAL REGISTRATION NUMBER

N/A.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/997?rss=1

STUDY QUESTION

How do young women, who were identified as carrying a BRCA gene mutation before they had children, approach reproductive decision-making and what are their attitudes towards reproductive genetic testing?

SUMMARY ANSWER

Reproductive decision-making within the context of cancer risk is complex and influenced by personal experiences of cancer. Younger women were not concerned with reproductive decision-making at the time of their genetic test; however, the impact on subsequent reproductive decision-making was considerable and left them with unanticipated dilemmas, such as having children who would be at risk of inheriting cancer predisposition, timing risk-reducing surgery and changing perceptions of responsibility.

WHAT IS KNOWN ALREADY

Individuals carrying gene mutations predisposing to hereditary breast/ovarian cancer have concerns about passing on the gene mutation to children.

STUDY DESIGN, SIZE, DURATION

Qualitative methodology and thematic analysis.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Data were collected through semi-structured interviews with 25 women aged 18–45 who had received a positive result for a BRCA1 or BRCA2 gene mutation while childless.

MAIN RESULTS AND THE ROLE OF CHANCE

Analysis revealed four central themes: (i) the impact of cancer on reproductive decision-making; (ii) motivation for genetic testing; (iii) risk management and timing of planning children; and (iv) optimism for future medical advancements.

LIMITATIONS, REASONS FOR CAUTION

This study explores the views of female BRCA carriers. Further research should explore the views of couples, men, and include samples with greater ethnic and social diversity.

WIDER IMPLICATIONS OF THE FINDINGS

This evidence highlights the need for reproductive decision-making to be addressed at the time of pretest genetic counselling. More information should be provided on reproductive options as well as counselling/support to guide women's reproductive decision-making and prenatal testing options at the time they undertake genetic testing.

STUDY FUNDING/COMPETING INTEREST(S)

This research was supported by Cancer Research UK (Number C1226 A7920) and NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and RMH. The authors have no conflicts of interest to declare.

TRIAL REGISTRATION NUMBER

Not applicable.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/1006?rss=1

STUDY QUESTION

What information is shared on Dutch internet forums with regard to infertility treatment in Belgium?

SUMMARY ANSWER

The online discussion mainly regards medical treatments, feelings and experiences, and financial implications. The general tone of the discussion on the forums about fertility treatment in Belgium is that Belgian clinics offer better quality of care.

WHAT IS KNOWN ALREADY

The internet is the most important source of information for cross-border patients. Many Dutch patients visit Belgian clinics for infertility treatment.

STUDY DESIGN, SIZE, DURATION

This study comprised an inductive thematic analysis of eight Dutch internet forums about infertility.

PARTICIPANTS/MATERIALS, SETTING, METHODS

All the threads that were active in a 15-month period (October 2010–December 2011) were retrieved and checked for relevance. This resulted in 77 threads containing 1813 posts that were used for thematic analysis.

MAIN RESULTS AND THE ROLE OF CHANCE

Eight themes emerged after data analysis: medical expertise and testing, feelings and experiences, costs, trying out different clinics, travel and waiting times, treatments in the Netherlands, cooperation between clinics/physicians and laws and regulations. Our analysis of shared patient experiences indicates that patients identify respect for the person behind the patient as the fundamental reason why quality of care is higher in Belgium. They define this respect as active involvement in the medical decision-making process, which is considered a form of patient-centred care.

LIMITATIONS, REASONS FOR CAUTION

The data from internet forums are not representative of the experience of Dutch IVF patients in Belgium. We are presenting a thematic analysis of information that circulates on the web, not making statements about IVF treatment in Belgium or the Netherlands.

WIDER IMPLICATIONS OF THE FINDINGS

This is the first study on what information (future) cross-border patients are likely to find when they look for information online.

STUDY FUNDING/COMPETING INTEREST(S)

W.V.H. has a Ph.D. grant and V.P. holds a Postdoctoral Mandate by the Flemish Foundation for Scientific Research (FWO-Vlaanderen). G.P. is supported by a full-time stipend at Ghent University. There are no competing interests.

TRIAL REGISTRATION NUMBER

N/A.

Source:
http://humrep.oxfordjournals.org/cgi/content/short/28/4/1013?rss=1

Human Reproduction System.mp4

By: Avtar Dhillon

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Human Reproduction System.mp4 - Video

BACKGROUND

Assisted reproduction technology (ART) is used worldwide, at increasing rates, and data show that some adverse outcomes occur more frequently than following spontaneous conception (SC). Possible explanatory factors for the well-known adverse perinatal outcome in ART singletons were evaluated.

METHODS

PubMed and Cochrane databases from 1982 to 2012 were searched. Studies using donor or frozen oocytes were excluded, as well as those with no control group or including <100 children. The main outcome measure was preterm birth (PTB defined as delivery <37 weeks of gestation), and a random effects model was used for meta-analyses of PTB. Other outcomes were very PTB, low-birthweight (LBW), very LBW, small for gestational age and perinatal mortality.

RESULTS

The search returned 1255 articles and 65 of these met the inclusion criteria. The following were identified as predictors for PTB in singletons: SC in couples with time to pregnancy (TTP) > 1 year versus SC singletons in couples with TTP ≤ 1 year [adjusted odds ratio (AOR) 1.35, 95% confidence interval (CI) 1.22, 1.50]; IVF/ICSI versus SC singletons from subfertile couples (TTP > 1 year; AOR 1.55, 95% CI 1.30, 1.85); conception after ovulation induction and/or intrauterine insemination versus SC singletons where TTP ≤ 1 year (AOR 1.45, 95% CI 1.21, 1.74); IVF/ICSI singletons versus their non-ART singleton siblings (AOR 1.27, 95% CI 1.08, 1.49). The risk of PTB in singletons with a ‘vanishing co-twin’ versus from a single gestation was AOR of 1.73 (95% CI 1.54, 1.94) in the narrative data. ICSI versus IVF (AOR 0.80, 95% CI 0.69–0.93), and frozen embryo transfer versus fresh embryo transfer (AOR 0.85, 95% CI 0.76, 0.94) were associated with a lower risk of PTB.

CONCLUSIONS

Subfertility is a major risk factor for adverse perinatal outcome in ART singletons, however, even in the same mother an ART singleton has a poorer outcome than the non-ART sibling; hence, factors related to the hormone stimulation and/or IVF methods per se also may play a part. Further research is required into mechanisms of epigenetic modification in human embryos and the effects of cryopreservation on this, whether milder ovarian stimulation regimens can improve embryo quality and endometrial conditions, and whether longer culture times for embryos has a negative influence on the perinatal outcome.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/2/87?rss=1

BACKGROUND

In response to the ongoing debate on the long-term effects of assisted reproduction technologies, such as IVF, we systematically reviewed and meta-analyzed available evidence on the association between controlled ovarian hyperstimulation for IVF and risk of ovarian, endometrial and cervical cancer.

METHODS

Eligible studies were identified and pooled effect estimates for relative risk (RR) were calculated by cancer type among two reference groups (general population or infertile women), through fixed- or random-effects models as appropriate.

RESULTS

Nine cohort studies were synthesized, corresponding to a total size of 109 969 women exposed to IVF, among whom 76 incident cases of ovarian, 18 of endometrial and 207 cases of cervical cancer were studied. The synthesis of studies with general population as the reference group pointed to a statistically significant positive association between IVF and increased risk for ovarian (RR = 1.50, 95% confidence interval (CI): 1.17–1.92) and endometrial (RR = 2.04, 95% CI: 1.22–3.43), but not cervical (RR = 0.86, 95% CI: 0.49–1.49) cancers. On the contrary, when infertile women were used as the reference group, no significant associations with ovarian, endometrial or cervical cancer types were noted (RR = 1.26, 95% CI: 0.62–2.55 RR = 0.45, 95% CI: 0.18–1.14 and RR = 5.70, 95% CI: 0.28–117.20, respectively).

CONCLUSIONS

IVF does not seem to be associated with elevated cervical cancer risk, nor with ovarian or endometrial cancer when the confounding effect of infertility was neutralized in studies allowing such comparisons. Of note, only one study provided follow-up longer than 10 years for the group exposed to IVF. Future cohort studies should preferably use infertile women as the reference group, rely on IVF-registered valid exposure data, adjust for a variety of meaningful confounders and adopt relatively longer follow-up periods before sound conclusions are drawn.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/2/105?rss=1

BACKGROUND

The goal of this systematic review and meta-analysis was to estimate the rate of compliance with assisted reproductive technologies (ART) and examine its relationship with treatment success rates.

METHODS

Six databases were systematically searched from 1978 to December 2011. Studies were included if they reported data on patient progression through three consecutive standard ART cycles. Compliance was estimated for the first three ART cycles (typical ART Regimen Compliance, TARC) and after the first and the second failed cycles (CAF1, CAF2). Treatment success rates for all patients who started ART and for those who fully complied with the three ART cycles were estimated.

RESULTS

Ten studies with data for 14 810 patients were included. TARC was 78.2% [95% confidence interval (CI) 68.8–85.3%], CAF1 was 81.8% (73.3–88.1%) and CAF2 was 75.3% (68.2–81.2%). The overall success rate was 42.7% (32.6–53.6%) for all patients starting ART and 57.9% (49.4–65.9%) for those who complied with three ART cycles. Compliance rates did not vary according to study quality, but TARC was higher for studies that reported data on doctor-censored patients versus those that did not (84.2% 95% CI 75.5–90.2 versus 70.6% 95% CI 58.3–80.5, P = 0.043). Analysis of funnel plots and the Egger test indicated publication bias for CAF1.

CONCLUSIONS

Findings from this meta-analysis should reassure clinics and patients that most patients are able to comply with three cycles of ART. Compliers could increase their chances of success by as much as 15%. A more detailed assessment of compliance requires monitoring long-term treatment trajectories through the creation of national registries.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/2/124?rss=1

BACKGROUND

The aim of this systematic review was to evaluate the fertility outcome after borderline ovarian tumor (BOT) management and the results of conservative management, risk of recurrence and alternative options.

METHODS

The search strategy was based on relevant terms concerning BOT using Medline and the Central Cochrane Library. Both early and advanced stages of serous and mucinous BOT were included, but not rare entities such as endometrioid, Brenner or clear-cell BOT because of their low incidence. We considered all articles—case reports, original studies, meta-analyses and reviews—in English and French.

RESULTS

Overall, 230 articles were screened of which 120 were retained for review. Most pregnancies were spontaneous but some data were obtained from studies analyzing the contribution of assisted reproductive technology (ART). However, not all studies differentiated spontaneous pregnancy from those obtained after fertility treatment including ovulation induction, intrauterine insemination and IVF. Conservative management of early stage BOT resulted in a pooled estimate for spontaneous pregnancy rate of 54% with a low risk of lethal recurrence (pooled estimate: 0.5%). In patients with advanced stage BOT, the spontaneous pregnancy rates was lower (34% in the single series reporting pregnancy rate in this context) and the risk of lethal recurrence increased (pooled estimate: 2%).

CONCLUSIONS

This systematic review underlines that fertility subsequent to treatment of BOT depends mainly on histology and initial staging to distinguish early from advanced stages. In patients with advanced stage BOT, several alternative options to conservative management are available to allow patients to conceive without compromising their prognosis.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/2/151?rss=1

BACKGROUND

During the seminiferous epithelial cycle, restructuring takes places at the Sertoli–Sertoli and Sertoli–germ cell interface to accommodate spermatogonia/spermatogonial stem cell renewal via mitosis, cell cycle progression and meiosis, spermiogenesis and spermiation since developing germ cells, in particular spermatids, move ‘up and down’ the seminiferous epithelium. Furthermore, preleptotene spermatocytes differentiated from type B spermatogonia residing at the basal compartment must traverse the blood–testis barrier (BTB) to enter the adluminal compartment to prepare for meiosis at Stage VIII of the epithelial cycle, a process also accompanied by the release of sperm at spermiation. These cellular events that take place at the opposite ends of the epithelium are co-ordinated by a functional axis designated the apical ectoplasmic specialization (ES)—BTB—basement membrane. However, the regulatory molecules that co-ordinate cellular events in this axis are not known.

METHODS

Literature was searched at http://www.pubmed.org and http://scholar.google.com to identify published findings regarding intercellular adhesion molecules (ICAMs) and the regulation of this axis.

RESULTS

Members of the ICAM family, namely ICAM-1 and ICAM-2, and the biologically active soluble ICAM-1 (sICAM-1) are the likely regulatory molecules that co-ordinate these events. sICAM-1 and ICAM-1 have antagonistic effects on the Sertoli cell tight junction-permeability barrier, involved in Sertoli cell BTB restructuring, whereas ICAM-2 is restricted to the apical ES, regulating spermatid adhesion during the epithelial cycle. Studies in other epithelia/endothelia on the role of the ICAM family in regulating cell movement are discussed and this information has been evaluated and integrated into studies of these proteins in the testis to create a hypothetical model, depicting how ICAMs regulate junction restructuring events during spermatogenesis.

CONCLUSIONS

ICAMs are crucial regulatory molecules of spermatogenesis. The proposed hypothetical model serves as a framework in designing functional experiments for future studies.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/2/167?rss=1

BACKGROUND

Three quarters of individuals infected with human immunodeficiency virus (HIV) are in their reproductive years and may consider pregnancy planning. Techniques have been developed which can minimize the risk of HIV transmission in these couples, and the current literature on this topic is reviewed here.

METHODS

We reviewed the literature for the following topics: risk of HIV transmission, effects of HIV infection on fertility, reproductive assistance in industrialized and low-income countries, pre-exposure chemoprophylaxis (PrEP) and timed intercourse in HIV-discordant couples for both male and female positivity. Relevant publications were identified through searches of the EMBASE Medline and PubMed databases, the Google-indexed scientific literature and periodic specialized magazines from the on-line Library Service of the University of Milan, Italy.

RESULTS

In serodiscordant couples in which the man is positive, the primary method used to prevent HIV transmission is ‘sperm washing’, followed by IUI or IVF. Data show that sperm washing in HIV-positive men has not produced seroconversion in women or their offspring; however, the evidence is limited. Recently, increasing evidence describing PrEP for HIV prevention has been published and PrEP could be an alternative to ART for fertile couples. Usually HIV-infected women undergo self-insemination around the time of ovulation. Few studies have been published on IVF outcome in HIV-infected women.

CONCLUSIONS

Assisted reproduction programmes should be integrated into global public health services against HIV. For HIV serodiscordant couples with infected men, sperm washing should be the first choice. However, timed intercourse and PrEP for HIV prevention has been reported. Recent data highlight the possible impairment of fertility in HIV-infected women. Efforts to design a multicentric study should be strengthened.

Source:
http://humupd.oxfordjournals.org/cgi/content/short/19/2/136?rss=1