Natural conception: repeated predictions over time.

STUDY QUESTION: How can we predict chances of natural conception at various time points in couples diagnosed with unexplained subfertility? SUMMARY ANSWER: We developed a dynamic prediction model that can make repeated predictions over time for couples with unexplained subfertility that underwent a fertility workup at a fertility clinic. WHAT IS KNOWN ALREADY: The most frequently used prediction model for natural conception (the 'Hunault model') estimates the probability of natural conception only once per couple, that is, after completion of the fertility workup. This model cannot be used for a second or third time for couples who wish to know their renewed chances after a certain period of expectant management. STUDY DESIGN, SIZE, DURATION: A prospective cohort studying the long-term follow-up of subfertile couples included in 38 centres in the Netherlands between January 2002 and February 2004. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary endpoint was time to natural conception, leading to an ongoing pregnancy. Follow-up time was censored at the start of treatment or at the last date of contact. In developing the new dynamic prediction model, we used the same predictors as the Hunault model, i.e. female age, duration of subfertility, female subfertility being primary or secondary, sperm motility and referral status. The performance of the model was evaluated in terms of calibration and discrimination. Additionally, we assessed the utility of the model in terms of the variability of the calculated predictions. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 4999 couples in the cohort, 1053 (21%) women reached a natural conception leading to an ongoing pregnancy within a mean follow-up of 8 months (5th and 95th percentile: 1-21). Our newly developed dynamic prediction model estimated the median probability of conceiving in the first year after the completion of the fertility workup at 27%. For couples not yet pregnant after half a year, after one year and after one and a half years of expectant management, the median probability of conceiving over the next year was estimated at 20, 15 and 13%, respectively. The model performed fair in an internal validation. The prediction ranges were sufficiently broad to aid in counselling couples for at least two years after their fertility workup. LIMITATIONS, REASONS FOR CAUTION: The dynamic prediction model needs to be validated in an external population. WIDER IMPLICATIONS OF THE FINDINGS: This dynamic prediction model allows reassessment of natural conception chances after various periods of unsuccessful expectant management. This gives valuable information to counsel couples with unexplained subfertility that are seen for a fertility workup. STUDY FUNDING/COMPETING INTERESTS: This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests.

Versican and vascular endothelial growth factor expression levels in peritoneal metastases from colorectal cancer are associated with survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can increase survival of colorectal cancer (CRC) patients with peritoneal metastases (PM). This treatment is associated with high morbidity and mortality rates. Therefore, improvement of patient selection is necessary. Assuming that the clinical phenotype is dictated by biological mechanisms, biomarkers could play a crucial role in this process. Since it is unknown whether and to what extent angiogenesis influences the course of disease in patients with PM, we investigated the expression of two angiogenesis-related markers and their relation to overall survival (OS) in CRC patients after CRS and HIPEC. Clinicopathological data and tissue samples were collected from 65 CRC patients with isolated metastases to the peritoneum that underwent CRS and HIPEC. Whole tissue specimens from PM were evaluated for versican (VCAN) expression, VEGF expression and microvessel density (MVD) by immunohistochemistry. The relation between these markers and OS was assessed using univariate and multivariate analysis. Associations between VEGF expression, VCAN expression, MVD and clinicopathological data were tested. High stromal VCAN expression was associated with high MVD (p = 0.001), better resection outcome (p = 0.003) and high T-stage (p = 0.027). High epithelial VCAN expression was associated with MVD (p = 0.007) and a more complete resection (p < 0.001). In multivariate analysis, simplified peritoneal cancer index (p = 0.001), VEGF expression levels (p = 0.012), age (p = 0.030), epithelial VCAN expression levels (p = 0.042) and lymph node status (p = 0.053) were associated with OS. Concluding, VCAN and VEGF were associated with survival in CRC patients with PM after CRS and HIPEC. Independent validation in a well-defined patient cohort is required to confirm the putative prognostic role of these candidate biomarkers.

Angiogenesis-Related Markers and Prognosis After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Metastatic Colorectal Cancer.

BACKGROUND: Patients presenting with peritoneal metastases (PM) of colorectal cancer (CRC) can be curatively treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Angiogenesis is under control of multiple molecules of which HIF1a, SDF1, CXCR4, and VEGF are key players. We investigated these angiogenesis-related markers and their prognostic value in patients with PM arising from CRC treated with CRS and HIPEC. PATIENTS AND METHODS: Clinicopathological data and tissue specimens were collected in 2 tertiary referral centers from 52 patients who underwent treatment for isolated PM of CRC. Whole tissue specimens were subsequently analyzed for protein expression of HIF1a, SDF1, CXCR4, and VEGF by immunohistochemistry. Microvessel density (MVD) was analyzed by CD31 immunohistochemistry. The relationship between overall survival (OS) and protein expression as well as other clinicopathological characteristics was analyzed. RESULTS: Univariate analysis showed that high peritoneal cancer index (PCI), resection with residual disease and high expression of VEGF were negatively correlated with OS after treatment with CRS and HIPEC (P < 0.01, P < 0.01, and P = 0.02, respectively). However, no association was found between the other markers and OS (P > 0.05). Multivariate analysis showed an independent association between OS and PCI, resection outcome and VEGF expression (multivariate HR: 6.1, 7.8 and 3.8, respectively, P ≤ 0.05). CONCLUSIONS: An independent association was found between high VEGF expression levels and worse OS after CRS and HIPEC. The addition of VEGF expression to the routine clinicopathological workup could help to identify patients at risk for early treatment failure. Furthermore, VEGF may be a potential target for adjuvant treatment in these patients.

Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival.

BACKGROUND: Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity. METHODS: The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)-BRCA pathway, ATM-ATR pathway and enzymatic activation of MMC. Functionality of the FA-BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20). RESULTS: High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA-BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04). CONCLUSIONS: Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.

Clinical prediction models to inform individualized decision-making in subfertile couples: a stratified medicine approach.

Infertility is defined as failure to conceive after 1 year of unprotected intercourse. This dichotomization into fertile versus infertile, based on lack of conception over 12-month period, is fundamentally flawed. Time to conception is strongly influenced by factors such as female age and whilst a minority of couples have absolute infertility (sterility), many are able to conceive without intervention but may take longer to do so, reflecting the degree of subfertility. This natural variability in time to conception means that subfertility reflects a prognosis rather than a diagnosis. Current clinical prediction models in fertility only provide individualized estimates of the probability of either treatment-independent pregnancy or treatment-dependent pregnancy, but do not take account of both. Together, prognostic factors which are able to predict natural pregnancy and predictive factors of response to treatment would be required to estimate the absolute increase in pregnancy chances with treatment. This stratified medicine approach would be appropriate for facilitating personalized decision-making concerning whether or not to treat subfertile patients. Published models are thus far of little value for decisions regarding when to initiate treatment in patients who undergo a period of, ultimately unsuccessful, expectant management. We submit that a dynamic prediction approach, which estimates the change in subfertility prognosis over the course of follow-up, would be ideally suited to inform when the commencement of treatment would be most beneficial in those undergoing expectant management. Further research needs to be undertaken to identify treatment predictive factors and to identify or create databases to allow these approaches to be explored. In the interim, the most feasible approach is to use a combination of previously published clinical prediction models.

Comparison of two models predicting IVF success; the effect of time trends on model performance.

STUDY QUESTION: How well does the recently developed UK model predicting the success rate of IVF treatment (the 2011 Nelson model) perform in comparison with a UK model developed in the early 1990s (the Templeton model)? SUMMARY ANSWER: Both models showed similar performance, after correction for the increasing success rate over time of IVF. WHAT IS KNOWN ALREADY: For counselling couples undergoing IVF treatment it is of paramount importance to be able to predict success. Several prediction models for the chance of success after IVF treatment have been developed. So far, the Templeton model has been recommended as the best approach after having been validated in several independent patient data sets. The Nelson model, developed in 2011 and characterized by the largest development sample containing the most recently treated couples, may well perform better. STUDY DESIGN, SIZE, DURATION: We tested both models in couples that were included in a national cohort study carried out in the Netherlands between the beginning of January 2002 and the end of December 2004. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed the IVF cycles of Dutch couples with primary infertility (n = 5176). The chance of success was calculated using the two UK models that had been developed using the information collected in the Human Fertilisation and Embryology Authority database. Women were treated in 1991-1994 (Templeton) or 2003-2007 (Nelson). The outcome of success for both UK models is the occurrence of a live birth after IVF but the outcome in the Dutch data is an ongoing pregnancy. In order to make the outcomes compatible, we used a factor to convert the chance of live birth to ongoing pregnancy and use the overall terms 'success or no success after IVF'. The discriminative ability and the calibration of both models were assessed, the latter before and after adjustment for time trends in IVF success rates. MAIN RESULTS AND THE ROLE OF CHANCE: The two models showed a similarly limited degree of discriminative ability on the tested data (area under the receiver operating characteristic curve 0.597 for the Templeton model and 0.590 for the Nelson model). The Templeton model underestimated the success rate (observed 21% versus predicted 14%); the Nelson model overestimated the success rate (observed 21% versus predicted 29%). When the models were adjusted for the changing success rates over time, the calibration of both models considerably improved (Templeton observed 21% versus predicted 20%; Nelson observed 21% versus predicted 24%). LIMITATIONS, REASONS FOR CAUTION: We could only test the models in couples with primary infertility because detailed information on secondary infertile couples was lacking in the Dutch data. This shortcoming may have negatively influenced the performance of the Nelson model. WIDER IMPLICATIONS OF THE FINDINGS: The changes in success rates over time should be taken into account when assessing prediction models for estimating the success rate of IVF treatment. In patients with primary infertility, the choice to use the Templeton or Nelson model is arbitrary.

Prenatal famine, birthweight, reproductive performance and age at menopause: the Dutch hunger winter families study.

STUDY QUESTION: Is there an association between acute prenatal famine exposure or birthweight and subsequent reproductive performance and age at menopause? SUMMARY ANSWER: No association was found between intrauterine famine exposure and reproductive performance, but survival analysis showed that women exposed in utero were 24% more likely to experience menopause at any age. WHAT IS KNOWN ALREADY: Associations between prenatal famine and subsequent reproductive performance have been examined previously with inconsistent results. Evidence for the effects of famine exposure on age at natural menopause is limited to one study of post-natal exposure. STUDY DESIGN, SIZE, DURATION: This cohort study included men and women born around the time of the Dutch famine of 1944-1945. The study participants (n = 1070) underwent standardized interviews on reproductive parameters at a mean age of 59 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were grouped as men and women with prenatal famine exposure (n = 407), their same-sex siblings (family controls, n = 319) or other men and women born before or after the famine period (time controls, n = 344). Associations of famine exposure with reproductive performance and menopause were analysed using logistic regression and survival analysis with competing risk, after controlling for family clustering. MAIN RESULTS AND THE ROLE OF CHANCE: Gestational famine exposure was not associated with nulliparity, age at birth of first child, difficulties conceiving or pregnancy outcome (all P> 0.05) in men or women. At any given age, women were more likely to experience menopause after gestational exposure to famine (hazard ratio 1.24; 95% CI 1.03, 1.51). The association was not attenuated with an additional control for a woman's birthweight. In this study, there was no association between birthweight and age at menopause after adjustment for gestational famine exposure. LIMITATIONS, REASON FOR CAUTION: Age at menopause was self-reported and assessed retrospectively. The study power to examine associations with specific gestational periods of famine exposure and reproductive function was limited. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support previous results that prenatal famine exposure is not related to reproductive performance in adult life. However, natural menopause occurs earlier after prenatal famine exposure, suggesting that early life events can affect organ function even at the ovarian level. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the NHLBI/NIH (R01 HL-067914). TRIAL REGISTRATION NUMBER: Not applicable.

Cytoreductive surgery and HIPEC for peritoneal metastases combined with curative treatment of colorectal liver metastases: Systematic review of all literature and meta-analysis of observational studies.

OBJECTIVE: Assess the overall outcome in colorectal cancer (CRC) patients that present with a combination of peritoneal metastases (PM) and liver metastases (CRLM) after curative resection and hyperthermic intraperitoneal chemotherapy (HIPEC) in the current literature. METHODS: A systematic literature search according to the PRISMA guidelines was conducted using the PubMed database of the U.S. National library of Medicine using the keywords: colorectal cancer, liver metastasis, extra-hepatic, peritoneal metastases, peritoneal carcinomatosis, cytoreductive surgery (CRS), HIPEC and combinations hereof. Papers focussing on CRS and HIPEC for PM combined with curative treatment of CRLM were included, provided sufficient information on survival outcomes could be extracted. Duplicate publications were excluded. Meta-analysis was performed using the method described by Tierney et al. RESULTS: After screening and full-text assessment of 39 papers, six articles were included containing data on combined PM and CRLM in patients treated with curative resection of both sites and HIPEC or early postoperative intraperitoneal chemotherapy (EPIC). Three articles provided enough statistical information for meta-analysis. Pooled hazard ratio (HR) was extracted from survival curves and was 1.24 (CI 0.96-1.60). A comparison was made with patients presenting with isolated PM undergoing CRS and HIPEC and with patients with disseminated disease undergoing (modern) systemic chemotherapy. CONCLUSIONS: In the absence of randomized controlled studies, we found in this systematic review and meta-analysis of patients with a combination of colorectal metastases in the liver as well as in the peritoneum show a trend towards a lower overall survival after curative resection and HIPEC, when compared to patients with isolated peritoneal metastases after CRS and HIPEC (pooled HR1.24, CI 0.96-1.60). However, patients with metastatic CRC show a tendency towards increased median overall survival after CRS and HIPEC combined with resection of liver metastases when compared to treatment with modern systemic chemotherapy.

Understanding molecular mechanisms in peritoneal dissemination of colorectal cancer : future possibilities for personalised treatment by use of biomarkers.

When colorectal cancer (CRC) metastasizes, this is mostly to the liver via the portal circulation. In addition, 10-25 % of CRC patients eventually show metastases in the peritoneum. A selection of these patients is treated with cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC). However, several clinical needs still exist in which biomarkers could play an important role. Relatively little is known about the biology of peritoneal spread of CRC. The development of peritoneal metastases (PM) involves several steps, including: detachment of malignant cells; anoikis evasion; attachment to and invasion of the peritoneal surface ultimately ending in a colonization phase in which the malignant cells thrive in the newly formed niche. In this paper, we provide an overview of molecules associated with peritoneal dissemination and explore the clinical possibilities of these candidate biomarkers. A literature search was conducted using the PubMed database of the U.S. National Library of Medicine and Medline to identify studies on the biological behaviour of PM of CRC. In a series of over 100 studies on PM published between 1990 and 2010, IGF-1, HIF1α, VEGF, EGFR and ITGB1 emerge as the most interesting candidates for possible clinical application. Even though these promising candidate biomarkers have been identified, all of these require extensive further validation prior to clinical application. Yet, the pace of the omics revolution makes that the question is not if, but when biomarkers will be introduced to improve diagnosis and ultimately outcome of patients with PM due to CRC.

High lymph node yield is related to microsatellite instability in colon cancer.

BACKGROUND: Lymph node (LN) yield in colon cancer resection specimens is an important indicator of treatment quality and has especially in early-stage patients therapeutic implications. However, underlying disease mechanisms, such as microsatellite instability (MSI), may also influence LN yield, as MSI tumors are known to exhibit more prominent lymphocytic antitumor reactions. The aim of the present study was to investigate the association of LN yield, MSI status, and recurrence rate in colon cancer. METHODS: Clinicopathological data and tumor samples were collected from 332 stage II and III colon cancer patients. DNA was isolated and PCR-based MSI analysis performed. LN yield was defined as "high" when 10 or more LNs were retrieved and "low" in case of fewer than 10 LNs. RESULTS: Tumors with high LN yield were significantly associated with the MSI phenotype (high LN yield: 26.3% MSI tumors vs low LN yield: 15.1% MSI tumors; P=.01), mainly in stage III disease. Stage II patients with high LN yield had a lower recurrence rate compared with those with low LN yield. Patients with MSI tumors tended to develop fewer recurrences compared with those with MSS tumors, mainly in stage II disease. CONCLUSIONS: In the present study, high LN yield was associated with MSI tumors, mainly in stage III patients. Besides adequate surgery and pathology, high LN yield is possibly a feature caused by biologic behavior of MSI tumors.

Anti-mullerian hormone predicts menopause: a long-term follow-up study in normoovulatory women.

CONTEXT: It has been hypothesized that a fixed interval exists between age at natural sterility and age at menopause. Both events show considerable individual variability, with a range of 20 yr. Correct prediction of age at menopause could open avenues of individualized prevention of age-related infertility and other menopause-related conditions, like cardiovascular disease and breast carcinoma. OBJECTIVE: The aim of this study was to explore the ability of ovarian reserve tests to predict age at menopause. DESIGN AND SETTING: We conducted a long-term follow-up study at an academic hospital. PARTICIPANTS: A total of 257 normoovulatory women (age, 21-46 yr) were derived from three cohorts with highly comparable selection criteria. INTERVENTIONS: Anti-Müllerian hormone (AMH), antral follicle count, and FSH were assessed at time 1 (T1). At time 2 (T2), approximately 11 yr later, cycle status (strictly regular, menopausal transition, or postmenopause) and age at menopause were inventoried. MAIN OUTCOME MEASURES: Accuracy of the ovarian reserve tests in predicting time to menopause was assessed by Cox regression, and a nomogram was constructed for the relationship between age-specific AMH concentrations at T1 and age at menopause. RESULTS: A total of 48 (19%) women had reached postmenopause at T2. Age, AMH, and antral follicle count at T1 were significantly related with time to menopause (P < 0.001) and showed a good percentage of correct predictions (C-statistic, 0.87, 0.86, and 0.84, respectively). After adjusting for age, only AMH added to this prediction (C-statistic, 0.90). From the constructed nomogram, it appeared that the normal distribution of age at menopause will shift considerably, depending on the individual age-specific AMH level. CONCLUSIONS: AMH is highly predictive for timing of menopause. Using age and AMH, the age range in which menopause will subsequently occur can be individually calculated.

The use of fluorescent dyes and probes in surgical oncology.

AIMS AND BACKGROUND: Improved visualization of surgical targets inside of the patient helps to improve radical resection of the tumor while sparing healthy surrounding tissue. In order to achieve an image, optical contrast must be generated by properties intrinsic to the tissue, or require the attachment of special visualization labels to the tumor. In this overview the current status of the clinical use of fluorescent dyes and probes are reviewed. METHODS: In this review, all experimental and clinical studies concerning fluorescent imaging were included. In addition, in the search for the optimal fluorescent imaging modality, all characteristics of a fluorescent dye were described. FINDINGS AND CONCLUSIONS: Although the technique of imaging through fluorescence sounds promising and several animal models show efficacy, official approval of these agents for further clinical evaluation, is eagerly awaited.

HER-family gene amplification and expression in resected pancreatic cancer.

AIMS: Despite surgical resection, pancreatic cancer carries a poor prognosis. In search for new molecular therapeutic targets, we investigated the expression of the HER-family and gene amplification of HER-2 in pancreatic adenocarcinomas of different stages. METHODS: Tissue of 45 resected patients was analyzed for all HER-family 1-4 expression by immunohistochemistry and HER-2 gene amplification was assessed by multiplex ligation-dependent probe amplification and chromogenic in situ hybridization. The type of surgery, location, stage and grade of the tumor, as well as involvement of the resection margins were correlated with HER-expressions and univariate and multivariate survival analysis performed. RESULTS: Normal pancreatic tissue lacked HER1-2 expression, but did show HER3-4 expression. In cancers, no membranous overexpression of HER-1 and HER-2 was seen nor gene amplification of HER-2 found. HER-3, HER-4 is physiologically expressed in the normal pancreas and loss of cytoplasmic HER-3 and HER-4 expression was seen in 33/45 (73%) and 8/45 (18%) of pancreatic cancers. Cytoplasmic HER-3 expression decreased from early to late stage (p=0.05). HER-4 expression was not associated with survival, stage or tumor grade. There were no statistically significant differences in HER1-4 expression between the papilla of Vater (n=13) and non-papilla cancers (n=32). Multivariate survival analysis showed only stage to be of independent prognostic value (p=0.015). CONCLUSIONS: HER-1 and HER-2 are not overexpressed in pancreatic cancers. HER-3 and HER-4 are expressed in the normal pancreas but expression is lost in pancreatic cancer. HER-targeted therapy in pancreatic cancer is not supported by HER-expression of the tumor.

[Sensible family planning: pitfalls and dilemmas]. / Verstandige gezinsplanning: valkuilen en dilemma's.

In a recent article in this journal it was stated that Dutch women were sensible in having their first child between the ages of 25 and 35 years. One of the conclusions was that associated health risks increase after the age of 35 but are still acceptable even at the age of 40. We demonstrate that these conclusions were based on flawed assumptions. Postponing pregnancy until after the age of 30 increases the risks of infertility and breast cancer. Motherhood at a later age is associated with an increase in obstetrical complications, miscarriage and other adverse effects on the child. Therefore, for couples planning a family with 2 children or more, it would be sensible to have the first pregnancy not long after the mother reaches the age of 30 years, or even earlier. Couples should be informed on the risks of late parenthood in order to be able to take the right decisions concerning family planning.

[Reduction of patient discomfort, risks and costs, but not pregnancies, by a mild strategy for in-vitro fertilisation]. / Minder risico's, patiëntenongemak en kosten, maar niet minder zwangerschappen in de milde behandelstrategie voor ivf.

OBJECTIVE: To compare a so-called mild in-vitro fertilisation (IVF) treatment strategy with the standard IVF treatment on the following aspects: the chance of a pregnancy resulting in full-term live birth within 1 year, patient discomfort, multiple pregnancies, and costs. DESIGN: Randomised, open-label, prospective trial (www.controlledtrials.com, number ISRCTN35766970). METHOD: 404 patients were assigned to undergo either a mild treatment, consisting of ovarian stimulation with a gonadotrophin releasing hormone (GnRH) antagonist combined with single embryo transfer, or the standard treatment consisting of prolonged stimulation with a GnRH agonist combined with the transfer of two embryos. The primary outcome measures were: (1) the percentage of cumulative pregnancies within one year after randomisation leading to full-term live birth; (2) total costs per couple and child up to 6 weeks after expected delivery; and (3) overall patient discomfort. Analysis was done according to the intention-to-treat principle and was intended to show that the mild treatment was not inferior to the standard treatment; the non-inferiority threshold was -12.5%. RESULTS: The proportion of cumulative pregnancies resulting in full-term live birth after 1 year was 43.4% in the mild and 44.7% in the standard treatment group. The lower limit of the one-sided 95% confidence interval was equal to -9.8%. The respective proportion of couples with multiple pregnancies was 0.5% versus 13.1% (p < 0.0001), and the average total costs were Euro 8,333.- versus Euro 10,745.- (difference: Euro 2,412.-, 95% CI: 703-4,131). There were no statistically significant differences between the groups with regard to anxiety, depression, physical discomfort, and sleep quality. CONCLUSION: After 1 year of treatment, the cumulative percentage of pregnancies leading to full-term live birth and the total patient discomfort were the same for the mild treatment (average 2.3 IVF-cycles) and the standard treatment (average 1.7 IVF-cycles). The mild treatment significantly reduced the number of multiple pregnancies and the overall costs.

Minimally invasive pediatric surgery: Increasing implementation in daily practice and resident's training.

BACKGROUND: In 1998, the one-year experience in minimally invasive abdominal surgery in children at a pediatric training center was assessed. Seven years later, we determined the current status of pediatric minimally invasive surgery in daily practice and surgical training. METHODS: A retrospective review was undertaken of all children with intra-abdominal operations performed between 1 January 2005 and 31 December 2005. RESULTS: The type of operations performed ranged from common interventions to demanding laparoscopic procedures. 81% of all abdominal procedures were performed laparoscopically, with a complication rate stable at 6.9%, and conversion rate decreasing from 10% to 7.4%, compared to 1998. There were six new advanced laparoscopic procedures performed in 2005 as compared to 1998. The children in the open operated group were significantly smaller and younger than in the laparoscopic group (p < 0.001 and p = 0.001, respectively). The majority (64.2%) of the laparoscopic procedures were performed by a trainee. There was no difference in the operating times of open versus laparoscopic surgery, or of procedures performed by trainees versus staff surgeons. Laparoscopy by trainees did not have a negative impact on complication or conversion rates. CONCLUSIONS: Laparoscopy is an established approach in abdominal procedures in children, and does not hamper surgical training.

[The consequences of postponing pregnancy]. / Gevolgen van uitstel van zwangerschap.

The postponement of childbearing is determined by societal factors and is related to the fact that it is often difficult for women to combine an education, a job or a career with having children and taking care of a family. Especially gynaecologists are increasingly confronted with women who undergo the medical consequences of such postponement. Postponing the first pregnancy is accompanied by an increased risk of unwanted infertility. If women do succeed in becoming pregnant later in life, there is an increased risk of complications during pregnancy and delivery. The child runs a greater risk of chromosomal aberrations and of mental and physical handicaps related to increased numbers of premature births and fertility treatments. All these problems begin to increase after age 30, but especially after age 35. Finally, the risk of breast cancer is also increased if a woman delays the birth of her first child or remains childless.

Cumulative live birth rates following IVF in 41- to 43-year-old women presenting with favourable ovarian reserve characteristics.

For women aged 41-43 years old, success rates in IVF are generally poor. This study aimed to assess cumulative live birth rate related to treatment costs over a maximum of three IVF cycles in selected women who were considered to still have adequate ovarian reserve. Fifty-five patients (38% of the total cohort, n = 144) were excluded from IVF treatment based on low antral follicle count (<5 follicles) and/or elevated basal FSH (>15 IU/l). Of those admitted, 66 (74%) actually started and completed a total of 125 IVF/intracytoplasmic sperm injection cycles. Treatment resulted in 10 live births (8% per cycle). Kaplan-Meier survival analysis revealed a realistic cumulative live birth rate after three cycles of 17%. The direct medical costs per live birth were calculated to be approximately 44,000 euro. These results show that selection towards favourable ovarian reserve status in the female age group 41-43 years yielded disappointing results in terms of cumulative live birth rates after IVF. In view of the costs raised per live birth, improvement of selection parameters for treatment in this age group is warranted.

Intra-uterine insemination for unexplained subfertility.

BACKGROUND: Intra-uterine insemination (IUI) is a widely used fertility treatment for couples with unexplained subfertility. Although IUI is less invasive and less expensive than in vitro fertilisation (IVF), the safety of IUI in combination with ovarian hyperstimulation (OH) is debated. The main concern about IUI treatment with OH is the increase in multiple pregnancy rates. OBJECTIVES: To determine whether for couples with unexplained subfertility IUI improves the live birth rate compared with timed intercourse (TI), both with and without ovarian hyperstimulation. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorder and Subfertility Group Trials Register (searched March 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 4), MEDLINE (1966 to November 2005), EMBASE (1980 to November 2005), SCIsearch and reference lists of articles. Authors of identified studies were contacted for missing or unpublished data. SELECTION CRITERIA: Truly randomised controlled trials (RCTs) with at least one of the following comparisons were included: --IUI versus TI, both in a natural cycle; --IUI versus TI, both in a stimulated cycle; --IUI in a natural cycle versus IUI in a stimulated cycle; --IUI with OH versus TI in natural cycle; --IUI in a natural cycle versus TI with OH. Only couples with unexplained subfertility were included. DATA COLLECTION AND ANALYSIS: Quality assessment and data extraction were performed independently by two review authors. Outcomes were extracted and the data were pooled. Subgroup analyses and sensitivity analyses were done where possible. MAIN RESULTS: In the six trials where IUI was compared with TI, both in stimulated cycles, there was evidence of an increased chance of pregnancy (six RCTs, 517 women: OR 1.68, 95% CI 1.13 to 2.50). A significant increase in pregnancy rate was also found for women where IUI with OH was compared with IUI in a natural cycle (three RCTs, 415 women: OR 2.33, 95% CI 1.46 to 3.71). However, the trials provided insufficient data to investigate the impact of IUI with or without OH on several important outcomes including live birth, multiple pregnancies, miscarriage and risk of ovarian hyperstimulation. There was no evidence of a difference in pregnancy rate for IUI with OH compared with TI in a natural cycle (one RCT, 51 women: OR 4.05, 95% CI 0.39 to 41.87). No RCTs were found for the other two comparisons. AUTHORS' CONCLUSIONS: There is evidence that IUI with OH increases the live birth rate compared to IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared to TI both in stimulated cycles. There is insufficient data on multiple pregnancies and other adverse events for treatment with OH. Therefore, couples should be fully informed about the risks of IUI and OH as well as alternative treatment options.