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A previous chlamydia infection did not result in fewer pregnant women, but among women with a pregnancy intention, time to pregnancy was longer compared with women without a previous infection. Supplemental digital content is available in the text., Background A Chlamydia trachomatis infection (chlamydia) can result in tubal factor infertility in women. To assess if this association results in fewer pregnant women, we aimed to assess pregnancy incidences and time to pregnancy among women with a previous chlamydia infection compared with women without one and who were participating in the Netherlands Chlamydia Cohort Study (NECCST). Methods The NECCST is a cohort of women of reproductive age tested for chlamydia in a chlamydia screening trial between 2008 and 2011 and reinvited for NECCST in 2015 to 2016. Chlamydia status (positive/negative) was defined using chlamydia screening trial–nucleic acid amplification test results, chlamydia immunoglobulin G presence in serum, or self-reported chlamydia infections. Data on pregnancies were collected via questionnaires in 2015–2016 and 2017–2018. Overall pregnancies (i.e., planned and unplanned) and time to pregnancy (among women with a pregnancy intention) were compared between chlamydia-positive and chlamydia-negative women using Cox regressions. Results Of 5704 women enrolled, 1717 (30.1%; 95% confidence interval [CI], 28.9–31.3) women was chlamydia positive. Overall pregnancy proportions were similar in chlamydia-positive and chlamydia-negative women (49.0% [95% CI, 46.5–51.4] versus 50.5% [95% CI, 48.9–52.0]). Pregnancies per 1000 person-years were 53.2 (95% CI, 51.5–55.0) for chlamydia negatives and 83.0 (95% CI, 78.5–87.9) for chlamydia positives. Among women with a pregnancy intention, 12% of chlamydia-positive women had a time to pregnancy of >12 months compared with 8% of chlamydia negatives (P < 0.01). Conclusions Overall pregnancy rates were not lower in chlamydia-positive women compared with chlamydia-negative women, but among women with a pregnancy intention, time to pregnancy was longer and pregnancy rates were lower in chlamydia-positive women. Trial registration number: Dutch Trial Register NTR-5597.

STUDY QUESTION Do different oxygen levels during human IVF embryo culture affect embryo utilization, cumulative IVF success rates per cycle and neonatal birthweight? SUMMARY ANSWER After 2 days of culture, a lower oxygen level (5%) leads to more good-quality embryos and more embryos that can be cryopreserved, and thereby to a higher cumulative live birth rate per cycle when compared to embryo culture in 20% oxygen, while birthweights are similar. WHAT IS KNOWN ALREADY Several studies have compared IVF outcome parameters after embryo culture in a more physiological level of 5% oxygen and the atmospheric level of 20%. Although there is consensus that embryo development improves in 5% oxygen, effects on pregnancy and live birth rates are mainly seen in blastocyst, but not cleavage-stage transfers. A major drawback of these studies is that only fresh embryo transfers were included, not taking additional frozen-thawed transfers from these cycles into account. This might have underestimated the effects of oxygen level, especially in cleavage-stage embryo transfers. Furthermore, little is known about the effect of oxygen level during culture on birthweight. STUDY DESIGN, SIZE, DURATION This is a cohort study in 871 consecutive patients who had an IVF cycle between January 2012 and December 2013, and 5–7 years follow-up to allow transfer of frozen-thawed embryos. Based on daily availability of positions in the incubators, all oocytes and embryos of one cycle were allocated to one of the three incubators with traditional ambient oxygen levels (6% CO2 and 20% O2 in air), or to a fourth incubator that was adjusted to have low oxygen levels of 5% (6% CO2, 5% O2 and 89% N2). Embryos were cultured under 5 or 20% oxygen until Day 2 or 3, when embryos were transferred or cryopreserved, respectively. Clinical and other laboratory procedures were similar in both groups. PARTICIPANTS/MATERIALS, SETTING, METHODS To compare embryo characteristics and (cumulative) pregnancy outcomes between the two oxygen groups, for each patient only the first cycle in the study period was included in the analysis, resulting in 195 cycles in the 5% group (1627 oocytes) and 676 in the 20% oxygen group (5448 oocytes). Embryo characteristics were analysed per cycle and per embryo and were corrected for maternal age, cycle rank order, fertilization method (IVF or ICSI) and cause of subfertility. Perinatal data from the resulting singletons (n = 124 after fresh and 45 after frozen-thawed embryo transfer) were collected from delivery reports from the hospitals or midwife practices. MAIN RESULTS AND THE ROLE OF CHANCE In the 5% oxygen group, there were significantly more embryos of good quality (45.8 versus 30.9% in the 20% group, adjusted odds ratio (OR) [95% CI] = 1.9 [1.6–2.4]). This did not result in higher live birth rates per cycle, but after fresh transfers more good-quality spare embryos could be cryopreserved (46.1 versus 29.7%, adjusted OR [95% CI] = 2.0 [1.7–2.5]). After a follow-up period of 5–7 years, in which 82.4% of the cryopreserved embryos from the 5% oxygen group and 85.4% from the 20% oxygen group were thawed, the percentage of patients with at least one live birth resulting from the study cycle was significantly higher in the low oxygen group (adjusted OR [95% CI] = 1.5 [1.01–2.2]). In 124 live born singletons from fresh embryo transfers and in 45 from transfers of cryopreserved embryos, birthweight was similar in both oxygen groups after correction for confounding factors. LIMITATIONS, REASONS FOR CAUTION This is a retrospective study, and treatment allocation was not randomised. The study was not powered for a predefined birthweight difference. With the number of live births in our study, small differences in birthweight might not have been detected. The selection of embryos to be cryopreserved was based on embryo morphology criteria that might be different in other clinics. WIDER IMPLICATIONS OF THE FINDINGS Improved embryo utilization by more cryopreservation leading to higher cumulative live birth rates per cycle favours the use of 5% instead of 20% oxygen during human IVF embryo culture. This study also demonstrates that for comparison of different IVF treatment regimens, the cumulative outcome, including transfers of fresh and frozen-thawed embryos, is to be preferred instead of analysis of fresh embryo transfers only. STUDY FUNDING/COMPETING INTEREST(S) No external funding was received for this study. None of the authors has a conflict of interest to declare. TRIAL REGISTRATION NUMBER NA

STUDY QUESTION Do children conceived by ART have an increased risk of cancer?SUMMARY ANSWER Overall, ART-conceived children do not appear to have an increased risk of cancer.WHAT IS KNOWN ALREADY Despite the increasing use of ART, i.e. IVF or ICSI worldwide, information about possible long-term health risks for children conceived by these techniques is scarce.STUDY DESIGN, SIZE, DURATION A nationwide historical cohort study with prospective follow-up (median 21 years), including all live-born offspring from women treated with subfertility treatments between 1980 and 2001.PARTICIPANTS/MATERIALS, SETTING, METHODS All offspring of a nationwide cohort of subfertile women (OMEGA study) treated in one of the 12 Dutch IVF clinics or two fertility clinics. Of 47 690 live-born children, 24 269 were ART-conceived, 13 761 naturally conceived and 9660 were conceived naturally or through fertility drugs, but not by ART. Information on the conception method of each child and potential confounders were collected through the mothers' questionnaires and medical records. Cancer incidence was ascertained through linkage with The Netherlands Cancer Registry from 1 January 1989 until 1 November 2016. Cancer risk in ART-conceived children was compared with risks in naturally conceived children from subfertile women (hazard ratios [HRs]) and with the general population (standardized incidence ratios [SIRs]).MAIN RESULTS AND THE ROLE OF CHANCE The median follow-up was 21 years (interquartile range (IQR): 17-25) and was shorter in ART-conceived children (20 years, IQR: 17-23) compared with naturally conceived children (24 years, IQR: 20-30). In total, 231 cancers were observed. Overall cancer risk was not increased in ART-conceived children, neither compared with naturally conceived children from subfertile women (HR: 1.00, 95% CI 0.72-1.38) nor compared with the general population (SIR = 1.11, 95% CI: 0.90-1.36). From 18 years of age onwards, the HR of cancer in ART-conceived versus naturally conceived individuals was 1.25 (95% CI: 0.73-2.13). Slightly but non-significantly increased risks were observed in children conceived by ICSI or cryopreservation (HR = 1.52, 95% CI: 0.81-2.85; 1.80, 95% CI: 0.65-4.95, respectively). Risks of lymphoblastic leukemia (HR = 2.44, 95% CI: 0.81-7.37) and melanoma (HR = 1.86, 95% CI: 0.66-5.27) were non-significantly increased for ART-conceived compared with naturally conceived children.LIMITATIONS, REASONS FOR CAUTION Despite the large size and long follow-up of the cohort, the number of cancers was rather small for subgroup analyses as cancer in children and young adults is rare.WIDER IMPLICATIONS OF THE FINDINGS Overall, ART-conceived children do not appear to have an increased cancer risk after a median follow-up of 21 years. This large study provides important results, enabling physicians to better inform couples considering ART about the long-term safety of ART for their children. However, larger studies with prolonged follow-up are needed to investigate cancer risk in adults and in children conceived by ICSI and/or from cryopreserved embryos.STUDY FUNDING/COMPETING INTEREST(S) This work was supported by The Dutch Cancer Society (NKI 2006-3631) which funded the OMEGA-women's cohort and Children Cancer Free (KIKA;147) which funded the OMEGA-offspring cohort. We declare no competing interests.

STUDY QUESTION: Do age, ovulatory status, severity of obesity and body fat distribution affect the effectiveness of lifestyle intervention in obese infertile women? SUMMARY ANSWER: We did not identify a subgroup in which lifestyle intervention increased the healthy live birth rate however it did increase the natural conception rate in anovulatory obese infertile women. WHAT IS KNOWN ALREADY: Obese women are at increased risk of infertility and are less likely to conceive after infertility treatment. We previously demonstrated that a 6-month lifestyle intervention preceding infertility treatment did not increase the rate of healthy live births (vaginal live birth of a healthy singleton at term) within 24 months of follow-up as compared to prompt infertility treatment in obese infertile women. Natural conceptions occurred more frequently in women who received a 6-month lifestyle intervention preceding infertility treatment. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of a multicentre RCT (randomized controlled trial), the LIFEstyle study. Between 2009 and 2012, 577 obese infertile women were randomly assigned to a 6-month lifestyle intervention followed by infertility treatment (intervention group) or to prompt infertility treatment (control group). Subgroups were predefined in the study protocol, based on frequently used cut-off values in the literature: age (≥36 or

Problem Tubal factor infertility (TFI) is a severe complication of genital Chlamydia trachomatis infections. In fertility workup, chlamydia antibody test (CAT) is used to predict TFI. The predictive value for TFI of most commonly used CAT is moderate. Method of study A total of 183 infertile Dutch Caucasian women were included in this study. All underwent tubal patency testing (hysterosalpingography [HSG] or laparoscopy). Cases had TFI, and controls had no TFI (ie normal findings during HSG or laparoscopy). TFI was categorized based on severity (TFI 1-TFI 4). This study investigated the predictive values of major outer membrane protein (MOMP), translocated actin-recruiting phosphoprotein (TARP), chlamydial protease-like activity factor (CPAF), heat shock protein-60 (HSP60) and outer membrane protein 2 (OMP2) for TFI. A predictive algorithm is developed to detect TFI with a high certainty based on combinations of antibody titres. Serum was tested with the Mikrogen recomLine immunoblot and quantified with the recomScan. A greedy algorithm that explores all possible antibody combinations was developed. Results Significant differences in the distributions of antigen titres between cases and controls were observed for CPAF (P = 0.0021), HSP60 (P = 0.0061), MOMP (P = 0.0497) and OMP2 (P = 0.0016). Single antibodies could not discriminate between TFI and controls by themselves. The greedy algorithm performs better in specificity, positive predictive value (PPV), accuracy and clinical utility index than the original Mikrogen algorithm. CPAF combined with HSP60 identified 18.2% of TFI cases with 100% certainty. Most of the TFI 4 cases were identified with cut-offs of CPAF > 10.7 or OMP2 > 3.9. Conclusion This proof-of-principle study shows that combinations of antibodies in serum are predictive for TFI. A commercially available test can be adapted to predict TFI with a 100% specificity.

Objectives Chlamydia trachomatis (CT) IgG serology is used in many fertility clinics in order to estimate the risk for tubal factor infertility (TFI) in the fertility work-up. The predictive value for TFI of the currently used mono-target CT serology test should be improved. This study compares the performance of the new multi-target Mikrogen recomWell CT IgG ELISA with the Mikrogen recomLine CT immunoblot and visualizes distribution of individual antibodies in serum with the immunoblot in order to potentially improve the current CT IgG serology test that is clinically used. Methods Study population consisted of 183 Dutch Caucasian infertile women who underwent laparoscopy and/or hysterosalpingography. 48 women had TFI, 135 were controls. Serum was tested with Mikrogen CT IgG ELISA, which detects 3 CT IgG antibodies in one well, and Mikrogen CT immunoblot, which can individually detect 5 CT IgG antibodies. Tests were compared based on the results in general and in the case and control group also taking the individual antibodies into account. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), Kappa value and distribution of individual antibodies in positive samples were calculated. Results In 183 patients 51% tested positive in the ELISA versus 35% in the immunoblot. 32% versus 65% tested negative. Difference between PPV was not statistically significant (33% and 39% respectively) and NPV in both tests was 81%. Difference in sensitivity and specificity was statistically significant, respectively 65% vs. 52% and 54% vs. 71%. Kappa was only 45%. 64.5% of samples that tested positive with ELISA were positive for at least 4 individual CT antibodies with the immunoblot. Conclusion The concordance between CT ELISA and CT immunoblot is moderate. Due to separate criteria for positivity of both tests there is a significant difference in sensitivity and specificity. PPV and NPV, the most relevant characteristics for clinicians, of both tests did not differ significantly. The distribution of individual antibodies and the adjustment of the immunoblot algorithm will be further explored in the future in order to develop a potentially better prediction method for TFI with a higher clinical accuracy.

The study is to investigate the effect of anti-caspase treatment on anti-chlamydia immune response in mice. Both the humoral and aspects of cell-mediated immune response against Chlamydia trachomatis were studied. Antibody response was measured using the ELISA technique to identify all common isotypes, and cytokine response was measured using the PCR technique. The antibody levels (IgG, IgG1, IgG2a and IgA) in Z-VAD-FMK treated group were significantly higher than nontreated group. ELISA results [showed a significantly higher amount of antibodies (IgG, IgG1, Ig G2a Original Research Article

STUDY QUESTION: Are bile acids (BA) and their respective subspecies present in human follicular fluid (FF) and do they relate to embryo quality in modified natural cycle IVF (MNC-IVF)?SUMMARY ANSWER: BAconcentrations are 2-fold higher in follicular fluid than in serum and ursodeoxycholic acid (UDCA) derivatives were associated with development of top quality embryos on Day 3 after fertilization.WHAT IS KNOWN ALREADY: Granulosa cells are capable of synthesizing BA, but a potential correlation with oocyte and embryo quality as well as information on the presence and role of BA subspecies in follicular fluid have yet to be investigated.STUDY DESIGN, SIZE, DURATION: Between January 2001 and June 2004, follicular fluid and serum samples were collected from 303 patients treated in a single academic centre that was involved in a multicentre cohort study on the effectiveness of MNC-IVF.PARTICIPANTS/MATERIALS, SETTING, METHODS: Material from patients who underwent a first cycle of MNC-IVF was used. Serum was not stored from all patients, and the available material comprised 156 follicular fluid and 116 matching serum samples. Total BA and BA subspecies were measured in follicular fluid and in matching serum by enzymatic fluorimetric assay and liquid chromatography-mass spectrometry, respectively. The association of BA in follicular fluid with oocyte and embryo quality parameters, such as fertilization rate and cell number, presence of multinucleated blastomeres and percentage of fragmentation on Day 3, was analysed.MAIN RESULTS AND THE ROLE OF CHANCE: Embryos with eight cells on Day 3 after oocyte retrieval were more likely to originate from follicles with a higher level of UDCA derivatives than those with fewer than eight cells (P LIMITATIONS, REASONS FOR CAUTION: Only samples originating from first cycle MNC-IVF were used, which resulted in 14 samples only from women with an ongoing pregnancy, therefore further prospective studies are required to confirm the association of UDCA with IVF pregnancy outcomes. The inter-cycle variability of BA levels in follicular fluid within individuals has yet to be investigated. We checked for macroscopic signs of contamination of follicular fluid by blood but the possibility that small traces of blood were present within the follicular fluid remains. Finally, although BA are considered stable when stored at -20 degrees C, there was a time lag of 10 years between the collection and analysis of follicular fluid and serum samples.WIDER IMPLICATIONS OF THE FINDINGS: The favourable relation between UDCA derivatives in follicular fluid and good embryo development and quality deserves further prospective research, with live birth rates as the end-point.

Is there an association between trisomic pregnancy, a marker for decreased oocyte quality, and the reduced oocyte quantity that follows ovarian surgery?Previous ovarian surgery is not associated with an increased risk for a subsequent trisomic pregnancy.Ovarian surgery diminishes the number of oocytes. The risk for a trisomic pregnancy is suggested to be higher in women with fewer oocytes, independent of their chronological age.This is a matched case-control study. Cases are women with a confirmed trisomic pregnancy occurring between 1 January 2000 and 31 December 2010 regardless of pregnancy outcome and controls are women that had a live born child without a trisomy. In total, there were 8573 participants in the study; 1723 cases and 6850 controls.Data were obtained from Danish medical registries. Matching criteria were maternal age and year of conception. Number of controls matched per case ranged from one to four. Among cases and controls with a trisomic pregnancy, 2.7% (46/1723) versus 2.5% (172/6850) had undergone ovarian surgery before pregnancy.History of ovarian surgery is not associated with a higher risk for a subsequent trisomic pregnancy (odds ratio = 1.00, 95% confidence interval 0.99-1.01). Subgroup analyses by indication of surgery and interval between ovarian surgery and pregnancy do not show an effect on trisomic pregnancy risk.The medical registries used to select cases and controls did not contain information on surgical technique nor volume of ovarian tissue resected, previous trisomic pregnancy prior to the ovarian surgery or long-term use of oral contraceptives. Therefore, correction for these factors was not performed.We did not confirm the hypothesis that ovarian surgery, a marker for decreased oocyte quantity, is related to trisomic pregnancy, a marker for decreased oocyte quality. This suggests that ovarian surgery, which has a direct reductive effect on the size of the follicle pool, may affect oocyte quality differently when compared with the reduction in follicle pool size due to ageing.The study was supported by grants from the Gratama Stichting, University of Groningen and the University Medical Center Groningen, The Netherlands. Ø.L. has within the last 3 years received honoraria for speeches in pharmacoepidemiological issues, not related to this study. The Department of Obstetrics and Gynaecology receives unrestricted educational grants from Ferring Pharmaceuticals. A.H. received a grant from ZonMW (i.e. National Dutch Scientific funding) for a RCT not related to this publication. Dr A.H. received speakers fee from MSD for an educational presentation. All other authors have no conflict of interest.

Objective: Cigarette smoking is a risk factor for earlier menopause. Animal studies show that in-utero smoke exposure is toxic to developing ovaries. Our aim was to evaluate whether in-utero smoke exposed women reach menopause earlier compared with nonexposed women.Methods: This is a cohort study within the Avon Longitudinal Study of Parents and Children. Participants included in this study were followed from 1991/1992 until 2010. Participant characteristics for the current analysis were obtained from obstetric records and from annual follow-up questionnaires. When not available, age at natural menopause was estimated by age at filling in the questionnaire minus 1 year. Cox proportional hazards modeling was used to estimate hazard ratios of menopause for in-utero exposed and nonexposed women.Results: There were 695/2,852 postmenopausal women, of whom 466 had natural menopause, 117 had hormonal therapy, and 112 had surgical menopause. Age at natural menopause was 50.6 +/- 3.7 years. Of all participants, 20.2% (577/2,852) were exposed to smoke in-utero. Participants who were in-utero exposed but were not smokers did not have higher hazards of menopause (adjusted hazard ratio [HR] 0.92, 95% CI 0.72-1.18), whereas participants who were ever smokers (current or previous) and were in-utero exposed (adjusted HR 1.41, 95% CI 1.01-1.95) or were ever smokers but not exposed (adjusted HR 1.24, 95% CI 1.00-1.53) did have higher hazards of earlier menopause.Conclusions: In-utero smoke exposure was not associated with earlier menopause, but the effect of in-utero smoke exposure was modified by the smoking habits of the participants themselves increasing the risk for smokers who were in-utero exposed.

There is a need for more accurate Chlamydia trachomatis (CT) IgG antibody tests for tubal factor infertility (TFI) diagnostics. We evaluated the predictive value for TFI of Medac ELISA plus (MOMP) and multitarget Mikrogen ELISA (MOMP-CPAF-TARP). Based on Medac ELISA plus results, 183 subfertile women underwent either hysterosalpingography or laparoscopy to diagnose TFI. TFI was defined as extensive adhesions and/or distal occlusion of at least one tube. Women not fulfilling the definition of TFI served as controls. Serum was subsequently tested with Mikrogen ELISA and results were compared. 48 patients had TFI, 135 were controls. Mikrogen ELISA tested 125 patients positive/borderline of which 32% had TFI. Medac ELISA plus tested 77 patients positive/borderline of which 29.9% had TFI. Mikrogen tested 40 out of 48 TFI patients positive/borderline, Medac 23 out of 48. Kappa value was 0.34. PPV of Mikrogen ELISA and Medac ELISA plus were respectively 32% (95% CI 26%-39%) and 30% (95% CI 24%-37%), and NPV 86% (95% CI 81%-91%) and 76% (95% CI 70%-82%). Both tests were comparable in the prediction of TFI. However, Mikrogen ELISA had a higher NPV and might be more reliable in identifying patients without TFI. Kappa-value showed limited concordance between both tests.

STUDY QUESTION: What is the prevalence of chromosomal abnormalities in azoospermic men and what are the clinical consequences in terms of increased risk for absent spermatogenesis, miscarriages and offspring with congenital malformations?SUMMARY ANSWER: The prevalence of chromosomal abnormalities in azoospermia was 14.4%, and the number of azoospermic men needed to be screened (NNS) to identify one man with a chromosomal abnormality with increased risk for absence of spermatogenesis was 72, to prevent one miscarriage 370-739 and to prevent one child with congenital malformations 4751-23 757.WHAT IS KNOWN ALREADY: Infertility guidelines worldwide advise screening of non-iatrogenic azoospermic men for chromosomal abnormalities, but only few data are available on the clinical consequences of this screening strategy.STUDY DESIGN, SIZE, DURATION: This retrospective multicentre cross-sectional study of non-iatrogenic azoospermic men was performed at the University Hospital Brussels, Belgium, and the University Medical Centre Groningen, The Netherlands, between January 2000 and July 2016.PARTICIPANTS/MATERIALS, SETTING, METHODS: Analysis of clinical registries retrospectively identified 1663 non-iatrogenic azoospermic men with available results of karyotyping and FSH serum levels. Iatrogenic azoospermia was an exclusion criterion, defined as azoospermia after spermatotoxic medical treatment, exogenous androgen suppletion or vasectomy and/or vasovasostomy. Also, men with a clinical diagnosis of anejaculation or hypogonadotropic hypo-androgenism and/or FSH values = 10 U/l) azoospermia. We estimated the NNS for chromosomal abnormalities to identify one man with absence of spermatogenesis and to prevent one miscarriage or one child with congenital malformations, and calculated the surgical sperm retrieval rates per chromosomal abnormality.MAIN RESULTS AND THE ROLE OF CHANCE: The overall prevalence of chromosomal abnormalities in azoospermia was 14.4% (95% CI 12.7-16.1%), its prevalence being higher in hypergonadotropic azoospermia (20.2%, 95% CI 17.8-22.7%) compared to normogonadotropic azoospermia (4.9%, 95% CI 3.2-6.6%, P LIMITATIONS, REASONS FOR CAUTION: The absolute number of chromosomal abnormalities associated with clinical consequences and adverse pregnancy outcomes in our study was limited, thereby increasing the role of chance. Further, as there are currently no large series on outcomes of pregnancies in men with chromosomal abnormalities, our conclusions are partly based on assumptions derived from the literature.WIDER IMPLICATIONS OF THE FINDINGS: The NNS found can be used in future cost-effectiveness studies and the evaluation of current guidelines on karyotyping in non-iatrogenic azoospermia.

Background: Chlamydia trachomatis (CT), the most common bacterial sexually transmitted infection (STI) among young women, can result in serious sequelae. Although the course of infection is often asymptomatic, CT may cause pelvic inflammatory disease (PID), leading to severe complications, such as prolonged time to pregnancy, ectopic pregnancy, and tubal factor subfertility. The risk of and risk factors for complications following CT-infection have not been assessed in a long-term prospective cohort study, the preferred design to define infections and complications adequately. Methods: In the Netherlands Chlamydia Cohort Study (NECCST), a cohort of women of reproductive age with and without a history of CT-infection is followed over a minimum of ten years to investigate (CT-related) reproductive tract complications. This study is a follow-up of the Chlamydia Screening Implementation (CSI) study, executed between 2008 and 2011 in the Netherlands. For NECCST, female CSI participants who consented to be approached for follow-up studies (n = 14,685) are invited, and prospectively followed until 2022. Four data collection moments are foreseen every two consecutive years. Questionnaire data and blood samples for CT-Immunoglobulin G (IgG) measurement are obtained as well as host DNA to determine specific genetic biomarkers related to susceptibility and severity of infection. CT-history will be based on CSI test outcomes, self-reported infections and CT-IgG presence. Information on (time to) pregnancies and the potential long-term complications (i.e. PID, ectopic pregnancy and (tubal factor) subfertility), will be acquired by questionnaires. Reported subfertility will be verified in medical registers. Occurrence of these late complications and prolonged time to pregnancy, as a proxy for reduced fertility due to a previous CT-infection, or other risk factors, will be investigated using longitudinal statistical procedures. Discussion: In the proposed study, the occurrence of late complications following CT-infection and its risk factors will be assessed. Ultimately, provided reliable risk factors and/or markers can be identified for such late complications. This will contribute to the development of a prognostic tool to estimate the risk of CT-related complications at an early time point, enabling targeted prevention and care towards women at risk for late complications. Trial registration: Dutch Trial Register NTR-5597. Retrospectively registered 14 February 2016.

ObjectivesA better understanding ofChlamydia trachomatisinfection (chlamydia)–related sequelae can provide a framework for effective chlamydia control strategies. The objective of this study was to estimate risks and risk factors of pelvic inflammatory disease (PID), ectopic pregnancy and tubal factor infertility (TFI) with a follow-up time of up until 8 years in women previously tested for chlamydia in the Chlamydia Screening Implementation study (CSI) and participating in the Netherlands Chlamydia Cohort Study (NECCST).MethodsWomen who participated in the CSI 2008–2011 (n=13 498) were invited in 2015–2016 for NECCST. Chlamydia positive was defined as a positive CSI-PCR test, positive chlamydia serology and/or self-reported infection (time dependent). Data on PID, ectopic pregnancy and TFI were collected by self-completed questionnaires. Incidence rates and HRs were compared between chlamydia-positive and chlamydia-negative women corrected for confounders.ResultsOf 5704 women included, 29.5% (95% CI 28.3 to 30.7) were chlamydia positive. The incidence rate of PID was 1.8 per 1000 person-years (py) (1.6 to 2.2) overall, 4.4 per 1000 py (3.3 to 5.7) among chlamydia positives compared with 1.4 per 1000 py (1.1 to 1.7) for chlamydia negatives. For TFI, this was 0.4 per 1000 py (0.3 to 0.5) overall, 1.3 per 1000 py (0.8 to 2.1) and 0.2 per 1000 py (0.1 to 0.4) among chlamydia positives and negatives, respectively. And for ectopic pregnancy, this was 0.6 per 1000 py (0.5 to 0.8) overall, 0.8 per 1000 py (0.4 to 1.5) and 0.6 per 1000 py (0.4 to 0.8) for chlamydia negatives. Among chlamydia-positive women, the strongest risk factor for PID was symptomatic versus asymptomatic infection (adjusted HR 2.88, 1.4 to 4.5) and for TFI age 24 years at first infection (HR 4.35, 1.1 to 16.8).ConclusionWe found a considerably higher risk for PID and TFI in chlamydia-positive women, but the incidence for ectopic pregnancy was comparable between chlamydia-positive and chlamydia-negative women. Overall, the incidence rates of sequelae remained low.Trial registrationNTR-5597.

Objective To compare the means and changes over time of intra-abdominal fat (IAF) and subcutaneous abdominal fat (SAF) measured by abdominal ultrasound (US) and computerized tomography (CT). Design and Methods Prospective cohort study of 53 women with obesity and infertility undergoing a lifestyle program. Results The Pearson's correlation between IAF measurement by US compared to CT was good at baseline, month 3 and 6 (all r ≥ 0.72). The correlation of SAF measurement by US compared to CT was reasonable at baseline (r = 0.54; 95%CI 0.30-0.78) and weak at month 3 and 6 (all r ≤ 0.39). The correlation between the changes in IAF over 3 and 6 months by US compared to CT was reasonable and significant respectively (all r > 0.48). US could not measure the changes of SAF over time. The Bland–Altman plot showed good agreement between US and CT for IAF measurements (−1.1 [95%CI -3.9-1.6] cm lower mean in US) at baseline. For changes of IAF over time, mean estimates were in agreement. Conclusion In women with obesity and infertility, measuring IAF by US is in good agreement with the CT scan methodology but the measurement of SAF by US is unreliable.

Item does not contain fulltext A low number of antral follicles may result in the selection of suboptimal oocytes that are prone to meiotic errors. The aim of this case-control study was to evaluate women receiving IVF treatment with low oocyte yield (defined as three or fewer oocytes retrieved after ovarian stimulation) who are at an increased risk of a trisomic pregnancy. Data were obtained from Danish and Dutch medical registries between 1983 and 2011. Analyses were carried out in 105 cases and 442 controls matched by age and year of IVF treatment. Cases were women with a trisomic pregnancy (trisomies 13, 18 or 21) resulting from fresh IVF treatment and confirmed by karyotyping. Cases were included regardless of pregnancy outcome. Controls were women with a live born child without a trisomy, resulting from fresh IVF treatment. Low oocyte yield was observed in 6.6% (29/440) of the women, of which 8.4% (7/83) were cases and 6.2% (22/357) controls. Low oocyte yield in IVF treatment was not associated with a higher risk of trisomic pregnancy (OR 1.43, 95% CI 0.64 to 3.19). Stratification for female age, adjustment for history of ovarian surgery, and gonadotrophin-releasing hormone protocol used did not change the results.

FSH inactivity due to secondary hypoglycosylation has been suggested as a potential mechanism for primary ovarian insufficiency in classic galactosemia. To investigate the role of FSH and to gain insight in the timing of the damage, ovarian stimulation tests were performed and data on ovarian imaging collected. Fifteen patients with primary ovarian insufficiency underwent ovarian stimulation with gonadotropins. Only one patient showed a normal increase in estradiol level, all the others had a low or no estradiol response. Anti-Mullerian hormone measurement in all girls and women showed levels below the detection limit of 0.10 mu g/l. Ovarian volumes were evaluated by MRI in 14 patients and compared to age matched controls, prepubertal controls and postmenopausal controls. The ovarian volumes of the galactosemic girls were smaller than those of the age matched controls (p = 0.001) and the prepubertal ovaries (p = 0.008), and did not differ significantly from postmenopausal ovarian volumes (p = 0.161). In conclusion we found no evidence that FSH inactivity plays a role in primary ovarian insufficiency in classic galactosemia. Moreover, ovarian imaging results point to an early onset of ovarian failure in this disease.

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

BACKGROUNDSmall lifestyle-intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcomes, but large randomized, controlled trials are lacking.METHODSWe randomly assigned infertile women with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 29 or higher to a 6-month lifestyle intervention preceding treatment for infertility or to prompt treatment for infertility. The primary outcome was the vaginal birth of a healthy singleton at term within 24 months after randomization. RESULTS We assigned women who did not conceive naturally to one of two treatment strategies: 290 women were assigned to a 6-month lifestyle-intervention program preceding 18 months of infertility treatment (intervention group) and 287 were assigned to prompt infertility treatment for 24 months (control group). A total of 3 women withdrew consent, so 289 women in the intervention group and 285 women in the control group were included in the analysis. The discontinuation rate in the intervention group was 21.8%. In intention-to-treat analyses, the mean weight loss was 4.4 kg in the intervention group and 1.1 kg in the control group (PCONCLUSIONSIn obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization. (Funded by the Netherlands Organization for Health Research and Development; Netherlands Trial Register number, NTR1530.)

How many infertile men who wish to conceive need to be screened for chromosomal abnormalities to prevent one miscarriage or the birth of one child with congenital anomalies (CAs)?In azoospermic men, the prevalence of chromosomal abnormalities is 15.2 and the number needed to be screened (NNS; minimummaximum estimate) for a miscarriage is 8088 and for a child with CAs is 7903951. The prevalence of chromosomal abnormalities in non-azoospermic men is 2.3 and the NNS are 315347 and 254312 723, respectively.Guidelines advise the screening of infertile men for chromosomal abnormalities to prevent miscarriages and children with congenital abnormalities, but no studies have been published on the effectiveness of this screening strategy.Retrospective cohort study of 1223 infertile men between 1994 and 2007.Men with azoospermia and men eligible for ICSI treatment visiting a university hospital fertility clinic in The Netherlands who underwent chromosomal analysis between 1994 and 2007 were identified retrospectively in a registry. Only cases of which at least one sperm analysis was available were included. Data were collected by chart review, with a follow-up of pregnancies and their outcomes until 2010. The chromosomal abnormalities were categorized according to their risk of unbalanced offspring, i.e. miscarriage and/or child with CAs. Multi-level analysis was used to estimate the impact of chromosomal abnormalities on the outcome of pregnancies in the different subgroups of our cohort. NNS for miscarriages and children with CAs were calculated based on data from our cohort and data published in the literature.A chromosomal abnormality was found in 12 of 79 men with azoospermia (15.2) and in 26 of 1144 non-azoospermic men (2.3). The chromosomal abnormalities were categorized based on the literature, into abnormalities with and abnormalities without increased risk for miscarriage and/or child with CAs. In our study group, there was no statistically significant difference between the subgroups with and without increased risk respectively, regarding the frequency of children born with CAs (1/20; 5.0 versus 1/14; 7.1), miscarriage (9/20; 45.0 versus 2/14; 14.3) or unaffected liveborn children (9/20; 45.0 versus 9/14; 64.3). The prevalence of chromosomal abnormalities with a theoretically increased risk of unbalanced progeny was 1.0 in non-azoospermic men and 3.8 in men with azoospermia. For the calculation of the NNS, the risk of an adverse pregnancy outcome in our cohort was compared with the incidence ranges of miscarriage and children with CAs in the general population. The number of azoospermic men that needs to be screened to prevent one miscarriage (8088) or one child with CAs (7903951) was considerably lower compared with the NNS in the non-azoospermic group (315347 and 254312 723, respectively).The prevalence of chromosomal abnormalities in infertile men is low, and although we included 1223 men, our conclusions are based on a small number (38) of abnormal karyotypes. As there are no large series on outcomes of pregnancies in infertile men with chromosomal abnormalities, our conclusions had to be partly based on assumptions derived from the literature.Based on the NNS calculated in our study, screening for chromosomal abnormalities is recommended in all azoospermic men. In non-azoospermic infertile men, screening might be limited to men with an additional risk factor (e.g. a history of recurrent miscarriage or a positive family history for recurrent miscarriage or children with CAs). The NNS can be used in future cost-effectiveness studies and the evaluation of current guidelines on karyotyping infertile men.Our institution has received research grants from Merck Sharpe Dohme BV, Ferring Pharmaceuticals and Merck Serono, The Netherlands. No competing interests declared.

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.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.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) 0.610.65]. For any tubal pathology, the addition of HSG significantly improved the predictive performance to an AUC of 0.74 (95 CI 0.730.76) (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 0.740.79).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.

BACKGROUND: Knowledge of patients' preferences for elective single embryo transfer (eSET) or double embryo transfer (DET) and for singletons or twins is of great importance in counselling for embryo transfer (ET) strategies. In this study, the stability of IVF patients' preferences over time for either a healthy single child or healthy twins was measured and we investigated which factors could explain preference shifts.METHODS: Infertile women (n = 177) who participated in an RCT comparing one cycle eSET with one cycle DET were included. A satisfaction questionnaire was developed to measure patient preferences and attitudes at two moments in time, i.e. at 2 weeks before ET and at 2 weeks following ET, after the results of the pregnancy test. Regression analysis examined the effect of several variables on preference shifts.RESULTS: Before ET, most patients expressed a preference for a singleton, whereas most patients were indifferent 2 weeks after ET, resulting in an overall preference shift towards twins (P = 0.002; n = 145). Overall, 62% of patients showed a preference shift. Preference shifts were explained by patients' global satisfaction of the information given by the fertility clinic staff received by the fertility clinic staff, and an interaction between the occurrence of pregnancy and transfer policy (eSET or DET).CONCLUSIONS: In general, patients' preferences for a singleton or twins are not stable during IVF treatment. Possible explanations of a shift in preference are that pregnant patients attuned their preferences to what they expect their pregnancy to result in, whereas non-pregnant patients shifted towards a preference for twins in order to be able to fulfil their ultimate child wish.

BACKGROUND: It is not clear why some anovulatory women with polycystic ovary syndrome (PCOS) and obesity resume ovulation and others remain anovulatory after weight loss. The objective of this study was to compare the changes in body fat distribution and specifically intra-abdominal fat (IAF) and subcutaneous abdominal fat (SAF) between a group of anovulatory women with PCOS and obesity who resume ovulation (RO+) to those who remain anovulatory (RO-) during a lifestyle program.METHODS: In a prospective pilot cohort study, anovulatory women with PCOS underwent a 6 month lifestyle program in a tertiary fertility clinic. Body fat distribution was assessed by anthropometrics, dual-energy X-ray absorptiometry (DEXA) and single slice abdominal CT scan at intake, after 3 months and after 6 months. Baseline-corrected changes over time were analysed using generalized estimating equations longitudinal regression analysis.RESULTS: In 32 anovulatory women with PCOS (age, 28 +/- 4 years; BMI, 37.5 +/- 5.0 kg/m(2)), there were no significant baseline differences in anthropometrics and biochemical assessment between 14 RO+ participants and 18 RO- participants. RO+ women lost more weight (6.3 versus 3.0%) and abdominal fat on DEXA (15.0 versus 4.3%) compared with RO- women. Resumption of ovulation was associated with early and consistent loss of IAF (12.4 versus 5.0% at 3 months and 18.5 versus 8.6% at 6 months). Loss of SAF between the RO+ women and the RO- women was similar at 3 months (6.2 versus 6.1%) but did not change any further in RO- women (6.1%) as it did in RO+ women (11.4%) at 6 months.CONCLUSIONS: In anovulatory women with PCOS and obesity undergoing a lifestyle program, RO+ women lose more body weight and abdominal fat on DEXA than RO- women. In addition, this study shows that early and consistent loss of IAF is associated with resumption of ovulation. Future studies should address the mechanisms behind these changes and should assess interventions aimed at loss of IAF to facilitate resumption of ovulation.

Context: The most frequent cause of virilization in postmenopausal women is excessive androgen production of ovarian origin. Bilateral oophorectomy is usually performed, even in cases of benign tumors or hyperthecosis. This is the first report of a case series of long-term GnRH-agonist treatment of hyperandrogenism in postmenopausal women. Objective: We present three women with postmenopausal hyperandrogenism of ovarian origin who were treated with GnRH agonists. Patients: We describe three cases of postmenopausal women with virilization and hyperandrogenism of presumed ovarian origin, all with slight enlargement of the ovaries but without visualization of a tumor, who had long-term treatment with GnRH agonists. No histological diagnosis was available, and therefore all patients received careful follow-up, including periodic testing of androgen levels and ovarian imaging by computed tomography scans. The three patients responded in different ways to treatment with GnRH agonists. Conclusions: Long-term GnRH agonist treatment is an acceptable choice for treatment of postmenopausal hyperandrogenism in patients where ovarian origin of androgen excess is ascertained, and especially in those patients who have an increased risk for surgery due to comorbidities or who are unwilling to undergo bilateral oophorectomy.

Background: Thyroid dysfunction and thyroid autoimmunity are prevalent among women of reproductive age and are associated with adverse pregnancy outcomes. Preconception or early pregnancy screening for thyroid dysfunction has been proposed but is not widely accepted. We conducted a systematic review of the literature on the clinical significance of thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy. Methods: Relevant studies were identified by searching Medline, EMBASE and the Cochrane Controlled Trials Register. Results: From a total of 14 208 primary selected titles, 43 articles were included for the systematic review and 38 were appropriate for meta-analyses. No articles about hyperthyroidism were selected. Subclinical hypothyroidism in early pregnancy, compared with normal thyroid function, was associated with the occurrence of pre-eclampsia [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1-2.6] and an increased risk of perinatal mortality (OR 2.7, 95% CI 1.6-4.7). In the meta-analyses, the presence of thyroid antibodies was associated with an increased risk of unexplained subfertility (OR 1.5, 95% CI 1.1-2.0), miscarriage (OR 3.73, 95% CI 1.8-7.6), recurrent miscarriage (OR 2.3, 95% CI 1.5-3.5), preterm birth (OR 1.9, 95% CI 1.1-3.5) and maternal post-partum thyroiditis (OR 11.5, 95% CI 5.6-24) when compared with the absence of thyroid antibodies. Conclusions: Pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of complications, especially pre-eclampsia, perinatal mortality and (recurrent) miscarriage. Future research, within the setting of clinical trials, should focus on the potential health gain of identification, and effect of treatment, of thyroid disease on pregnancy outcome.

Introduction: Couples who have not achieved a pregnancy within one year of unprotected intercourse qualify for a fertility work-up. A semen analysis is part of this work-up and includes the assessment of sperm concentration, motility and morphology. The predictive value of sperm morphology has been

Guidelines on karyotyping infertile men before ICSI treatment are not consistent. Most guidelines recommend chromosomal screening in azoospermic and severe oligozoospermic men, because they are assumed to have the highest risk of abnormalities. We performed a retrospective cohort study in azoospermic men and men eligible for ICSI. We determined the prevalence of chromosomal abnormalities in relation to sperm concentration and compared our data to studies in the literature. A high prevalence of chromosomal abnormalities in azoospermic men was found, but no difference in the prevalence of abnormalities was seen between different sperm concentration categories in non-azoospermic men. This raises the question of who should be screened for chromosomal abnormalities before ICSI treatment. Considering the costs and benefits, we would propose limiting screening to infertile couples with non-obstructive azoospermia.

Objective: To determine the incidence of couples dropping out of the in vitro fertilization (IVF) waiting list and to describe the couples' reasons.Design: Prospective cohort study.Setting: Fertility center in an academic hospital.Patient(s): 674 women placed consecutively on the IVF waiting list between June 2000 and July 2003.Intervention(s): None.Main Outcome Measure(s): Number of dropouts and reasons for dropping out.Result(s): Follow-up information was collected in 2005 and 2008. Of the 674 couples on the waiting list, 87% started IVF, and 13% dropped out before starting their first IVF cycle. Follow-up data were obtained for 85 of 86 patients (98.8%): 37% dropped out because of spontaneous pregnancy, 36% for personal reasons (passive censoring), and 27% for medical reasons (active censoring). Most of the pregnancies occurred within 3 months after the patient had been placed on the waiting list (30 of 32, 94%). Of the 54 censored couples, four became pregnant.Conclusion(s): On a 6-month waiting list for IVF, 13% of the couples dropped out before starting treatment. The single most important reason for dropout was (spontaneous) pregnancy. Most of these pregnancies occurred within 3 months, which suggests that psychological factors such as stress relief after being placed on the waiting list might be operative. (Fertil Steril (R) 2010; 94:1713-6. (C) 2010 by American Society for Reproductive Medicine.)

BACKGROUND: The majority of Chlamydia trachomatis infections in women are asymptomatic, but may give rise to pelvic inflammatory disease (PID) and tubal infertility. Screening programmes aim at reducing morbidity in individuals by early detection and treatment, and at decreasing the overall prevalence of infection in the population. A number of modelling studies have tried to calculate the threshold prevalence of chlamydia lower genital tract infection above which screening becomes cost-effective. There is considerable debate over the exact complication rates after chlamydia infections, and more precise estimates of PID and tubal infertility are needed, for instance to be inserted in economic models.METHODS: With reference to key studies and systematic reviews, an overview is provided focusing on the epidemiology of chlamydia infection and the risk-estimates of its late complications.RESULTS: In the literature, the generally assumed risk of developing PID after lower genital tract chlamydia infection varies considerably, and is up to 30%. For developing tubal infertility after PID the risks are 10-20%. This implies that the risk of test-positive women of developing tubal infertility would range between 0.1 and 6%. We included chlamydia IgG antibody testing in a model and estimated a risk of tubal infertility up to 4.6%.CONCLUSION: The risk of developing late complications after chlamydia lower genital tract infection appears low. High quality RCTs dealing with the transition from cervicitis to infertility are needed to broaden the evidence. In screening programmes, chlamydia antibody testing, as an intermediate marker for potential adverse sequelae, might enable more precise estimates.

BACKGROUND: Different screening strategies exist to estimate the risk of tubal factor subfertility, preceding laparoscopy. Three screening strategies, comprising Chlamydia trachomatis IgG antibody testing (CAT), highsensitivity C-reactive protein (hs-CRP) testing and hysterosalpingography (HSG), were explored using laparoscopy as reference standard and the occurrence of a spontaneous pregnancy as a surrogate marker for the absence of tubal pathology. METHODS: In this observational study, 642 subfertile women, who underwent tubal testing, participated. Data on serological testing, HSG, laparoscopy and interval conception were collected. Multiple imputations were used to compensate for missing data. RESULTS: Strategy A (HSG) has limited value in estimating the risk of tubal pathology. Strategy B (CAT!HSG) shows that CAT significantly discerns patients with a high versus low risk of tubal pathology, whereas HSG following CAT has no additional value. Strategy C (CAT!hs-CRP!HSG) demonstrates that hs-CRP may be valuable in CAT-positive patients only and HSG has no additional value. CONCLUSIONS: CAT is proposed as first screening test for tubal factor subfertility. In CAT-negative women, HSG may be performed because of its high specificity and fertility-enhancing effect. In CAT-positive women, hs-CRP seems promising, whereas HSG has no additional value. The position and timing of laparoscopy deserves critical reappraisal.

Despite the high prevalence of premature ovarian failure (POF) and subsequent infertility in galactosemic women, spontaneous pregnancies occur and may not be as rare as is generally assumed. This is important for counseling these women on fertility. The purpose of this review is to assess the occurrence and predicting factors of pregnancy, and to evaluate the impact of pregnancy on the mother's and child's health. The female Dutch galactosemia population (age18 years) was studied, and a literature search on articles reporting pregnancy in galactosemic women, published between January 1971 and December 2007, was performed. Twenty-two galactosemic women were studied. Nine women have tried to conceive, of which 4 were successful. Three mothers were diagnosed with POF before the first pregnancy and/or in between pregnancies. In literature, 50 pregnancy reports were found. In 10 pregnancy reports from the literature, the mother's genotype is known. Four women were homozygous for the Q188R mutation, which equals the incidence of 40-45% of classic galactosemia caused by this mutation. This study challenges the current opinion that the chance of becoming pregnant is small in classic galactosemia. Despite POF in most galactosemic women, pregnancies do occur. The genotype and GALT-activity do not seem to predict the chance of becoming pregnant, whereas the occurrence of spontaneous menarche might. No evidence for the need of additional check-ups during the pregnancy and puerperium was found. Elevations in galactose-metabolites do occur, but without evidence of clinical impact for the mother or the child, although possible long-term effects have not been thoroughly investigated.ObstetriciansGynecologists, Family Physicians.After completion of this article, the reader should be able to summarize the purported causes and sequelae of galactosemia, explain the possible sequelae of galactosemia, distinguish alterations of the ovary and the hypothalamic-pituitary axis, identify the frequency of pregnancy and the possible outcome of the offspring, and outline dietary management of patients with galactosemia.

Chlamydia trachomatis infections demonstrate remarkable differences in clinical course that are approximately 40% based on host genetic variation. Here, we study the single nucleotide polymorphisms (SNPs) and their haplotypes in TLR2, TLR4 and TLR9 (TLR2+2477G > A; TLR2 -16934T > A; TLR4+896A > G; TLR9-1237T > C and TLR9 +2848G > A) in relation to the susceptibility to, and severity of C. trachomatis infections. We analysed the five SNPs in a cohort of 770 Dutch Caucasian women either attending a sexually transmitted diseases outpatient clinic (n = 731) or having complaints of subfertility (n = 39). Haplotype analyses showed a trend for TLR2 haplotype I (-16934T/+2477G) to protect against the development of symptoms and tubal pathology (P-trend = 0.03) after Chlamydia infection. In the susceptibility cohort, TLR9 haplotype III (-1237C/+2848A) showed a significant decreasing trend in the development of symptoms after C. trachomatis infection (P = 0.02, OR: 0.55, 95% CI: 0.33-0.91). Logistic regression of the TLR2 haplotypes, TLR4+896A > G, and TLR9 haplotypes showed that the TLR2 haplotype combinations AG-TA and AG-TG confer risk (OR 3.4 (P = 0.01) and 1.6 (P = 0.03)), while the TLR9 haplotype combination TG-TA protects against C. trachomatis infections (OR: 0.4, P = 0.004). Our study shows that both TLR2 and TLR9 genes and SNP combinations do influence the clinical course of Chlamydia infections.

Previous studies have shown that both exogenous and endogenous estrogens and progestogens increase the risk of breast cancer. it has been suggested that in vitro fertilization (IVF) procedures may increase breast cancer risk. This risk could be could be due to a temporary decrease in estradiol and progesterone levels (during down-regulation of the natural cycle), as well as strongly elevated levels (during stimulation phase). Results of previous studies investigating breast cancer risk after IVF treatment were inconclusive because of limited follow-up. Recent studies have reported no increased risk of this cancer after IVT at a mean follow-up of 8 and 16 years. This historical cohort (OMEGA) study quantified long-term risk of breast cancer after ovarian stimulation for IVF. The aim of the study was to compare the long-term risk of breast cancer among a nationwide cohort of women receiving ovarian stimulation for IVF with that of women receiving other fertility treatments and those in the general population. The study was conducted in 12 IVF clinics in the Netherlands. The cohort was composed of 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women who started other fertility treatments between 1980 and 1995 (non-IVF group) Data were obtained from all 12 IVF clinics. There was complete follow-up through December 2013 for 96% of the cohort. At end of follow-up, the median age was 53.8 years in the IVF group and 55.3 years in the non-IVF group. Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was obtained from medical records and mailed questionnaires. First invasive and in situ breast cancer incidence among women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Risk of breast cancer in the IVF group was compared with risk in the non-IVF group (hazard ratios [HRs]) and the general population (standardized incidence ratios [SIRs]). In the total cohort, the mean age at baseline was 32.8 years, and the mean number of IVF cycles was 3.6. After a median follow-up of 21.1 years, 839 of the cohort had invasive breast cancer, and 109 had in situ breast cancer. Compared with the general population, breast cancer risks were not increased either in the IVF group (SIR, 1.01; 95% confidence interval [CI], 0.93-1.09) or the non-IVF group (SIR, 1.00; 95% CI, 0.88-1.15). At the age of 55 years, cumulative incidence rates of breast cancer were 3.0% in the IVF group and 2.9% in the non-IVF group (P = 0.85). With longer time since treatment (>= 20 years), the SIR did not increase in the IVF group (SIR, 0.92; 95% CI, 0.73-1.15) or in the non-IVF group (SIR, 1.03; 95% CI, 0.82-1.29). Women with 7 or more IVF cycles had a significantly decreased risk of breast cancer than did women who were treated with 1 to 2 IVF cycles; the HR was 0.55, with a 95% CI of 0.39 to 0.77. The risk was also significantly lower (HR, 0.77; 95% CI, 0.61-0.96) after poor response to the first IVF cycle ( = 4 collected oocytes). These data show that IVT treatment did not increase the risk of breast cancer in a cohort of women undergoing fertility treatment in the Netherlands between 1980 and 1995 when compared with women who received non-IVF treatment or those in the general population after a median follow-up of 21 years. These findings are consistent with those from recent reviews showing no significant increase in long-term risk of breast cancer among IVF-treated women.

INTRODUCTION: In several clinics, elective single-embryo transfer (eSET) is applied in a selected group of patients based on age and the availability of a good-quality embryo. Whether or not eSET can be applied irrespective of the presence of a good-quality embryo in the first cycle, to further reduce the twin pregnancy rate, remains to be elucidated. METHODS: In patients

Multiple pregnancies lead to complications and induce high costs. The most successful way to decrease multiple pregnancies in IVF is to transfer only one embryo, which might reduce the efficacy of treatment. The objective of this review is to determine which embryo-transfer policy is most cost-effective: elective single-embryo transfer (eSET) or double-embryo transfer (DET). Several databases were searched for (cost* or econ*) and (single embryo* or double embryo* or one embryo* or two embryo* or elect* embryo or multip* embryo*). On the basis of five exclusion criteria, titles and abstracts were screened by two individual reviewers. The remaining papers were read for further selection, and data were extracted from the selected studies. A total of 496 titles were identified through the searches and resulted in the selection of one observational study and three randomized studies. Study characteristics, total costs and probability of live births were extracted. Besides this, cost-effectiveness and incremental cost-effectiveness were derived. It can be concluded that DET is the most expensive strategy. DET is also most effective if performed in one fresh cycle. eSET is only preferred from a cost-effectiveness point of view when performed in good prognosis patients and when frozen/thawed cycles are included. If frozen/thawed cycles are excluded, the choice between eSET and DET depends on how much society is willing to pay for one extra successful pregnancy.

BACKGROUND: Persistent C. trachomatis infections are assumed to increase the risk of tubal pathology. We studied whether serological markers, assumed to be associated with persistent C. trachomatis infections, could identify subfertile women at risk of tubal pathology. METHODS: Sera of 313 subfertile women, who all underwent a laparoscopy with tubal testing to assess the grade of tubal pathology, were tested for the presence of immunoglobulin (Ig) G and IgA antibodies to C. trachomatis, IgG antibodies to chlamydia heat shock protein 60 (cHSP60) and C-reactive protein (CRP). RESULTS: C. trachomatis IgA, cHSP60 IgG and CRP, all serological markers of persistent infections, were significantly more prevalent in women with tubal pathology as compared to those without tubal pathology. The predictive value of the currently used screening test for tubal pathology (IgG to C. trachomatis) could be significantly improved by adding the CRP test. CONCLUSIONS: In subfertile women with tubal pathology, serological markers of persistent C. trachomatis infections are significantly more common as compared to women without tubal pathology. C. trachomatis IgG-positive subfertile women with slightly elevated (

BACKGROUND: We evaluated whether measuring chlamydia genus- and species-specific immunoglobulin (Ig) G antibodies might improve the predictive value of C. trachomatis antibody testing (CAT) in screening for distal tubal pathology (DTP). METHODS: Serum of 313 subfertile women was tested for the presence of species-specific antibodies to C. trachomatis, C. pneumoniae and C. psittaci and genus-specific antibodies to chlamydia lipopolysaccharide (LPS). Only patients who had undergone a laparoscopy with tubal testing, to assess the grade of DTP, were included in this study. RESULTS: The presence of C. trachomatis antibodies was the only independent predictor for DTP. The predictive value of CAT for DTP could not be improved by adding test results of C. pneumoniae or LPS antibody testing. The role of C. psittaci could not be evaluated, due to the absence of C. psittaci-positive patients in our cohort. CONCLUSIONS: In spite of the high interspecies homology, C. pneumoniae does not contribute to the development of DTP. Anti-LPS antibodies, which are considered to be markers for ongoing infections, do not identify C. trachomatis-positive subfertile women who are at highest risk of DTP. The high prevalence of anti-LPS antibodies in C. trachomatis-positive subfertile women may suggest that C. trachomatis remains more active in the upper genital tract than currently is presumed.

When searching the medical care literature for evidence on a diagnostic test, three questions should be addressed each time a study is found: (1) Is this evidence about a diagnostic test valid? (2) Does the test accurately discriminate between patients who do and patients who do not have a specific disorder? (3) Can the test be applied to this patient who is right now sitting in front of me? We will discuss hysterosalpingography (HSG) as an example of a valid and accurate diagnostic test to be applied in a general population of subfertile couples to assess tubal patency (specificity 0.83). HSG is an unreliable test for diagnosing tubal occlusion however (sensitivity 0.65). If HSG were normal, other investigations could be pursued and diagnostic laparoscopy (LS) only performed if conception had not occurred by a later date. If HSG were abnormal, LS would be needed to confirm or exclude tubal occlusion. Patients with risk factors for pelvic or tubal disease, including an abnormal Chlamydia antibody test (CAT) and those showing abnormalities at pelvic examination, should proceed directly to LS because they are significantly more likely to have pelvic pathology. A completely different issue would be HSG as a prognostic test for the occurrence of pregnancy. In theory, the occurrence of pregnancy may be considered a gold standard; however, in reproductive medicine, with so many causes of subfertility other than tubal pathology, a diagnostic test for one single disorder, if normal, will never be able to accurately predict the eventual occurrence of pregnancy.

Since Waddlia chondrophila is closely related to Chlamydia trachomatis, we hypothesise that W. chondrophila may also be associated with tubal factor infertility (TFI) in women, a major complication of chronic C. trachomatis infection. Five hundred twenty serum samples were tested for anti-Waddlia antibodies by ELISA. Among the 520 investigated women, a total number of 142 (27.3%) has had laparoscopic diagnosis performed, and were either classified TFI positive or negative. Presence of high titres of W. chondrophila antibodies was linked to TFI (p

BACKGROUND Chlamydia (C.) trachomatis antibody testing in screening for tubal factor subfertility is limited by false negative results, i.e. negative Chlamydia antibody tests in patients with tubal pathology at laparoscopy. The present study was performed to determine whether decline in C. trachomatis IgG antibodies over time is responsible for those false negative results. METHODS A total of 39 women with an initial titre of > or =64 were re-studied after 4-7 years. A new serum sample was collected from each patient. The initial and the second serum sample were tested for C. trachomatis IgG antibodies using a micro-immunofluorescence assay (MIF). A species-specific enzyme-linked immunosorbent assay (ELISA) was used to validate the MIF test results. All patients filled out a questionnaire to determine risk factors for renewed C. trachomatis infection between the initial and second serum sample. RESULTS Seven of the 39 patients (18.0%) showed a decline (>2 titre steps) in IgG antibodies by MIF over a period of 4-7 years, but IgG antibodies never became undetectable. In the 7/39 patients who showed a decline by MIF, signal/cut-off values by ELISA did not change. CONCLUSION A decline in IgG antibody titre is not a significant cause of false negative Chlamydia antibody test results.

Objective: To investigate the effect of the nationwide age shift toward later conception on the corresponding subfertile population. Design: Observational study. Setting: General population, the Netherlands. Subfertile population, Maastricht University Medical Centre. Patient(s): Women delivering their first child, women entering fertility care. Intervention(s): Between 1985 and 2008 the age of women at their first visit to our fertility clinic was recorded prospectively. Data concerning the general population were extracted from the database of Statistics Netherlands. Main Outcome Measure(s): Age shift in women's mean age at first fertility presentation; correlation age shift of general population and subfertile population; age-related ratio of number of women attending our fertility clinic compared with nationwide number of women delivering a first child. Result(s): We found a 3.7-year increase in age at first fertility presentation during the study period. For each year of increase in age at first delivery we found a 1.10-year increase in age of women entering fertility care (R = 0.93). The ratio between the number of new subfertility patients and the number of women delivering their first child stratified per age was calculated. With the ratio set to 1 at the age of 25 years, the ratio was 2.5 at age 35 years and 6.5 at age 40 years. Conclusion(s): The demographic age shift toward later conception is accompanied by an increased age in the subfertile population and by an increased demand for medical care. (Fertil Steril (R) 2011; 95: 61-3.)

Do paternal and maternal lifestyle factors influence the risk of hypertensive pregnancy complications, gestational diabetes mellitus (GDM), spontaneous preterm birth and small-for-gestational-age (SGA)?Paternal lifestyle factors do not exert an independent effect on the investigated outcomes while maternal prepregnancy BMI and maternal smoking during pregnancy influence the risk of hypertensive pregnancy complications, GDM and SGA.Maternal lifestyle factors are associated with perinatal complications, but the impact of paternal lifestyle factors is unclear.Data from the GECKO (Groningen Expert Center for Kids with Obesity) Drenthe cohort, a prospective population-based birth-cohort of children born between April 2006 and April 2007 in a northern province of The Netherlands, were analysed. The parents of 2958 children (62 of those approached) gave their consent to participate in the study and the data of 2264 (77) couples were available for analysis.All pregnant women in the Dutch province of Drenthe with an expected date of delivery between April 2006 and April 2007 were invited to participate and included during the third trimester of their pregnancy or within 6 months after delivery. All consenting couples received extensive questionnaires including lifestyle, biological and socio-demographic-related questions covering the period of 6 months prior to conception. Outcome data were obtained from midwives and hospital registries. Univariable and multivariable logistic regression analyses were used to determine the impact of the lifestyle factors on the primary outcome measures.Of all 2264 women, 241 women (10.6) developed a hypertensive pregnancy complication, 50 women (2.2) developed GDM, 79 (3.5) children were spontaneously delivered preterm and 155 children (6.8) were SGA. All paternal and maternal lifestyle factors were positively correlated. Multivariable analysis showed that paternal lifestyle factors did not have an independent influence on the investigated outcomes. Of the maternal factors, prepregnancy BMI was independently associated with an increased risk of a hypertensive disorder during pregnancy (odds ratio (OR): 1.12, 95 CI 1.091.16), a higher risk of GDM (OR BMI 23 kg/m(2), per BMI unit: 1.13, 95 CI 1.081.18) and with a decreased risk of SGA (OR per BMI point 0.94, 95 CI 0.900.99). Maternal smoking during pregnancy was significantly associated with SGA (OR 3.00, 95 CI 1.804.99) in multivariable analysis.The retrospective nature of the questionnaire may have induced recall bias. Selection bias might have occurred, as ethnic minorities were less willing to co-operate in the GECKO Drenthe study. The possibility of misclassification bias regarding the primary outcome measures cannot be ruled out. Inclusion bias might have occurred as not all questionnaires of the parents of the children participating in the GECKO Drenthe cohort were completed.Paternal lifestyle factors do not have an independent effect on the investigated adverse pregnancy outcomes. However, as paternal and maternal lifestyles are positively correlated, both partners should be involved in preconception counselling regarding the investigated outcome measures.GECKO is supported and funded by an unrestricted grant from Hutchison Whampoa Ltd, University of Groningen and Well Baby Clinic Foundation Icare, Drenthe, The Netherlands. M.A.Q.M. is supported by a research grant from the Dutch Organization for Health Research and Development (ZonMw; Prevention Program-Health Care Efficiency Research; project number 50-50110-96-518). The department of Obstetrics and Gynaecology received research grants from Merck Sharpe and Dohme BV, Ferring pharmaceuticals, Merck Serono, the Netherlands.

Objectives Chlamydia trachomatis (CT) reporting rates from sexually transmitted infection clinics and general practitioners have shown a rising trend in the Netherlands. It is unknown to what extent this reflects increased CT transmission or improved case finding. To achieve more insight into the CT epidemic, we explored the CT IgG seroprevalence (a marker of past CT infection) in the general population of the Netherlands in 1996 and in 2007.Methods From two population-based studies in 1996 and 2007, serum samples, demographic and sexual behaviour outcomes were examined, including 1246 men and 1930 women aged 15-39 years. Serum CT IgG antibodies were analysed using the Medac CT IgG ELISA test. Multivariate logistic regression analyses explored the seroprevalence and determinants over time.Results The CT IgG seroprevalence was higher in women than in men (10% vs 6%). Among women aged 25-39 years the seroprevalence was lower in 2007 (9%) than in 1996 (14%; adjusted OR (aOR) 0.6, 95% CI 0.4 to 0.8). There was no statistical evidence of a difference in seroprevalence within birth cohorts. Factors associated with seropositivity were male gender (aOR 0.4, 95% CI 0.3 to 0.7), a self-reported history of CT infection (aOR 5.1, 95% CI 2.6 to 10.0), age 25-39 years (aOR 1.7, 95% CI 1.1 to 2.7), non-Western ethnicity (aOR 2.2, 95% CI 1.4 to 3.3) and >= recent sexual partners (aOR 2.2, 95% CI 1.3 to 3.5).Conclusions Between 1996 and 2007 the proportion of individuals in the general population with CT IgG antibodies was lower among women aged 25-39 years, but remained similar among younger women and men.

Reproductive research benefits from combining animal and clinical studies. In Leuven, rabbits have constituted an animal model for many reproductive disorders, especially for those that involved surgical treatment. Much of what has been learned from animal experiments has been applied to human clinical reproductive research soon after. In this manuscript we wish to address the problem of the constant intra-abdominal battle between the menstrual aggressor and the peritoneal defense. From all published evidence we may conclude that endometriosis appears to be a dynamic disease, especially in the early phase, with subtle, atypical lesions emerging and vanishing again. In the end however the peritoneal defense system will prevail and the disease will be contained in the majority of patients. When doing repeat laparoscopies in young patients one should be prepared to encounter more advanced histological types of lesions, which not necessarily do have to indicate more advanced stages of the disease: the classical, blue and black powderburn spots and blueberry lesions reflect the extinguishing phase of the dynamic endometriotic process, and herald its inactivated histological end-stage. The dynamic phase of the disease may involve a varying interval of each patient's life, and medical suppression of the activity of the implants during this interval may lead one to conclude erroneously that treatment has been effective. If subsequently (after the end of medical suppression of the activity of the lesions) ovarian activity resumes and the lesions are stimulated again by ovarian steroids, their productive activity returns. Recurrence of disease may be diagnosed if at that stage a laparoscopy would be performed, whereas in reality only reactivation of temporarily obscured lesions did occur. The suppressed, dormant (but never absent) lesions produce mucus again, desquamation occurs, and reaction by the surrounding tissue. The inflammatory response, the local hyperemia and the neogenesis of vessels accentuate the presence of previously invisible endometriosis lesions and make them visible again. Endometriosis resumes its temporarily halted natural course of development, tissue remodeling occurs again, the battle between the aggressor and the defense resumes and waxing and waning of the several types of lesions, red, white and black, can be found again.

Objective: To evaluate whether the predictive ability of a normal FSH level on cycle day 3 can be enhanced by levels of estradiol-17β (E 2 ) on cycle day 3. Design: Prospective cohort study. Setting: University hospital–based, tertiary care infertility center. Patient(s): Two hundred thirty-one consecutively seen patients who attended the center for their first IVF attempt. Intervention(s): Blood samples were collected on day 3 of the cycle preceding IVF; IVF was performed in all patients. Main Outcome Measure(s): Patient's age, number of ampules of hMG, cancellation rate, number of oocytes, fertilization rate, and clinical pregnancy rate. Result(s): In patients with elevated FSH levels on cycle day 3, a low oocyte yield was achieved (7 versus 11) and a high number of ampules of hMG was necessary (56 versus 33). Their cancellation rate was high (67% versus 16%). In patients with normal basal FSH levels, high E 2 levels predicted a high cancellation rate (56%, versus 13% in patients with low E 2 levels) and a low oocyte yield (9, versus 11 in patients with low E 2 levels). Patients with both normal FSH levels and low E 2 levels on cycle day 3 fared best. Conclusion(s): The basal E 2 level on cycle day 3 is a useful prognosticator of response to stimulation in IVF patients with normal basal FSH levels.