Objective: To assess the effectiveness of controlled ovarian hyperstimulation (COH) in intrauterine insemination (IUI) for subfertile couples with an abnormal postcoital test and a poor prognosis.Design: Randomized clinical trial.Setting: Twenty-four fertility centers in the Netherlands.Patient(s): Subfertile couples with a well-timed nonprogressive PCT and additional factors that reduce fertility.Intervention(s): Couples were randomly allocated to three cycles of IUI with COH or three cycles of IUI without COH.Main Outcome Measure(s): Ongoing pregnancy within three IUI cycles.Result(s): We randomly allocated 132 couples to IUI with COH, and 133, to IUI without COH. We observed 33 pregnancies (25%) in the couples allocated to IUI with COH, of which 28 were ongoing (21%), vs. 28 pregnancies (21%) in the couples allocated to IUI without COH, of which 23 were ongoing (17%; relative risk of an ongoing pregnancy, 1.2; 95% confidence interval, 0.75 to 2.0). Two multiple pregnancies occurred in the IUI with COH group, and one, in the IUI without COH group.Conclusion(s): In couples with an abnormal PCT and a poor prognosis, IUI with COH leads to pregnancy rates comparable to those for IUI without COH. We propose to perform IUI without COH in couples with an abnormal PCT. (Fertil Steril((R)) 2007;88:1618-24. (c) 2007 by American Society for Reproductive Medicine.).

IMPORTANCE Early plasma transfusion for women with severe postpartum hemorrhage (PPH) is recommended to prevent coagulopathy. However, there is no comparative, quantitative evidence on the association of early plasma transfusion with maternal outcomes. OBJECTIVE To compare the incidence of adverse maternal outcomes among women who received plasma during the first 60 minutes of persistent PPH vs women who did not receive plasma for similarly severe persistent PPH. DESIGN, SETTING, AND PARTICIPANTS This multicenter cohort study used a consecutive sample of women with persistent PPH, defined as PPH refractory to first-line measures to control bleeding, between January 1, 2011, and January 1, 2013. Time-dependent propensity score matching was used to select women who received plasma during the first 60 minutes of persistent PPH and match each of them with a woman who had shown the same severity and received the same treatment of PPH but who had not received plasma at the moment of matching. Transfusions were not guided by coagulation tests. Statistical analysis was performed from June 2018 to June 2019. EXPOSURES Transfusion of plasma during the first 60 minutes of persistent PPH vs no or later plasma transfusion. MAIN OUTCOMES AND MEASURES Incidence of adverse maternal outcomes, defined as a composite of death, hysterectomy, or arterial embolization. RESULTS This study included 1216 women (mean [SD] age, 31.6 [5.0] years) with persistent PPH, of whom 932 (76.6%) delivered vaginally and 780 (64.1%) had PPH caused by uterine atony. Seven women (0.6%) died because of PPH, 62 women (5.1%) had a hysterectomy, and 159 women (13.1%) had arterial embolizations. Among women who received plasma during the first 60 minutes of persistent PPH, 114 women could be matched with a comparable woman who had not received plasma at the moment of matching. The incidence of adverse maternal outcomes was similar between the women, with adverse outcomes recorded in 24 women (21.2%) who received early plasma transfusion and 23 women (19.9%) who did not receive early plasma transfusion (odds ratio, 1.09; 95% CI, 0.57-2.09). Results of sensitivity analyses were comparable to the primary results. CONCLUSIONS AND RELEVANCE In this cohort study, initiation of plasma transfusion during the first 60 minutes of persistent PPH was not associated with adverse maternal outcomes compared with no or later plasma transfusion, independent of severity of PPH.

One of the aims in reproductive medicine is to differentiate between couples that have favourable chances of conceiving naturally and those that do not. Since the development of the prediction model of Hunault, characteristics of the subfertile population have changed. The objective of this analysis was to assess whether additional predictors can refine the Hunault model and extend its applicability. Consecutive subfertile couples with unexplained and mild male subfertility presenting in fertility clinics were asked to participate in a prospective cohort study. We constructed a multivariable prediction model with the predictors from the Hunault model and new potential predictors. The primary outcome, natural conception leading to an ongoing pregnancy, was observed in 1053 women of the 5184 included couples (20%). All predictors of the Hunault model were selected into the revised model plus an additional seven (woman's body mass index, cycle length, basal FSH levels, tubal status,history of previous pregnancies in the current relationship (ongoing pregnancies after natural conception, fertility treatment or miscarriages), semen volume, and semen morphology. Predictions from the revised model seem to concur better with observed pregnancy rates compared with the Hunault model; c-statistic of 0.71 (95% CI 0.69 to 0.73) compared with 0.59 (95% CI 0.57 to 0.61).

Background: Standardization of the semen analysis may improve reproducibility. We assessed variability between laboratories in semen analyses and evaluated whether a transformation using Z scores and regression statistics was able to reduce this variability.Materials and Methods: We performed a retrospective cohort study. We calculated between-laboratory coefficients of variation (CVB) for sperm concentration and for morphology. Subsequently, we standardized the semen analysis results by calculating laboratory specific Z scores, and by using regression. We used analysis of variance for four semen parameters to assess systematic differences between laboratories before and after the transformations, both in the circulation samples and in the samples obtained in the prospective cohort study in the Netherlands between January 2002 and February 2004.Results: The mean CVB was 7% for sperm concentration (range 3 to 13%) and 32% for sperm morphology (range 18 to 51%). The differences between the laboratories were statistically significant for all semen parameters (all P<0.001). Standardization using Z scores did not reduce the differences in semen analysis results between the laboratories (all P<0.001).Conclusion: There exists large between-laboratory variability for sperm morphology and small, but statistically significant, between-laboratory variation for sperm concentration. Standardization using Z scores does not eliminate between-laboratory variability.

Esther Leushuis1,2,*, Jan Willem van der Steeg3, Pieternel Steures4, Sjoerd Repping2, Patrick M.M. Bossuyt5, Ben Willem J. Mol2, Peter G.A. Hompes1, and Fulco van der Veen2 Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands Center for Reproductive Medicine, Academic Medical Center, Amsterdam, The Netherlands Department of Obstetrics and Gynaecology, Jeroen Bosch Ziekenhuis, ‘s Hertogenbosch, The Netherlands Department of Obstetrics and Gynaecology, St. Elisabeth Ziekenhuis, Tilburg Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands

STUDY QUESTION:Do two semen analyses predict natural conception better than a single semen analysis and will adding the results of repeated semen analyses to a prediction model for natural pregnancy improve predictions?SUMMARY ANSWER:A second semen analysis does not add helpful information for predicting natural conception compared with using the results of a single semen analysis and addition of the second analysis to a prediction model for natural conception did not improve predictions.WHAT IS KNOWN ALREADY:A major problem with semen analyses is the large variability of results within an individual. High-quality evidence is lacking on how many semen analyses need to be performed during the fertility workup to achieve an accurate prediction of conception.STUDY DESIGN, SIZE, DURATION:We conducted a prospective cohort study of 897 consecutive couples presenting with subfertility in two university hospitals in the period 2002-2004 in the Netherlands.PARTICIPANTS/MATERIALS, SETTING, AND METHODS:The laboratories scored sperm parameters according to the 1999 WHO criteria. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of ×200. All assessments were performed by trained laboratory technicians. Follow-up started at the completion of the infertility workup and ended after 12 months. Primary end-point was natural conception resulting in an ongoing pregnancy. We constructed models for three strategies for the prediction of natural conception, using univariable and multivariable Cox hazard regression analyses. We evaluated the performance of the three strategies by comparing goodness-of-fit, discrimination and calibration. First, we analysed the semen parameters only. Secondly, we analysed the semen parameters in addition to the multivariable Hunault prediction model.MAIN RESULTS AND THE ROLE OF CHANCE:Of the 897 couples, 132 (15%) achieved a pregnancy by natural conception. Using the results of a single semen analysis only, the calculated probabilities of natural conception within 12 months across the study population ranged from 0.12 to 0.38, with a median of 0.16 (IQR: 0.16-0.17). Using the results of two semen analyses did not lead to a better goodness-of-fit. Discriminative capacity was rather poor, with an area under the ROC curve (AUC) ranging from 0.51 to 0.56. Using the Hosmer-Lemeshow test statistic we found no signs of poor calibration. Using the results of two semen analyses in combination with the Hunault model did not significantly increase goodness-of-fit compared with using a single semen analysis. The Hunault model with the addition of the semen parameters fitted the data significantly better than the Hunault model itself (difference in -2 Log likelihood: 13; 3 df; P = 0.002). Using the Hosmer-Lemeshow test statistic we found no signs of poor calibration.LIMITATIONS, REASONS FOR CAUTION:The academic setting possibly explains the relatively low natural conception rates, with only 15% achieving a natural conception within 1 year. Men with azoospermia were excluded.WIDER IMPLICATIONS OF THE FINDINGS:Performing more than one semen analysis will not increase the prognostic power of the test in clinical practice. Adding the first semen analysis to the Hunault model for the prediction of natural conception improved performance significantly compared with using the Hunault model alone. External validation, in other populations, should follow to confirm our conclusions, and to evaluate the generalizability or transportability of the extended Hunault model.STUDY FUNDING/COMPETING INTEREST(S):No external funding was involved in this study. None of the authors has any conflict of interest to declare.

OBJECTIVE:To evaluate whether baseline characteristics and prognostic profiles differed between couples who drop out from intrauterine insemination (IUI) and couples that continue IUI, and the reasons for couples dropping out from IUI programs.DESIGN:Retrospective observational cohort study.SETTING:Fertility centers.PATIENT(S):Consecutive subfertile couples undergoing IUI.INTERVENTION(S):None.MAIN OUTCOME MEASURE(S):Characteristics and prognosis of ongoing pregnancy after IUI at the start of treatment of couples that dropped out compared with couples that continued treatment or achieved an ongoing pregnancy.RESULT(S):We studied 803 couples who underwent 3,579 IUI cycles of whom 221 couples dropped out (28%). Couples dropping out completed 2.8 (SD ±1.4) cycles per couple compared with 4.5 (SD ±2.3) cycles per couple for those continuing treatment. Couples dropping out had a higher female age, longer subfertility duration, and higher basal FSH. Mean prognosis to achieve an ongoing pregnancy after IUI at start of treatment was 7.9% (SD ±2.4) per cycle for couples who dropped out and 8.5% (SD ±2.5) per cycle for couples continuing treatment. Of the dropouts, 100 couples (45%) were actively censored from the IUI program, 87 couples (39%) because of poor prognosis; 121 couples (55%) were passively censored from the program, of whom 62 (28%) dropped out owing to personal reasons; 59 couples (27%) were lost to follow-up.CONCLUSION(S):We found significant differences in prognostic profile between couples continuing treatment and couples dropping out, although these differences seem limited from a clinical perspective. We conclude that overestimation of ongoing pregnancy rates after IUI due to couples dropping out is limited.

Objective: A previous randomized clinical trial (RCT) compared immediate treatment with intrauterine insemination (IUI) to expectant management for six months in subfertile couples with an isolated cervical factor. That study showed higher ongoing pregnancy rates in couples receiving intrauterine insemination. The current study compared the long-term effectiveness and costs of this intervention.Study design: We followed all couples (N = 99) who were previously included in the RCT for three years after randomization and registered pregnancies and treatments. After the initial trial period, couples in both groups were offered further treatment according to local protocol. The primary outcome was an ongoing pregnancy after three years.Results: After three years, there were 36 ongoing pregnancies in the immediate IUI group (N = 51 couples) and 38 ongoing pregnancies in the expectant management group (N = 48 couples). The ongoing pregnancy rates were 71% and 79% respectively (RR 0.89 (95% confidence interval (CI) 0.7-1.1)).Conclusions: In couples with an isolated cervical factor, a treatment strategy including immediate treatment with IUI does not result in higher ongoing pregnancy rates on the long term. Initial expectant management is therefore justified in these couples and identifying a cervical factor by a post-coital test is unnecessary. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

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Please cite this paper as: Boogaard N van den, Hompes P, Barnhart K, Bhattacharya S, Custers I, Coutifaris C, Goverde A, Guzick D, Litvak P, Steures P, Veen F van der, Bossuyt P, Mol B. The prognostic profile of subfertile couples and treatment outcome after expectant management, intrauterine insemination and in vitro fertilisation: a study protocol for the meta‐analysis of individual patient data. BJOG 2012;119:953–957.Objective The current evidence concerning the best treatment option for couples with unexplained and male subfertility is inconclusive. Most studies that have evaluated the effectiveness of treatment options, such as expectant management (EM), intrauterine insemination (IUI), with or without controlled ovarian stimulation (COS), and in vitro fertilisation (IVF), have not taken the couples’ prognosis into account. It is very likely that the individual prognosis of the couple influences the effect of treatment. Individual patient data analyses allow us to take these prognostic factors into account, and to evaluate their effect on treatment outcome. This study aims to use anonymised data from relevant published trials to perform an individual patient data meta‐analysis, evaluating the effect of couples’ prognosis on the effectiveness of EM, IUI, with or without COS, and IVF.Methods Based on earlier systematic reviews and an updated search, randomised controlled trials will be considered for inclusion. Untreated subfertile couples with unexplained or male subfertility included in trials comparing EM, IUI, with or without COS, and IVF are included. Authors of the included studies will be invited to share their original anonymised data. The data will be assessed on validity, quality and completeness. The prognosis of the individual couple will be calculated with existing prognostic models. The effect of the prognosis on treatment outcome will be analysed with marker‐by‐treatment predictiveness curves, illustrating the effect of prognosis on treatment outcome. This study is registered in PROSPERO (registration number CRD42011001832).Conclusion Ultimately, this study may help to select the appropriate fertility treatment, tailored to the needs of an individual couple.

Unexplained or idiopathic infertility means no cause can be found to account for the infertility. This depends on the enthusiasm to look for the subtle causes like luteal phase defect (LPD), luteinizing unruptured follicle syndrome (LUFS), abnormal prolactin secretion, psychogenic, environmental, nutritional and immunological factors. Sometimes, these subclinical conditions can be corrected. Failing to identify these treatable conditions, various empirical treatments, laboratory manipulation or assisted reproductive techniques (ART) can be attempted to achieve conception.

Objective: To evaluate the capacity of the postcoital test (PCT) to predict spontaneous pregnancy in a large cohort study of subfertile couples.Design: Prospective study.Setting: Department of reproductive medicine of 38 hospitals in the Netherlands.Patient(s): Between January 2002 and February 2004, we prospectively included consecutive subfertile couples who had not been evaluated previously for subfertility.Intervention(s): We estimated the contribution of the PCT result to the existing prediction model for spontaneous pregnancy by calculating the adjusted hazard ratio (HR) of an abnormal PCT result. We constructed a second prediction model (PCT model) based on the reference model including the PCT.Main Outcome Measure(s): Primary endpoint in this study was ongoing pregnancy. We evaluated the performance of the PCT model in comparison with the reference model by calculating goodness of fit, discrimination, calibration, and the "net reclassification improvement''.Result(s): We included 3,021 couples of whom537 (18%) had a spontaneous pregnancy and 55 (1.8%) a nonsuccessful pregnancy; 1,316 (44%) started treatment within 12months, 824 (27%) neither started treatment nor became pregnant, and 289 (10%) became lost to follow-up within 12 months. The adjusted HR for an abnormal PCTwas 0.76 (95% confidence interval [CI]: 0.62 to 0.94). The adjustedHRfor an abnormal PCTwas 0.63 (95% CI: 0.47 to 0.84) in case of no spermatozoa, 0.81 (95% CI: 0.57 to 1.2) in case of nonmotile spermatozoa, and 1.2 (95% CI: 0.8 to 1.8) in case of motile, nonprogressive spermatozoa. Adding the PCT result to the reference model did not improve goodness of fit. Discrimination was equally poor for the PCT model and the reference model. The calibration plots of both models showed comparably good calibration. The net reclassification improvement of the predictions of the PCT model compared with the reference model was -1.1%.Conclusion(s): This study demonstrated that the PCT has prognostic value but does not add substantially to a prognostic model for spontaneous pregnancy. (Fertil Steril (R) 2011; 95:2050-5. (C) 2011 byAmerican Society for Reproductive Medicine.)

Objective: To evaluate the effectiveness of IVF with elective single embryo transfer (IVF-eSET) vs. IUI with controlled ovarian stimulation (IUI-COS) as an alternative treatment to reduce the risk for a multiple pregnancy.Design: Randomized pilot trial.Setting: Three academic and six teaching hospitals in the Netherlands.Patient(s): Couples with unexplained or mild male subfertility and an unfavorable prognosis for natural conception.Intervention(s): One cycle of IVF-eSET or three cycles of IUI-COS.Main Outcome Measure(s): Ongoing pregnancy per couple.Result(s): We randomly allocated 116 women to IVF-eSET (n = 58) or IUI-COH (n = 58). There were 14 ongoing pregnancies (24%) in the IVF-eSET group and 12 pregnancies (21%) in the IUI-COS group (relative ratio 1.17; 95% confidence interval 0.60-2.30). There were two twin pregnancies in the IVF-eSET group (14%) and two twin pregnancies and one triplet pregnancy in the IUI-COH group (25%).Conclusion(s): In patients with unexplained or mild male subfertility and a poor prognosis for natural conception, one cycle of IVF-eSET might be as effective as three cycles of IUI-COS as primary treatment. Elective single embryo transfer does not seem an effective strategy in preventing multiple pregnancies in this particular population. In the future a strict SET policy (i.e., compulsory SET) might be an option. Our trial provides evidence for the feasibility and highlights the importance of a large definitive trial to determine the effectiveness and side effects of both strategies. (Fertil Steril (R) 2011;96:1107-11. (C) 2011 by American Society for Reproductive Medicine.)

BACKGROUND: The Chlamydia IgG antibody test (CAT) shows considerable variations in reported estimates of test accuracy, partly because of the use of different assays and cut-off values. The aim of this study was to reassess the accuracy of CAT in diagnosing tubal pathology by individual patient data (IPD) meta-analysis for three different CAT assays.METHODS: We approached authors of primary studies that used micro-immunofluorescence tests (MIF), immunofluorescence tests (IF) or enzyme-linked immunosorbent assay tests (ELISA). Using the obtained IPD, we performed pooled receiver operator characteristics analysis and logistic regression analysis with a random effects model to compare the three assays. Tubal pathology was defined as either any tubal obstruction or bilateral tubal obstruction.RESULTS: We acquired data of 14 primary studies containing data of 6191 women, of which data of 3453 women were available for analysis. The areas under the curve for ELISA, IF and MIF were 0.64, 0.65 and 0.75, respectively (P-value, < 0.001) for any tubal pathology and 0.66, 0.66 and 0.77, respectively (P-value = 0.01) for bilateral tubal pathology.CONCLUSIONS: In Chlamydia antibody testing, MIF is superior in the assessment of tubal pathology. In the initial screen for tubal pathology MIF should therefore be the test of first choice.

BACKGROUNDWe recently reported that treatment with intrauterine insemination and controlled ovarian stimulation (IUI-COS) did not increase ongoing pregnancy rates compared with expectant management (EM) in couples with unexplained subfertility and intermediate prognosis of natural conception. Long-term cost-effectiveness of a policy of initial EM is unknown. We investigated whether the recommendation not to treat during the first 6 months is valid, regarding the long-term effectiveness and cumulative costs.METHODSCouples with unexplained subfertility and intermediate prognosis of natural conception (n=253, at 26 public clinics, the Netherlands) were randomly allocated to 6 months EM or immediate start with IUI-COS. The couples were then treated according to local protocol, usually IUI-COS followed by IVF. We followed couples until 3 years after randomization and registered pregnancies and resources used. Primary outcome was time to ongoing pregnancy. Secondary outcome was treatment costs. Analysis was by intention-to-treat. Economic evaluation was performed from the perspective of the health care institution.RESULTSTime to ongoing pregnancy did not differ between groups (log-rank test P=0.98). Cumulative ongoing pregnancy rates were 72-73% for EM and IUI-COS groups, respectively [relative risk 0.99 (95% confidence interval (CI) 0.85-1.1)]. Estimated mean costs per couple were € 3424 (95% CI € 880-€ 5968) in the EM group and € 6040 (95% CI € 4055-€ 8125) in the IUI-COS group resulting in an estimated saving of € 2616 per couple (95% CI € 385-€ 4847) in favour of EM.CONCLUSIONSIn couples with unexplained subfertility and an intermediate prognosis of natural conception, initial EM for 6 months results in a considerable cost-saving with no delay in achieving pregnancy or jeopardizing the chance of pregnancy. Further comparisons between aggressive and milder forms of ovarian stimulation should be performed.

Objective: To evaluate the associations between the results of the male partner's semen analysis (classified according to the World Health Organization [WHO] criteria) and fathering a child without any treatment.Design: Prospective multicenter cohort study.Setting: Twenty subfertility centers in The Netherlands.Patient(s): A total of 3,345 consecutive couples presenting for subfertility.Intervention(s): None.Main Outcome Measure(s): Associations between the results of the male partner's semen analysis, classified according to the WHO criteria, and fathering a child without any treatment within a time horizon of 1 year. Subsequently, we redefined semen quality criteria and reevaluated the associations.Result(s): Follow-up data of 3,129 couples (94%) were available, of which 517 (17%) had a healthy pregnancy without treatment. The 1-year pregnancy rate in men with WHO normozoospermia did not differ significantly from that in men with WHO impaired semen (24% vs. 23%). In contrast, we observed lower chances of fathering a child for sperm concentrations <40 x 10(6)/mL, total sperm count <200 x 10(6), and sperm morphology <20% normal forms. With a multivariable regression model based on the redefined male semen subfertility criteria we were able to make a finer differentiation between subfertile men, with probabilities of fathering a child ranging from 7% to 41%.Conclusion(s): The current WHO criteria for semen quality do not discriminate between fertile and subfertile men. Our redefined and graded semen criteria have strong predictive value. If interpreted correctly, the fast and inexpensive semen analysis remains the gold standard for defining a man's role in subfertility. (Fertil Steril (R) 2011;95:1013-9. (C) 2011 by American Society for Reproductive Medicine.)

OBJECTIVE:To determine the precise degree of variability that is represented by the reproducibility and reliability of semen analysis. The general assumption is that semen analyses need to be repeated because of a high degree of within-individual variability. However, the precise degree of variability is not well established in male partners of subfertile couples.DESIGN:Retrospective cohort study.SETTING:Two university hospitals in the Netherlands, which routinely perform two semen analyses in the male partner of subfertile couples.PATIENT(S):Male partners of subfertile couples.INTERVENTIONS:None.MAIN OUTCOME MEASURE(S):We assessed the test-retest reproducibility, by calculating the coefficient of variation (CV(w)) for five semen parameters. The CV(w) expresses, on a relative scale, the degree of closeness of repeated measurements taken in the same subject. We also estimated the reliability of these semen parameters, in terms of the intraclass correlation coefficient, which expresses the ratio of the between-subject variability over the total variability.RESULT(S):We analyzed the data of 5,240 men and found that the CV(w) of all semen parameters ranged from 28% to 34%. The intraclass correlation coefficients of these semen parameters were moderate to high: volume: 0.70; concentration: 0.89; motility: 0.58; morphology: 0.60; total motile count: 0.73.CONCLUSION(S):This study affirmed the presumed large within-subject variability and the limited reproducibility of semen analyses in subfertile men. Whether this degree of variability within men justifies one or more repetitions of the semen analysis in view of consequences for clinical management should be the topic of future studies. Until then it seems reasonable to perform two semen analyses.