Abstract
STUDY QUESTION
Does starting IUI with ovarian stimulation (IUI-OS) within 1.5 years after completion of the fertility workup increase ongoing pregnancy rates compared to expectant management ...in couples with unexplained subfertility?
SUMMARY ANSWER
IUI-OS is associated with higher chances of ongoing pregnancy compared to expectant management in unexplained subfertile couples, specifically those with poor prognoses of natural conception, i.e. <15% over 6 months or <25% over 1 year.
WHAT IS KNOWN ALREADY
IUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found conflicting results. A cohort of couples with unexplained subfertility exposed to expectant management and IUI-OS offers an opportunity to determine the chances of conception after both strategies and to evaluate whether the effect of IUI-OS depends on a couple's prognosis of natural conception.
STUDY DESIGN, SIZE, DURATION
A prospective cohort study on couples with unexplained or mild male subfertility who could start IUI-OS at any point after completion of the fertility workup, recruited in seven Dutch centres between January 2002 and February 2004. Decisions regarding treatment were subject to local protocols, the judgement of the clinician and the wishes of the couple. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded. Follow up was censored at the start of IVF, after the last IUI cycle or at last contact and truncated at a maximum of 1.5 years after the fertility workup.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month ongoing pregnancy rates over the next 6 months of couples who started IUI-OS to couples who did not. We calculated the prognosis of natural conception for individual couples, updated this over consecutive failed cycles and evaluated whether prognosis modified the effect of starting IUI-OS. We corrected for known predictors of conception using inverse probability weighting.
MAIN RESULTS AND THE ROLE OF CHANCE
Data from 1896 couples were available. There were 800 couples whom had at least one IUI-OS cycle within 1.5 years post fertility workup of whom 142 couples conceived (rate: 0.50 per couple per year, median follow up 4 months). The median period between fertility workup completion and starting IUI-OS was 6.5 months. Out of 1096 untreated couples, 386 conceived naturally (rate: 0.31 per couple per year, median follow up 7 months). Starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.96 (95% CI: 1.47-2.62) compared to expectant management. The effect of treatment was modified by a couple's prognosis of achieving natural conception (P = 0.01), with poorer prognoses or additional failed natural cycles being associated with a stronger effect of treatment. The predicted 6-month ongoing pregnancy rate for a couple with a prognosis of 25% at completion of the fertility workup over the next six cycles (~40% over 1 year) was 25% (95% CI: 21-28%) for expectant management and 24% (95% CI: 9-36%) when starting IUI-OS directly. For a couple with a prognosis of 15% (25% over 1 year), these predicted rates were 17% (95% CI: 15-19%) for expectant management and 24% (95% CI: 15-32%) for starting IUI-OS.
LIMITATIONS, REASONS FOR CAUTION
The effect estimates are based on a prospective cohort followed up for 1.5 years after completion of the fertility workup. Although we balanced the known predictors of conception between treated and untreated couples using inverse probability weighting, observational data may be subject to residual confounding. The results need to be confirmed in external datasets.
WIDER IMPLICATIONS OF THE FINDINGS
These results explain the discrepancies between previous trials that compared IUI-OS to expectant management, but further studies are required to establish the threshold at which IUI-OS is (cost-)effective.
STUDY FUNDING/COMPETING INTEREST(S)
This study was facilitated by (Grant 945/12/002) from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. S.B. reports acting as Editor-in-Chief of HROpen. The other authors have no conflicts of interest.
The American Group Psychotherapy Association (AGPA) Practice Guidelines helped inspire the Dutch Group Therapy Association (NVGP) to develop the Dutch Practice Guidelines for Group Treatment. In this ...article, we provide a short review of the history of Dutch group psychotherapy. We discuss socioeconomic developments in the Netherlands and their consequences for health care in general and group psychotherapy in particular. After that, we introduce the procedures of the NVGP Dutch Task Force in developing their Practice Guidelines including their process to reach expert consensus. We then elaborate on the similarities and differences between the American and the Dutch Practice Guidelines. We end by presenting future directions and thoughts on international cooperation in the development of evidence-based practice guidelines for group treatment.
Abstract
STUDY QUESTION
How can we predict chances of natural conception at various time points in couples diagnosed with unexplained subfertility?
SUMMARY ANSWER
We developed a dynamic prediction ...model that can make repeated predictions over time for couples with unexplained subfertility that underwent a fertility workup at a fertility clinic.
WHAT IS KNOWN ALREADY
The most frequently used prediction model for natural conception (the ‘Hunault model’) estimates the probability of natural conception only once per couple, that is, after completion of the fertility workup. This model cannot be used for a second or third time for couples who wish to know their renewed chances after a certain period of expectant management.
STUDY DESIGN, SIZE, DURATION
A prospective cohort studying the long-term follow-up of subfertile couples included in 38 centres in the Netherlands between January 2002 and February 2004. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The primary endpoint was time to natural conception, leading to an ongoing pregnancy. Follow-up time was censored at the start of treatment or at the last date of contact. In developing the new dynamic prediction model, we used the same predictors as the Hunault model, i.e. female age, duration of subfertility, female subfertility being primary or secondary, sperm motility and referral status. The performance of the model was evaluated in terms of calibration and discrimination. Additionally, we assessed the utility of the model in terms of the variability of the calculated predictions.
MAIN RESULTS AND THE ROLE OF CHANCE
Of the 4999 couples in the cohort, 1053 (21%) women reached a natural conception leading to an ongoing pregnancy within a mean follow-up of 8 months (5th and 95th percentile: 1–21). Our newly developed dynamic prediction model estimated the median probability of conceiving in the first year after the completion of the fertility workup at 27%. For couples not yet pregnant after half a year, after one year and after one and a half years of expectant management, the median probability of conceiving over the next year was estimated at 20, 15 and 13%, respectively. The model performed fair in an internal validation. The prediction ranges were sufficiently broad to aid in counselling couples for at least two years after their fertility workup.
LIMITATIONS, REASONS FOR CAUTION
The dynamic prediction model needs to be validated in an external population.
WIDER IMPLICATIONS OF THE FINDINGS
This dynamic prediction model allows reassessment of natural conception chances after various periods of unsuccessful expectant management. This gives valuable information to counsel couples with unexplained subfertility that are seen for a fertility workup.
STUDY FUNDING/COMPETING INTEREST(S)
This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests.
Hysterosalpingography (HSG) with an oil-based contrast has been shown to increase ongoing pregnancy rates compared with HSG with water-based contrast, but it remains unclear if an effect of HSG ...occurs compared with no HSG.
A secondary data-analysis of a prospective cohort study among 4556 couples that presented with unexplained subfertility in 38 clinics in the Netherlands between January 2002 and December 2004. A time-varying Cox regression with inverse probability of treatment weighing was used to analyse ongoing pregnancy rates in women after undergoing the HSG procedure (with the use of either water- or oil-based contrast media) compared with women who did not undergo HSG.
The probability of natural conception within 24 months after first presentation at the fertility clinic was increased after HSG, regardless of the type of contrast medium used, compared with no HSG (adjusted hazard ratio 1.48, 95% CI 1.26 to 1.73, corresponding to an absolute increase in 6-month pregnancy rate of +6%). When this analysis was limited to HSGs that were made with water-contrast, the treatment effect remained (adjusted hazard ratio 1.40, 95% CI 1.16 to 1.70).
HSG increases the ongoing pregnancy rate of couples with unexplained subfertility compared with no HSG, regardless of the contrast medium used. Results need to be validated in future, preferably randomized, studies.
BACKGROUND: Prediction models for spontaneous pregnancy may be useful tools to select subfertile couples that have good fertility prospects and should therefore be counselled for expectant ...management. We assessed the accuracy of a recently published prediction model for spontaneous pregnancy in a large prospective validation study. METHODS: In 38 centres, we studied a consecutive cohort of subfertile couples, referred for an infertility work-up. Patients had a regular menstrual cycle, patent tubes and a total motile sperm count (TMC) >3 × 106. After the infertility work-up had been completed, we used a prediction model to calculate the chance of a spontaneous ongoing pregnancy (www.freya.nl/probability.php). The primary end-point was time until the occurrence of a spontaneous ongoing pregnancy within 1 year. The performance of the pregnancy prediction model was assessed with calibration, which is the comparison of predicted and observed ongoing pregnancy rates for groups of patients and discrimination. RESULTS: We included 3021 couples of whom 543 (18%) had a spontaneous ongoing pregnancy, 57 (2%) a non-successful pregnancy, 1316 (44%) started treatment, 825 (27%) neither started treatment nor became pregnant and 280 (9%) were lost to follow-up. Calibration of the prediction model was almost perfect. In the 977 couples (32%) with a calculated probability between 30 and 40%, the observed cumulative pregnancy rate at 12 months was 30%, and in 611 couples (20%) with a probability of ≥40%, this was 46%. The discriminative capacity was similar to the one in which the model was developed (c-statistic 0.59). CONCLUSIONS: As the chance of a spontaneous ongoing pregnancy among subfertile couples can be accurately calculated, this prediction model can be used as an essential tool for clinical decision-making and in counselling patients. The use of the prediction model may help to prevent unnecessary treatment.
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.
Conventional meta-analysis has estimated the sensitivity and specificity of hysterosalpingography (HSG) to be 65% and 83%. The impact of patient characteristics on the accuracy of HSG is unknown. The ...aim of this study was to assess by individual patient data meta-analysis whether the accuracy of HSG is associated with different patient characteristics.
We approached authors of primary studies reporting on the accuracy of HSG using findings at laparoscopy as the reference. We assessed whether patient characteristics such as female age, duration of subfertility and a clinical history without risk factors for tubal pathology were associated with the accuracy of HSG, using a random intercept logistic regression model.
We acquired data of seven primary studies containing data of 4521 women. Pooled sensitivity and specificity of HSG were 53% and 87% for any tubal pathology and 46% and 95% for bilateral tubal pathology. In women without risk factors, the sensitivity of HSG was 38% for any tubal pathology, compared with 61% in women with risk factors (P = 0.005). For bilateral tubal pathology, these rates were 13% versus 47% (P = 0.01). For bilateral tubal pathology, the sensitivity of HSG decreased with age factor 0.93 per year (P = 0.05). The specificity of HSG was very stable across all subgroups.
The accuracy of HSG in detecting tubal pathology was similar in all subgroups, except for women without risk factors in whom sensitivity was lower, possibly due to false-positive results at laparoscopy. HSG is a useful tubal patency screening test for all infertile couples.
BACKGROUND
The relation between Chlamydia trachomatis infection and subsequent tubal damage is widely recognized. As such, C. trachomatis antibody (CAT) testing can be used to triage women for ...immediate tubal testing with hysterosalpingography (HSG) or laparoscopy. However, once invasive tubal testing has ruled out tubal pathology, CAT serology status is ignored, as its clinical significance is currently unknown. This study aimed to determine whether positive CAT serology is associated with lower spontaneous pregnancy rates in women in whom HSG and/or diagnostic laparoscopy showed no visible tubal pathology.
METHODS
We studied ovulatory women in whom HSG or laparoscopy showed patent tubes. Women were tested for C. trachomatis immunoglobulin G (IgG) antibodies with either micro-immunofluorescence (MIF) or an ELISA. CAT serology was positive if the MIF titre was ≥1:32 or if the ELISA index was >1.1. The proportion of couples pregnant without treatment was estimated at 12 months of follow-up. Time to pregnancy was considered censored at the date of the last contact when the woman was not pregnant or at the start of treatment. The association between CAT positivity and an ongoing pregnancy was evaluated with Cox regression analyses.
RESULTS
Of the 1882 included women without visible tubal pathology, 338 (18%) had a treatment-independent pregnancy within 1 year estimated cumulative pregnancy rate 31%; 95% confidence interval (CI): 27–35%. Because of differential censoring after 9 months of follow-up, regression analyses were limited to the first 9 months after tubal testing. Positive C. trachomatis IgG serology was associated with a statistically significant 33% lower probability of an ongoing pregnancy adjusted fecundity rate ratio 0.66 (95% CI 0.49–0.89).
CONCLUSIONS
Even after HSG or laparoscopy has shown no visible tubal pathology, subfertile women with a positive CAT have lower pregnancy chances than CAT negative women. After external validation, this finding could be incorporated into existing prognostic models.
At present, it is unclear which treatment strategy is best for couples with unexplained or mild male subfertility. We hypothesized that the prognostic profile influences the effectiveness of assisted ...conception. We addressed this issue by analysing individual patient data (IPD) from randomized controlled trials (RCTs).
We performed an IPD analysis of published RCTs on treatment strategies for subfertile couples. Eligible studies were identified from Cochrane systematic reviews and we also searched Medline and EMBASE. The authors of RCTs that compared expectant management (EM), intracervical insemination (ICI), intrauterine insemination (IUI), all three with or without controlled ovarian stimulation (COS) and IVF in couples with unexplained or male subfertility, and had reported live birth or ongoing pregnancy as an outcome measure, were invited to share their data. For each individual patient the chance of natural conception was calculated with a validated prognostic model. We constructed prognosis-by-treatment curves and tested whether there was a significant interaction between treatment and prognosis.
We acquired data from 8 RCTs, including 2550 couples. In three studies (n = 954) the more invasive treatment strategies tended to be less effective in couples with a high chance of natural conception but this difference did not reach statistical significance (P-value for interaction between prognosis and treatment outcome were 0.71, 0.31 and 0.19). In one study (n = 932 couples) the strategies with COS (ICI and IUI) led to higher pregnancy rates than unstimulated strategies (ICI 8% versus 15%, IUI 13% versus 22%), regardless of prognosis (P-value for interaction in all comparisons >0.5), but at the expense of a high twin rate in the COS strategies (ICI 6% versus 23% and IUI 3% versus 30%, respectively). In two studies (n = 373 couples), the more invasive treatment strategies tended to be more effective in couples with a good prognosis but this difference did not reach statistical significance (P-value for interaction: 0.38 and 0.68). In one study (n = 253 couples) the differential effect of prognosis on treatment effect was limited (P-value for interaction 0.52), perhaps because prognosis was incorporated in the inclusion criteria. The only study that compared EM with IVF included 38 couples, too small for a precise estimate.
In this IPD analysis of couples with unexplained or male subfertility, we did not find a large differential effect of prognosis on the effectiveness of fertility treatment with IUI, COS or IVF.
INTRODUCTION
Prediction models for spontaneous pregnancy are useful tools to prevent overtreatment, complications and costs in subfertile couples with a good prognosis. The use of such models and ...subsequent expectant management in couples with a good prognosis are recommended in the Dutch fertility guidelines, but not fully implemented. In this study, we assess risk factors for non-adherence to tailored expectant management.
METHODS
Couples with mild male, unexplained and cervical subfertility were included in this multicentre prospective cohort study. If the probability of spontaneous pregnancy within 12 months was ≥40%, expectant management for 6–12 months was advised. Multivariable logistic regression was used to identify patient and clinical characteristics associated with non-adherence to tailored expectant management.
RESULTS
We included 3021 couples of whom 1130 (38%) had a ≥40% probability of a spontaneous pregnancy. Follow-up was available for 1020 (90%) couples of whom 214 (21%) had started treatment between 6 and 12 months and 153 (15%) within 6 months. A higher female age and a longer duration of subfertility were associated with treatment within 6 months (OR: 1.06, 95% CI: 1.01–1.1; OR: 1.4; 95% CI: 1.1–1.8). A fertility doctor in a clinical team reduced the risk of treatment within 6 months (OR: 0.62; 95% CI: 0.39–0.99).
CONCLUSIONS
In couples with a favorable prognosis for spontaneous pregnancy, there is considerable overtreatment, especially if the woman is older and duration of the subfertility is longer. The presence of a fertility doctor in a clinic may prevent early treatment.
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