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.).

Abstract STUDY QUESTION Can we identify patient characteristics that distinguish which ovulatory infertile women undergoing hysterosalpingography (HSG) benefit more or less from flushing with oil-based contrast medium compared to water-based contrast medium? SUMMARY ANSWER In ovulatory infertile women, HSG with oil-based contrast medium resulted in higher 6-month ongoing pregnancy and live birth rates as compared to HSG with water-based contrast medium and this treatment effect was independent of characteristics of the couple. WHAT IS KNOWN ALREADY We recently showed that in infertile women undergoing HSG, flushing with oil-based contrast medium resulted in more ongoing pregnancies than flushing with water-based contrast medium. STUDY DESIGN, SIZE, DURATION We used data from our randomized clinical trial (RCT) in which 1,119 ovulatory infertile women undergoing HSG during fertility work-up were randomized for use of oil-based (N = 557) or water-based (N = 562) contrast medium. PARTICIPANTS/MATERIALS, SETTING, METHODS We built logistic regression models to predict ongoing pregnancy and live birth (secondary outcome) as a function of the specific contrast, the specific marker, and marker-by-contrast-interaction. Markers considered were female age, maternal ethnicity, female smoking, body mass index (BMI), duration of infertility, infertility being primary or secondary, sperm quality, and previous appendectomy. MAIN RESULTS AND THE ROLE OF CHANCE The 6-month ongoing pregnancy rates in the overall population were 39.7% after use of oil-based contrast versus 29.1% after use of water-based contrast medium [relative risk (RR), 1.37; 95% confidence interval (CI), 1.16–1.61; P < 0.001]. Among the studied baseline characteristics, BMI (P = 0.002) and semen volume (P = 0.02) were statistically significant prognosticators. The treatment effect of oil-based contrast was stronger in women with a BMI ≤30 kg/m2 [RR, 1.54; 95% CI, 1.23–1.92; P = 0.002], and in women whose partner had a semen volume >3 ml [RR, 1.77; 95% CI, 1.28–2.46; P = 0.02]. Also, in women who smoked, the treatment effect of flushing with oil was stronger, but this interaction did not reach statistical significance (P = 0.066). We found no positive effect of oil-based contrast in obese women. We found similar but weaker associations for live birth, which was probably due to lower number of events resulting in less power. LIMITATIONS, REASONS FOR CAUTION The RCT was restricted to infertile ovulatory women younger than 39 years of age without endocrinological disorders and at low risk for tubal pathology. Our results should not be generalized to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS All infertile, ovulatory women younger than 39 years with a low risk for tubal pathology will benefit from an HSG with oil-based contrast; therefore, this should be offered to them after fertility work-up. STUDY FUNDING/COMPETING INTEREST(S) The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The study displayed in this paper was funded by an unconditional research grant from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). K.D. reports consultancy for Guerbet, during the conduct of the study, and also reports research grants from Guerbet. C.B.L. reports grants from Guerbet, during the conduct of the study, and grants from Ferring, grants from Merck, and personal fees from Ferring, outside the submitted work. P.H. reports grants from Guerbet, during the conduct of the study, and grants from Ferring and Merck, outside the submitted work. V.M. reports receiving travel and speakers fee as well as research grants from Guerbet. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, and Guerbet, and research grants from Guerbet and Merck. The other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER NTR 3270 www.trialregister.nl TRIAL REGISTRATION DATE 1 February 2012. DATE OF FIRST PATIENT’S ENROLMENT 3 February 2012.

Objective: To determine the cost effectiveness of the use of oil-based versus water-based contrast in infertile women undergoing hysterosalpingography (HSG). Design: Economic evaluation alongside a multicenter randomized trial. Setting: Hospitals. Patient(s): Infertile women with an ovulatory cycle, 18-39 years of age, low risk of tubal pathology. Intervention(s): Use of oil-based versus water-based contrast during HSG. Main Outcome Measure(s): Costs per additional ongoing pregnancy and per live birth within 6 months of randomization, incremental cost-effective ratios (ICERs). Result(s): A total of 1,119 women were randomized to HSG (oil-based contrast, n = 557; water-based contrast, n = 562). After HSG, most women had no additional treatment; a minority had IUI or IVF. In the oil group, 39.7% women had an ongoing pregnancy within 6 months of randomization versus 29.1% women in the water group. There was a 10.7% increase in the live birth rate in the oil group. For ongoing pregnancy, the mean costs per couple were US$2,014 in the oil group and US$1,144 in the water group, with a corresponding ICER of US$8,198 per additional ongoing pregnancy. For live birth, the mean costs per couple were US$11,532 in the oil group and US$8,310 in the water group, with a corresponding ICER of US$30,112 per additional live birth. Conclusion(s): Hysterosalpingography with oil-based contrast results in higher 6-month ongoing pregnancy and live birth rate. If society is willing to pay US$8,198 for an additional ongoing pregnancy, HSG with oil-based contrast is a cost-effective strategy compared with HSG with water-based contrast for infertile, ovulatory women at low risk for tubal pathology. Clinical Trial Registration Number: Dutch Trial Register, NTR 6577 (www.trialregister.nl). (C) 2018 by American Society for Reproductive Medicine.

Background: Clinical management of endometriomas, prior to starting treatment with assisted reproductive technologies (ART), has since long been a matter of debate. Whereas cystectomy has been advocated in the past, recently more evidence has emerged on the potential negative effect of surgery on ovarian reserve. Parallel to this, prolonged downregulation with GnRH-a (gonadotropin-releasing hormone agonists) has been described to improve ART pregnancy rates in women with endometriosis. However, none of these strategies have been assessed in a large randomized controlled trial. The aim of the EndoART study is to assess whether ovarian surgery or prolonged GnRH-a downregulation result in higher pregnancy rates after ART compared to no intervention in women with endometrioma(s). Methods/design: A parallel randomized multi-center trial has been designed to compare ART pregnancy rates in three different treatment groups: no intervention, ovarian surgery, and prolonged hormonal suppression by GnRH-a prior to ART. The primary outcome measure studied is the clinical pregnancy rate with fetal heart-beat within 6 months after initiation of a fresh ART cycle. Secondary outcome measures studied include live birth rate after one initiated fresh ART cycle, cumulative clinical pregnancy rate with fetal heart-beat and live birth rates (after one fully completed ART cycle: initiated fresh + eventual associated frozen embryo transfer cycles), ART–specific data (e.g. number of oocytes, number of good quality embryos), complications, pelvic pain, and quality of life. Conclusion: This trial may answer the most frequently asked questions by both women with endometriosis and physicians: how do you treat endometrioma in women prior to treatment with ART?

We recently showed in a randomized clinical trial (RCT) in 1,119 women that oil-based contrast during hysterosalpingogram (HSG) increases ongoing pregnancy rates as compared to water-based contrast.1 Here, we assess the impact of pain during HSG and used volume of contrast on the effectiveness of oil-based contrast. Secondary analysis of a multicentre RCT. During the study, pain during HSG was measured in seven centres by means of the Visual Analogue Scale (VAS) (range 0.0 to 10.0 in cm, with higher scores indicating more severe pain). The used volume of contrast was recorded in 16 centres. We assessed the impact of pain and volume of contrast on ongoing pregnancy rates, as well as the interaction between each of these two and the treatment effect using logistic regression analysis. Data were analysed according to intention to treat principle. Pain was measured in 400 women (overall median pain score of 5.0 (IQR 3.0-6.8), oil group 4.8 (IQR 3.0-6.4), water group 5.0 (IQR 3.0-6.7) (P=0.28)). There was significant interaction between pain and ongoing pregnancy (VAS cut-off 5.0, P=0.047). In women experiencing pain >5.0 HSG with oil contrast increased the ongoing pregnancy rate (oil versus water Relative Risk (RR) 1.7, 95% CI 1.1-2.5), while in women with a pain score ≤5.0 there was no effect of oil contrast compared to water contrast (RR 0.98, 95% CI 0.66-1.5). Volume of used contrast was recorded in 512 women (overall median volume of 8.3ml (IQR 5.8-14.0), 9.0ml (IQR 5.7-15.0) versus 8.0ml (IQR 5.9-13.0) (P=0.72)). There was no interaction between contrast volume and the type of contrast used. Also, pain and contrast volume were not related. The treatment effect of oil-based contrast during HSG is dependent on pain experienced during the procedure. This points at a mechanistic pathway of the use of oil-based contrast, for example by flushing debris or dislodge of mucus plugs from the tubes.Table 1Ongoing pregnancies after the use of oil and water contrast during HSG stratified for painOil-based contrast (n=199)Water-based contrast (n=201)Relative risk (95% CI)VAS ≤5.034/118 (28.8)33/113 (29.2)0.98 (0.66-1.5)VAS >5.040/81 (49.4)26/88 (29.6)1.7 (1.1-2.5) Open table in a new tab

(Abstracted from Lancet 2018;391:758–765) Clomifene citrate has long been used as a first-line ovulation induction agent for women wishing to conceive who have normogonadotropic anovulation (absent or irregular ovulation). Women who ovulate but do not conceive after several cycles with clomifene citrate are usually switched to ovulation induction with gonadotrophins, with or without intrauterine insemination.

Objective: To study the effectiveness of an intrauterine insemination (IUI) program compared to no treatment in subfertile couples with unexplained subfertility and a poor prognosis on natural conception.Study design: A retrospective matched cohort study in which ongoing pregnancy rates in 72 couples who voluntarily dropped out of treatment with IUI were compared to ongoing pregnancy rates in 144 couples who continued treatment with IUI. Couples with unexplained subfertility, mild male subfertility or cervical factor subfertility who started treatment with IUI between January 2000 and December 2008 were included. Couples were matched on hospital, age, duration of subfertility, primary or secondary subfertility and diagnosis. Primary outcome was cumulative ongoing pregnancy rate after three years. Time to pregnancy was censored at the moment couples were lost to follow up or when their child wish ended and, for the no-treatment group, when couples re-started treatment.Results: After three years, there were 18 pregnancies in the stopped treatment group (25%) versus 41 pregnancies in the IUI group (28%) (RR 1.1 (0.59-2.2)(p = 0.4)). The cumulative pregnancy rate after three years was 40% in both groups, showing no difference in time to ongoing pregnancy (shared frailty model p = 0.86).Conclusions: In couples with unexplained subfertility and a poor prognosis for natural conception, treatment with IUI does not to add to expectant management. There is need for a randomized clinical trial comparing IUI with expectant management in these couples. (C) 2017 Elsevier B.V. All rights reserved.

To evaluate the efficacy and safety of intrauterine insemination (IUI) in moderate to severe endometriosis patients, a systematic review and meta-analysis was conducted since the role of this treatment strategy in these patients is a matter of debate in the literature. Systematic searches were performed in PubMed, EMBASE, Cinahl, and The Cochrane Library from inception to September 1, 2016. Studies including moderate to severe endometriosis patients reporting pregnancy rates after IUI were selected. The primary outcome was live birth after IUI treatment compared to expectant management. Secondary noncomparative outcomes were live birth and clinical pregnancy, which were presented as weighed mean pregnancy rates. Nineteen articles (2 unclear design, 11 retrospective, 6 prospective) were included for the analysis. Our primary outcome measure was only addressed by one study, showing an odds ratio of 1.77 (95% confidence interval [CI], 0.86–3.63) on live birth favoring IUI versus no treatment. The calculated weighed mean live birth and clinical pregnancy rate per patient was 20.3% (95% CI, 11.2–29.4) and 32.7% (95% CI, 21.3– 44.0), respectively. This meta-analysis of observational data showed that IUI could be a feasible treatment in moderate to severe endometriosis. Whether this treatment should be structurally offered prior to in vitro fertilization needs to be investigated in a randomized, controlled trial, including time-to-pregnancy, safety, and cost-effectiveness.

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).

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 x 10(6) 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.

BACKGROUNDPregnancy rates among infertile women have been reported to increase after hysterosalpingography, but it is unclear whether the type of contrast medium used (oil-based or water-soluble contrast) influences this potential therapeutic effect.METHODSWe performed a multicenter, randomized trial in 27 hospitals in the Netherlands in which infertile women who were undergoing hysterosalpingography were randomly assigned to undergo this procedure with the use of oil-based or water-based contrast. Subsequently, couples received expectant management or the women underwent intrauterine insemination. The primary outcome was ongoing pregnancy within 6 months after randomization. Outcomes were analyzed according to the intention-to-treat principle.RESULTSA total of 1119 women were randomly assigned to hysterosalpingography with oil contrast (557 women) or water contrast (562 women). A total of 220 of 554 women in the oil group (39.7%) and 161 of 554 women in the water group (29.1%) had an ongoing pregnancy (rate ratio, 1.37; 95% confidence interval [CI], 1.16 to 1.61; P<0.001), and 214 of 552 women in the oil group (38.8%) and 155 of 552 women in the water group (28.1%) had live births (rate ratio, 1.38; 95% CI, 1.17 to 1.64; P<0.001). Rates of adverse events were low and similar in the two groups.CONCLUSIONSRates of ongoing pregnancy and live births were higher among women who underwent hysterosalpingography with oil contrast than among women who underwent this procedure with water contrast. (Netherlands Trial Register number, NTR3270.)

Objective: To evaluate the cost-effectiveness of single embryo transfer followed by an additional frozen thawed single embryo transfer, if more embryos are available, as compared to double embryo transfer in relation to female age.Study design: We used a decision tree model to evaluate the costs from a healthcare provider perspective and the pregnancy rates of two embryo transfer policies: one fresh single embryo transfer followed by an additional frozen-thawed single embryo transfer, if more embryos are available (strategy I), and double embryo transfer (strategy II). The analysis was performed on an intention-to-treat basis. Sensitivity analyses were carried out to evaluate the robustness of our model and to identify which model parameters had the strongest impact on the results.Results: SET followed by an additional frozen-thawed single embryo transfer if available was dominant, less costly and more effective, over DET in women under 32 years. In women aged 32 or older DET was more effective than SET followed by an additional frozen-thawed single embryo transfer if available but also more costly.Conclusion: SET followed by an additional frozen-thawed single embryo transfer should be the preferred strategy in women under 32 undergoing IVF. The choice for SET followed by an additional frozen-thawed single embryo transfer or DET in women aged 32 or older depends on individual patient preferences and on how much society is willing to pay for an extra child. There is a strong need for a randomized clinical trial comparing the cost and effects of SET followed by an additional frozen-thawed single embryo transfer and DET in the latter category of women. (C) 2017 Elsevier B.V. All rights reserved.

Trials assessing effectiveness in medically assisted reproduction (MAR) should aim to study the desired effect over multiple cycles, as this reflects clinical practice and captures the relevant perspective for the couple. The aim of this study was to assess the extent to which multiple cycles are reported in MAR trials. A sample of randomized controlled trials (RCT) was collected on MAR, published in four time periods, in 11 pre-specified peer-reviewed journals; 253 trials were included: 196 on IVF, 37 on intrauterine insemination and 20 on ovulation induction. Forty-eight (19%) reported on multiple cycles, which was significantly more common in trials on intrauterine insemination and ovulation induction compared with trials on IVF (P < 0.01). Both trials on IVF were multi-centre trials, and those using live birth as primary outcome, reported significantly more often on multiple cycles (OR 3.7 CI 1.1 to 12.5) and (OR 8.7 CI 1.8 to 40.3), respectively. Trials designed to compare protocol variations reported multiple cycles less often (OR 0.07 CI 0.01 to 0.74). Most RCT on MAR, especially those on IVF, do not report cumulative pregnancy rates. As not all women become pregnant in their first cycle, the clinical significance of these trials is limited.

OBJECTIVELittle is known about the aetiology of polycystic ovary syndrome (PCOS). Some suggest that elevated maternal androgens during gestation play a causative role. This implies placental passage of androgens during pregnancy. The aim of this study is to compare androgen and estrogen concentrations in maternal serum during pregnancy and in umbilical cord blood, between mothers with PCOS and their offspring compared to controls.DESIGNProspective case-control study.METHODSMaternal blood samples were collected around 20 weeks of gestation and at delivery. Umbilical cord blood was also taken at delivery. Androgens (testosterone (T), androstenedione (ADION), dehydroepiandrostenedione (DHEA)) and estrogens (estrone (E1), estradiol (E2), estriol (E3)) were measured using the liquid chromatography tandem mass spectrometry (LC-MS/MS) methods.RESULTSAt 20 weeks of gestation: T (P=0.019) and ADION (P=0.034) were higher in the PCOS mothers (pregnant with a girl), whereas DHEA, E1, E2, and E3 were not different. Maternal concentration at birth: T (P=0.004) and ADION (P=0.009) were also higher in the subgroup of PCOS mothers that were pregnant with a girl compared to the girl pregnancy controls. DHEA, E1, E2 and E3 were not different. In umbilical cord blood, no differences were found for T, ADION, DHEA, E2, E3, and AMH between the PCOS mothers and the controls respectively. E1 was lower in girls from PCOS mothers (P=0.007).CONCLUSIONSDespite elevated maternal androgen concentrations during pregnancy in PCOS mothers, offspring showed no signs of elevated androgen concentrations in cord blood at birth using the latest highly specific LC-MS/MS methods.

Objective: To assess the capacity of the postcoital test (PCT) to predict pregnancy in WHO II anovulatory women who are ovulatory on clomiphene citrate (CC). In these women, an abnormal PCT result could be associated with lower pregnancy chances, but this has never been proven or refuted.Study design: Prospective cohort study was performed between December 2009 and September 2012 for all women who started ovulation induction with CC in one university clinic and two teaching hospitals in the Netherlands. A PCT was performed in one of the first three ovulatory cycles. Ovulation induction with CC was continued for at least six cycles. The PCT was judged to be positive if at least one progressive motile spermatozo was seen in one of five high power fields at 400x magnification. The primary outcome was time to ongoing pregnancy, within six ovulatory cycles.Results: In 152 women the PCT was performed. 135 women had a reliable, well-timed PCT. The ongoing pregnancy rate was 44/107 (41%) for a positive and 10/28 (36%) for a negative PCT. The hazard rate for ongoing pregnancy was 1.3 (95% CI 0.64-2.5) for a positive versus a negative PCT.Thirty five of 77 (46%) women with clear mucus had an ongoing pregnancy versus 12 of 45 (27%) women in whom the mucus was not clear (HR 2.0; 95% CI 1.02-3.84, p = 0.04).Conclusion: The present study suggests that the outcome of the postcoital test in women with WHO-II anovulation that undergo ovulation induction with CC does not have a large effect on ongoing pregnancy chances over time. (C) 2016 Elsevier Ireland Ltd. All rights reserved.