Gonadotrophins versus clomiphene citrate with or without IUI in women with normogonadotropic anovulation and clomiphene failure: a cost-effectiveness analysis.

STUDY QUESTION: Are six cycles of ovulation induction with gonadotrophins more cost-effective than six cycles of ovulation induction with clomiphene citrate (CC) with or without IUI in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC? SUMMARY ANSWER: Both gonadotrophins and IUI are more expensive when compared with CC and intercourse, and gonadotrophins are more effective than CC. WHAT IS KNOWN ALREADY: In women with normogonadotropic anovulation who ovulate but do not conceive after six cycles with CC, medication is usually switched to gonadotrophins, with or without IUI. The cost-effectiveness of these changes in policy is unknown. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation of ovulation induction with gonadotrophins compared with CC with or without IUI in a two-by-two factorial multicentre randomized controlled trial in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC. Between December 2008 and December 2015 women were allocated to six cycles with gonadotrophins plus IUI, six cycles with gonadotrophins plus intercourse, six cycles with CC plus IUI or six cycles with CC plus intercourse. The primary outcome was conception leading to a live birth achieved within 8 months of randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a cost-effectiveness analysis on direct medical costs. We calculated the direct medical costs of ovulation induction with gonadotrophins versus CC and of IUI versus intercourse in six subsequent cycles. We included costs of medication, cycle monitoring, interventions, and pregnancy leading to live birth. Resource use was collected from the case report forms and unit costs were derived from various sources. We calculated incremental cost-effectiveness ratios (ICER) for gonadotrophins compared to CC and for IUI compared to intercourse. We used non-parametric bootstrap resampling to investigate the effect of uncertainty in our estimates. The analysis was performed according to the intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: We allocated 666 women in total to gonadotrophins and IUI (n = 166), gonadotrophins and intercourse (n = 165), CC and IUI (n = 163), or CC and intercourse (n = 172). Mean direct medical costs per woman receiving gonadotrophins or CC were €4495 versus €3006 (cost difference of €1475 (95% CI: €1457-€1493)). Live birth rates were 52% in women allocated to gonadotrophins and 41% in those allocated to CC (relative risk (RR) 1.24:95% CI: 1.05-1.46). The ICER was €15 258 (95% CI: €8721 to €63 654) per additional live birth with gonadotrophins. Mean direct medical costs per woman allocated to IUI or intercourse were €4497 versus €3005 (cost difference of €1510 (95% CI: €1492-€1529)). Live birth rates were 49% in women allocated to IUI and 43% in those allocated to intercourse (RR = 1.14:95% CI: 0.97-1.35). The ICER was €24 361 (95% CI: €-11 290 to €85 172) per additional live birth with IUI. LIMITATIONS, REASONS FOR CAUTION: We allowed participating hospitals to use their local protocols for ovulation induction and IUI, which may have led to variation in costs, but which increases generalizability. Indirect costs generated by transportation or productivity loss were not included. We did not evaluate letrozole, which is potentially more effective than CC. WIDER IMPLICATIONS OF THE FINDINGS: Gonadotrophins are more effective, but more expensive than CC, therefore, the use of gonadotrophins in women with normogonadotropic anovulation who have not conceived after six ovulatory CC cycles depends on society's willingness to pay for an additional child. In view of the uncertainty around the cost-effectiveness estimate of IUI, these data are not sufficient to make recommendations on the use of IUI in these women. In countries where ovulation induction regimens are reimbursed, policy makers and health care professionals may use our results in their guidelines. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by the Netherlands Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). The Eudract number for this trial is 2008-006171-73. The Sponsor's Protocol Code Number is P08-40. CBLA reports unrestricted grant support from Merck and Ferring. BWM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva and Guerbet. TRIAL REGISTRATION NUMBER: NTR1449.

Cost-effectiveness analysis of lifestyle intervention in obese infertile women.

STUDY QUESTION: What is the cost-effectiveness of lifestyle intervention preceding infertility treatment in obese infertile women? SUMMARY ANSWER: Lifestyle intervention preceding infertility treatment as compared to prompt infertility treatment in obese infertile women is not a cost-effective strategy in terms of healthy live birth rate within 24 months after randomization, but is more likely to be cost-effective using a longer follow-up period and live birth rate as endpoint. WHAT IS KNOWN ALREADY: In infertile couples, obesity decreases conception chances. We previously showed that lifestyle intervention prior to infertility treatment in obese infertile women did not increase the healthy singleton vaginal live birth rate at term, but increased natural conceptions, especially in anovulatory women. Cost-effectiveness analyses could provide relevant additional information to guide decisions regarding offering a lifestyle intervention to obese infertile women. STUDY DESIGN, SIZE, DURATION: The cost-effectiveness of lifestyle intervention preceding infertility treatment compared to prompt infertility treatment was evaluated based on data of a previous RCT, the LIFEstyle study. The primary outcome for effectiveness was the vaginal birth of a healthy singleton at term within 24 months after randomization (the healthy live birth rate). The economic evaluation was performed from a hospital perspective and included direct medical costs of the lifestyle intervention, infertility treatments, medication and pregnancy in the intervention and control group. In addition, we performed exploratory cost-effectiveness analyses of scenarios with additional effectiveness outcomes (overall live birth within 24 months and overall live birth conceived within 24 months) and of subgroups, i.e. of ovulatory and anovulatory women, women <36 years and ≥36 years of age and of completers of the lifestyle intervention. Bootstrap analyses were performed to assess the uncertainty surrounding cost-effectiveness. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Infertile women with a BMI of ≥29 kg/m2 (no upper limit) were allocated to a 6-month lifestyle intervention programme preceding infertility treatment (intervention group, n = 290) or to prompt infertility treatment (control group, n = 287). After excluding women who withdrew informed consent or who were lost to follow-up we included 280 women in the intervention group and 284 women in the control group in the analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Total mean costs per woman in the intervention group within 24 months after randomization were €4324 (SD €4276) versus €5603 (SD €4632) in the control group (cost difference of -€1278, P < 0.05). Healthy live birth rates were 27 and 35% in the intervention group and the control group, respectively (effect difference of -8.1%, P < 0.05), resulting in an incremental cost-effectiveness ratio of €15 845 per additional percentage increase of the healthy live birth rate. Mean costs per healthy live birth event were €15 932 in the intervention group and €15 912 in the control group. Exploratory scenario analyses showed that after changing the effectiveness outcome to all live births conceived within 24 months, irrespective of delivery within or after 24 months, cost-effectiveness of the lifestyle intervention improved. Using this effectiveness outcome, the probability that lifestyle intervention preceding infertility treatment was cost-effective in anovulatory women was 40%, in completers of the lifestyle intervention 39%, and in women ≥36 years 29%. LIMITATIONS, REASONS FOR CAUTION: In contrast to the study protocol, we were not able to perform the analysis from a societal perspective. Besides the primary outcome of the LIFEstyle study, we performed exploratory analyses using outcomes observed at longer follow-up times and we evaluated subgroups of women; the trial was not powered on these additional outcomes or subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Cost-effectiveness of a lifestyle intervention is more likely for longer follow-up times, and with live births conceived within 24 months as the effectiveness outcome. This effect was most profound in anovulatory women, in completers of the lifestyle intervention and in women ≥36 years old. This result indicates that the follow-up period of lifestyle interventions in obese infertile women is important. The scenario analyses performed in this study suggest that offering and reimbursing lifestyle intervention programmes in certain patient categories may be cost-effective and it provides directions for future research in this field. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). The department of obstetrics and gynaecology of the UMCG received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. B.W.J.M. is a consultant for ObsEva, Geneva. TRIAL REGISTRATION NUMBER: The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 1530.

Effectiveness of lifestyle intervention in subgroups of obese infertile women: a subgroup analysis of a RCT.

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 <36 years), ovulatory status (anovulatory or ovulatory), BMI (≥35 or <35 kg/m2) and waist-hip (WH) ratio (≥0.8 or <0.8). PARTICIPANTS/MATERIALS, SETTING, METHODS: Data of 564 (98%) randomized women who completed follow-up were analyzed. We studied the effect of the intervention program in various subgroups on healthy live birth rate within 24 months, as well as the rate of overall live births (live births independent of gestational age, mode of delivery and health) and natural conceptions within 24 months. Live birth rates included pregnancies resulting from both treatment dependent and natural conceptions. Logistic regression models with randomization group, subgroup and the interaction between randomization group and subgroup were used. Significant interaction was defined as a P-value <0.1. MAIN RESULTS AND THE ROLE OF CHANCE: Neither maternal age, ovulatory status nor BMI had an impact on the healthy live birth rate within 24 months, nor did they influence the overall live birth rate within 24 months after randomization. WH ratio showed a significant interaction with the effect of lifestyle intervention on healthy live birth rate (P = 0.05), resulting in a lower healthy live birth rate in women with a WH ratio <0.8. WH ratio had no interaction regarding overall live birth rate (P = 0.27) or natural conception rate (P = 0.38). In anovulatory women, the effect of lifestyle intervention resulted in more natural conceptions compared to ovulatory women (P-value for interaction = 0.02). There was no interaction between other subgroups and the effect of the intervention on the rate of natural conception. LIMITATIONS, REASONS FOR CAUTION: Since this was a subgroup analysis of a RCT and sample size determination of the trial was based on the primary outcome of the study, the study was not powered for analyses of all subgroups. WIDER IMPLICATIONS OF THE FINDINGS: Our finding that lifestyle intervention leads to increased natural conception in anovulatory obese women could be used in the counselling of these women, but requires further research using an appropriately powered study in order to confirm this result. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from ZonMw, the Dutch Organisation for Health Research and Development (50-50110-96-518). The Department of Obstetrics and Gynaecology of the UMCG received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. Ben Mol is a consultant for ObsEva, Geneva. Annemieke Hoek received a speaker's fee for a postgraduate education from MSD pharmaceutical company, outside the submitted work. TRIAL REGISTRATION NUMBER: The LIFEstyle study was registered at the Dutch trial registry (NTR 1530).

Cost-effectiveness of induction of labour at term with a Foley catheter compared to vaginal prostaglandin E2 gel (PROBAAT trial).

OBJECTIVE: To assess the economic consequences of labour induction with Foley catheter compared to prostaglandin E2 gel. DESIGN: Economic evaluation alongside a randomised controlled trial. SETTING: Obstetric departments of one university and 11 teaching hospitals in the Netherlands. POPULATION: Women scheduled for labour induction with a singleton pregnancy in cephalic presentation at term, intact membranes and an unfavourable cervix; and without previous caesarean section. METHODS: Cost-effectiveness analysis from a hospital perspective. MAIN OUTCOME MEASURES: We estimated direct medical costs associated with healthcare utilisation from randomisation to 6 weeks postpartum. For caesarean section rate, and maternal and neonatal morbidity we calculated the incremental cost-effectiveness ratios, which represent the costs to prevent one of these adverse outcomes. RESULTS: Mean costs per woman in the Foley catheter group (n = 411) and in the prostaglandin E2 gel group (n = 408), were €3297 versus €3075, respectively, with an average difference of €222 (95% confidence interval -€157 to €633). In the Foley catheter group we observed higher costs due to longer labour ward occupation and less cost related to induction material and neonatal admissions. Foley catheter induction showed a comparable caesarean section rate compared with prostaglandin induction, therefore the incremental cost-effectiveness ratio was not informative. Foley induction resulted in fewer neonatal admissions (incremental cost-effectiveness ratio €2708) and asphyxia/postpartum haemorrhage (incremental cost-effectiveness ratios €5257) compared with prostaglandin induction. CONCLUSIONS: Foley catheter and prostaglandin E2 labour induction generate comparable costs.

The SUPER study: protocol for a randomised controlled trial comparing follicle-stimulating hormone and clomiphene citrate for ovarian stimulation in intrauterine insemination.

OBJECTIVE: To study the effectiveness of four cycles of intrauterine insemination (IUI) with ovarian stimulation (OS) by follicle-stimulating hormone (FSH) or by clomiphene citrate (CC), and adherence to strict cancellation criteria. SETTING: Randomised controlled trial among 22 secondary and tertiary fertility clinics in the Netherlands. PARTICIPANTS: 732 women from couples diagnosed with unexplained or mild male subfertility and an unfavourable prognosis according to the model of Hunault of natural conception. INTERVENTIONS: Four cycles of IUI-OS within a time horizon of 6 months comparing FSH 75 IU with CC 100 mg. The primary outcome is ongoing pregnancy conceived within 6 months after randomisation, defined as a positive heartbeat at 12 weeks of gestation. Secondary outcomes are cancellation rates, number of cycles with a monofollicular or with multifollicular growth, number of follicles >14 mm at the time of ovulation triggering, time to ongoing pregnancy, clinical pregnancy, miscarriage, live birth and multiple pregnancy. We will also assess if biomarkers such as female age, body mass index, smoking status, antral follicle count and endometrial aspect and thickness can be used as treatment selection markers. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethical Committee of the Academic Medical Centre and from the Dutch Central Committee on Research involving Human Subjects (CCMO NL 43131-018-13). Results will be disseminated through peer-reviewed publications and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NTR4057.

Routine use of hysterosalpingography prior to laparoscopy in the fertility workup: a multicentre randomized controlled trial.

BACKGROUND: A multicentre randomized controlled trial with or without hysterosalpingography (HSG) was conducted to assess the usefulness of HSG as a routine investigation in the fertility workup prior to laparoscopy and dye. METHODS: From 1 April 1997 to 1 April 2002, subfertile women were allocated by a computer-based 1 : 1 ratio randomization procedure, either for an HSG followed by laparoscopy and dye (the intervention group) of for laparoscopy and dye only (the control group) as a part of their fertility workup. Cumulative pregnancy rate (CPR) within 18 months after randomization was the primary outcome of interest. RESULTS: 344 women were randomized to the intervention group (n = 169) and the control group (n = 175). There was no significant difference in CPR at 18 months in the intervention group (49.1%) [95% confidence interval (CI) 41.6 to 56.6] and the control group (50.3%) (95% CI 42.8 to 57.8), a difference of -1.2% (95% CI -11.8% to 9.5%). CONCLUSION: The routine use of HSG at an early stage in the fertility workup prior to laparoscopy and dye does not influence CPR, compared with the routine use of laparoscopy and dye without HSG.