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).

Cumulative pregnancy rates after sequential treatment with modified natural cycle IVF followed by IVF with controlled ovarian stimulation.

BACKGROUND: In modified natural cycle IVF (MNC-IVF), treatment is aimed at using the one follicle that spontaneously develops to dominance, using a GnRH-antagonist together with gonadotrophins in the late follicular phase only. The MNC-IVF is of interest because of its low-risk and patient-friendly profile. The effect of application of MNC-IVF preceding standard IVF with ovarian stimulation on overall results is unknown. METHODS: This single-center cohort study provides follow-up of an earlier study in which nine cycles of MNC-IVF were offered to 268 patients. Ongoing pregnancy rates and live birth rates, as well as time-to-pregnancy after controlled ovarian stimulation-IVF (COS-IVF) following MNC-IVF, were evaluated. RESULTS: Actual observed cumulative ongoing pregnancy rates and live birth rates after sequential treatment with MNC-IVF followed by COS-IVF were 51.5 (95% CI: 45.4-57.6) and 50.0% (95% CI: 43.9-56.1) per patient, of which 8.0 and 6.7% were twins. Median time to ongoing pregnancy was 28.8 weeks. Including treatment-independent pregnancies, cumulative ongoing pregnancy rate was 56.7% (95% CI: 50.7-62.8). CONCLUSIONS: Sequential treatment with MNC-IVF followed by COS-IVF does not appear to compromise overall success rates, while twin pregnancy rate is low. Because of its patient-friendly and low-risk profile, it seems appropriate to perform MNC-IVF preceding COS-IVF.

Cumulative pregnancy rates after a maximum of nine cycles of modified natural cycle IVF and analysis of patient drop-out: a cohort study.

BACKGROUND: In modified natural cycle IVF (MNV-IVF), treatment is aimed at using the one follicle that spontaneously develops to dominance, using a GnRH antagonist together with gonadotrophins in the late follicular phase only. METHODS: In this single-centre cohort study, nine cycles of MNV-IVF were offered to 268 patients. Cumulative pregnancy rates (CPRs) were calculated and drop-out was analysed. The present study is an extension of earlier studies in which three cycles of MNV-IVF were offered to the same patients. RESULTS: A total of 256 patients completed 1048 cycles (4.1 per patient). Embryo transfer rate was 36.5% per started cycle. Ongoing pregnancy rate was 7.9% per started cycle and 20.7% per embryo transfer. Including treatment-independent pregnancies, the observed CPR after up to nine cycles was 44.4% (95% confidence interval 38.3-50.5) per patient. Pregnancy rates per started cycle did not decline in higher cycle numbers (overall 9.9%). Drop-out rates were high (overall 47.8%). We found that cancellation of oocyte retrieval, fertilization failure and failure to reach embryo transfer are repeating phenomena in subsequent cycles and furthermore that these events predispose for drop-out. CONCLUSIONS: CPR after nine cycles of MNV-IVF in this study was 44.4%. Pregnancy rate per cycle did not decline in higher cycle numbers, possibly due to selective drop-out of poor prognosis patients. Due to the low-risk and patient-friendly nature of the MNC protocol, it seems a feasible treatment option for patients requiring IVF.

Cumulative pregnancy rates after three cycles of minimal stimulation IVF and results according to subfertility diagnosis: a multicentre cohort study.

BACKGROUND: In minimal stimulation IVF, treatment is aimed at using the single oocyte that spontaneously develops to dominance. To prevent untimely ovulation, a GnRH antagonist is administered in the late follicular phase of the natural cycle together with recombinant FSH for substitution. Owing to the lack of ovarian stimulation, minimal stimulation IVF is a low-risk and patient-friendly treatment. In this study, effectiveness of minimal stimulation IVF was studied. METHODS: In this prospective multicentre cohort study, minimal stimulation IVF was offered to 350 patients. All indications for conventional IVF were included. Main outcome measures were pregnancy rates per cycle and cumulative pregnancy rates after three cycles. RESULTS: A total of 336 patients completed 844 cycles (2.5 per patient). The overall ongoing pregnancy rate per started cycle was 8.3% [95% confidence interval (CI) 6.4-10.2%]. The cumulative ongoing pregnancy rate after up to three cycles was 20.8% (95% CI 16.4-25.3%) per patient. No differences were found according to indication for IVF. CONCLUSIONS: Minimal stimulation IVF seems suitable for all indications studied. Pregnancy rates are encouraging. Owing to the low-risk and patient-friendly nature of this protocol, it seems a feasible treatment option for patients requiring IVF.

Minimal stimulation IVF with late follicular phase administration of the GnRH antagonist cetrorelix and concomitant substitution with recombinant FSH: a pilot study.

BACKGROUND: The use of the natural cycle for IVF offers the advantage of a patient-friendly and low-risk protocol. Its effectiveness is limited, but may be improved by using a GnRH antagonist to prevent untimely LH surges. METHODS: In this pilot study, minimal stimulation IVF with late follicular phase administration of the GnRH antagonist cetrorelix and simultaneous substitution with recombinant FSH was applied for a maximum of three cycles per patient. Main outcome measures were pregnancy rates per started cycle and cumulative pregnancy rates after three cycles. RESULTS: A total of 50 patients completed 119 cycles (2.4 per patient). Fifty-two embryo transfers resulted in 17 ongoing pregnancies [14.3% per started cycle; 32.7% per embryo transfer; 95% confidence interval (CI) 7.9-20.7% and 19.7-45.7%, respectively]. One dizygotic twin pregnancy occurred after transfer of two embryos, the other pregnancies were singletons. The cumulative ongoing pregnancy rate after three cycles was 34% (95% CI 20.6-47.4%). Live birth rate was 32% per patient (95% CI 18.8-45.2%). CONCLUSIONS: Pregnancy rates after IVF with minimal, late follicular phase stimulation are encouraging. Considering the low-risk and patient-friendly nature of this protocol, it may be a feasible alternative to IVF with ovarian hyperstimulation.