Sildenafil Citrate adjuvant Ovulation Induction Therapy with Clomiphen Citrate in Polycystic Ovarian Syndrome for Successful Ovulation; Cross-Over, Randomized Controlled Trial

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Mustafa M Abbas ◽  
Ihab H. Abdel Fattah ◽  
Magdy H Kolaib ◽  
Walid E Mohammed ◽  
Mohammed M Salman
Keyword(s):  
Blood Flow ◽  
Endometrial Thickness ◽  
Controlled Trial ◽  
Clomiphene Citrate ◽  
Maternity Hospital ◽  
Sildenafil Citrate ◽  
Pregnancy Test ◽  
Induction Of Ovulation ◽  
Positive Pregnancy Test ◽  
Doppler Indices

Abstract Background Sildenafil Citrate (Respatio® 20 mg) as an adjuvant therapy in induction of ovulation along with Clomiphen Citrate (Clomid ®), is settled to enhance the endometrial receptivity through enhancing endometrial thickness and echogenicity. Yet, the exact role of Sildenafil in ovulation itself is still under study assuming that through increasing ovarian blood flow as a part of pelvic blood flow, will enhance the ovulation measured by the number and diameter of the growing follicles. Aim of the Work The aim of this study is to evaluate the efficacy of sildenafil citrate on the ovulation in PCOS women undergoing induction of ovulation using clomiphene citrate. Patients and Methods The current study was conducted in Ain Shams University Maternity Hospital- Infertility outpatient clinic during the period between January 2018 and December 2019. It included a total number of 595 patients who either were assessed for eligibility of the study, of which, 141 were excluded due to non-matching inclusion criteria or had exclusion criteria. 22 patients did not consent to participate in the study432 patients were matched, randomized and allocated to the two groups of the study each with 216 and received induction of ovulation according to the protocol of the study with either Clomiphen Citrate and Sildenafil Citrate or Clomiphen Citrate only, then they were followed up for 3 months. Those who didn't get pregnant given 2 months with no induction to wash over the effect and croos over the groups was done and followed up for another 3 months. Results Pregnancy test was positive in 39.8% in Clomiphen/Sildenafil group compared to just 30.1% in Clomiphen group. The patients that did not have positive pregnancy test in the first three months, have a rest for 2 months and then cross over of the groups took place. 145 patients shifted to Clomiphen/ Sildenafil protocol while 126 patients shifted to Clomiphen protocol and follow up for 3 months again and positive pregnancy test was 38% and 25% in the two groups in order. Conclusion using sildenafil citrate in patients with PCO syndrome undergoing induction of ovulation increases the chemical and clinical pregnancy rates through not only increasing the endometrial thickness and improving the endometrial pattern with improving the endometrial Doppler indices but also improving the ovulation by improving the ovarian arteries Doppler indices as well.

Effect of Sildenafil in Endometrial Ripening with Induction of Ovulation by Clomiphene Citrate in Polycystic Ovarian Syndrome; Double Blinded; Randomized Controlled Trial

2019 ◽  
Vol 2 (3) ◽  
pp. 01-10
Author(s):  
Dalia Mohammed Mohammed El-Khaldy ◽  
Mohamed Saeed Khallaf ◽  
Ahmed Mohamed Nour Eldin Hashad ◽  
Ibrahim Shazly Mohamed Amen Elshazly
Keyword(s):  
Randomized Controlled Trial ◽  
Polycystic Ovarian Syndrome ◽  
Controlled Trial ◽  
Clomiphene Citrate ◽  
Clinical Pregnancy ◽  
Sildenafil Citrate ◽  
Control Group ◽  
Induction Of Ovulation ◽  
Randomized Controlled ◽  
Ovarian Syndrome

Back ground: World Health Organization (WHO) defines infertility as a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse. Worldwide, 8 to 12 percent of couples experience fertility problems. Causes of infertility in women were as follows: menstrual disorders (disorders of cycle length and flow) 62.6%, diseases (obesity, thyroid diseases, diabetes) 58.7%, impaired ovulation (hormonal disorders, oligoovulation and anovulation) 50.3%, uterine causes 16.7%, tubal factor 15.4%, and cervical causes 7.9%. In the male factor fertility there was semen abnormalities (44.6%), genetic factors (29.8%), anti-spermatogenesis agents (11%), and vascular disorders (17.2%). Aim of the Study: The purpose of this study is to evaluate the effect of sildenafil in endometrial ripening with induction of ovulation by clomiphene citrate in polycystic ovarian syndrome. Patients and methods: It is a randomized controlled trial on 65 infertile women with polycystic ovarian syndrome; patients were randomly divided into two equal groups. In control group, 31 patients were given oral sildenafil, one tablet every 12 hrs. From 2nd day of the cycle till 12th day and clomiphene citrate, one tablet every 12 hours, for 5 days from 3rd day of the menstrual cycle. In study group, 34 patients were given oral placebo, one tablet every 12 hrs. From 2nd day of the cycle till 12th day and clomiphene citrate, one tablet every 12 hours, for 5 days from 3rd day of the menstrual cycle. A transvaginal ultrasound was performed to evaluated the endometrial thickness before and after treatment, the follicularometeric was measured on day 11 and day13. Uterine artery Doppler was then measured. Qualitative serum B-hCG level was checked 14 days after ovulation to assess clinical pregnancy rate. Design: Prospective, Double blinded randomized controlled trial. Setting: Obstetrics & Gynecology outpatient clinic, Ain Shams University Hospital. Study duration: 3 months. Results: The present study was a double-blind, randomized, controlled study that was conducted on 65 women with PCOS who underwent induction of ovulation by Clomiphene citrate in outpatient clinic of Ain Shams University hospital. Conclusion: Our systematic review and meta-analysis showed that follicular supplementation of sildenafil citrate (oral or vaginal), alone or adjuvant therapy can be used for improving the EM and clinical pregnancy rate in women undergoing assisted reproduction. However, given the methodological limitations the current evidence does not support its use in clinical practice yet. Future high-quality RCT with large sample size to evaluate the sildenafil citrate effect in women undergoing assisted reproduction are needed. Future RCTs should focus on type of processing, stage of embryo, embryo quality, dosage, time of administration, type of control group, in order to identify the groups of patients who would benefit the most from this intervention and the most appropriate dosage, time, and type of sildenafil citrate which would have the most positive effect and the less possible side effects.

scholarly journals The role of sildenafil citrate in the treatment of fetal growth restriction: a randomized controlled trial

2019 ◽  
Vol 8 (5) ◽  
pp. 1840
Author(s):  
Ahmed Abdelshafy ◽  
Khaled Ibrahim Abdullah ◽  
Sherif Ashoush ◽  
Heba E. Hosni
Keyword(s):  
Middle Cerebral Artery ◽  
Fetal Growth ◽  
Cerebral Artery ◽  
Fetal Growth Restriction ◽  
Umbilical Artery ◽  
Controlled Trial ◽  
Maternity Hospital ◽  
Growth Restriction ◽  
Sildenafil Citrate ◽  
Doppler Velocity

Background: This study was aimed to evaluate the effect of sildenafil citrate on Doppler velocity indices in patients with fetal growth restriction (FGR) associated with impaired placental circulation.Methods: A double-blinded, parallel group randomized clinical trial (clinicaltrials.gov NCT02590536) was conducted in Ain Shams Maternity Hospital, in the period between October 2015 and June 2017. Ninety pregnant women with documented intrauterine growth retardation at 24-37 weeks of gestation were randomized to either sildenafil citrate 25 mg orally every 8 hours or placebo visually-identical placebo tablets with the same regimen. The primary outcome of the study was the change in umbilical artery and fetal middle cerebral artery indices.Results: There was a significant improvement in umbilical and middle cerebral artery indices after sildenafil administration p<0.001. Present study observed that, sildenafil group, in comparison to placebo, has a significantly higher mean neonatal birth weight. 1783±241g vs 1570±455g (p<0.001). There was a significantly higher mean gestational age at delivery in women in sildenafil group 35.3±1.67 weeks, whereas it was lower in the placebo group 33.5±1.7 weeks. The side effects as headache, palpitation and facial flushing were significantly higher in sildenafil group compared to placebo group.Conclusions: The use sildenafil citrate in pregnancies with fetal growth restriction (FGR) improved the feto-placental Doppler indices (pulsatility index of umbilical artery and middle cerebral artery) and improved neonatal outcomes.

Comparison of letrozole and clomiphene citrate efficacy in terms of ovulation induction and pregnancy rate.

2021 ◽  
Vol 28 (05) ◽  
pp. 749-754
Author(s):  
Nadia Sharif ◽  
Uzma Manzoor ◽  
Saadia Bano ◽  
Uzma Shahzaad
Keyword(s):  
Pregnancy Rate ◽  
Ovulation Induction ◽  
Endometrial Thickness ◽  
Controlled Trial ◽  
Clomiphene Citrate ◽  
Epidemiological Data ◽  
P Value ◽  
Group A ◽  
The Mean ◽  
Group B

Objective: To compare the efficacy of Letrozole and clomiphene citrate in Patients of Anovulation polycystic ovarian syndrome with Infertility. Study Design: Randomized Controlled Trial Setting: Department of Obstetrics and Gynecology Independent Medical College Faisalabad. Period: 30-09-2019 to 29-6-2020. Material & Methods: This study included 100 patients with 50 patients in each group. Group A received 2.5 to 5mg letrozole in each cycle from day 3 to 7. Group B received clomiphene citrate 50 to 100 mg incremental dose depending on ovarian response. Both Drugs were given for consecutive 3 to 6 cycles to see response. Main outcome Measure included optimal follicle size (> 18mm), endometrial thickness, and pregnancy rate. Epidemiological data and efficacy outcome measures were recorded on a Performa. Statistical analysis was done using SPSS version 13. Chi-square test applied and p-value <o.o5 was considered significant. Both group included primary infertility patients. Results: The mean age of patients was 28.03+ 3.02 years. Mean age of group A patients was 29.04+3.44 and 28.47+3.90 group B patients. Mono ovulation in group A patients (88.9%) and 27 in group b patients (60.0%). The mean endometrial thickness was 9.6mm + 1.6 in letrozole group and 6.9mm + 1.2 in clomiphene citrate group A. In group A 18% got pregnant from Letrozole group and 1.1% from the group B. Conclusion: Efficacy was significantly higher in group A Patients received letrozole as compared to patients echo received clomiphene citrate. The effects of Letrozole showed better outcome in terms of Ovulation Induction Endometrial Thickness and Pregnancy rate.

scholarly journals Effects of Letrozole-HMG and Clomiphene-HMG on Incidence of Luteinized Unruptured Follicle Syndrome in Infertile Women Undergoing Induction Ovulation and Intrauterine Insemination: A Randomised Trial

2015 ◽  
Vol 8 (4) ◽  
pp. 244 ◽  
Author(s):  
Azra Azmoodeh ◽  
Mansoureh Pejman Manesh ◽  
Firouzeh Akbari Asbagh ◽  
Azizeh Ghaseminejad ◽  
Zeinab Hamzehgardeshi
Keyword(s):  
Menstrual Cycle ◽  
Endometrial Thickness ◽  
Intrauterine Insemination ◽  
Clomiphene Citrate ◽  
Randomised Trial ◽  
Induction Of Ovulation ◽  
Infertile Women ◽  
Significant Difference ◽  
Preovulatory Follicles ◽  
Luteinized Unruptured Follicle

<p><strong>BACKGROUND: </strong>Luteinized unruptured follicle (LUF) syndrome is considered a cause of ovulation failure and a subtle cause of infertility. Preovulatory injection of human chorionic gonadotropin (HCG) prevents or treats LUF syndrome, but it has also occurred after the induction of ovulation with clomiphene/HMG and HCG. This study was designed for evaluation and comparison of LUF incidence in eligible infertile women undergoing two stimulation protocols (clomiphene + HMG<strong> </strong>and letrozole + HMG) in addition to intrauterine insemination (IUI). Some related factors were compared between LUF and non-LUF cycles as secondary outcomes.</p> <p><strong>METHODS:</strong> The study was designed as a prospective randomized controlled trial. Patients were randomized using a table of random numbers into two equal protocol groups.<strong> </strong>For group A, (n = 90) clomiphene citrate was administrated orally in doses of 100 mg/day, and group B (n = 90) orally received letrozole 5 mg/day from day 3 to 7 of the menstrual cycle. Then HMG 75IU/day was administered intramuscularly in both groups on day 8 of the menstrual cycle and the dose was adjusted on the basis of ovarian response. The optimum size of preovulatory follicles for the injection of HCG (10,000 IU) was considered 18–23 mm. The number and size of preovulatory follicles were assessed by vaginal ultrasound 12 h before HCG (D0). Endometrial thickness was measured as well. IUI was performed on all patients 38–40 h after HCG. The second ultrasound examination was performed to observe the evidence of oocyte releasing at the time of IUI (D1). If the follicles were unruptured,<strong> </strong>a<strong> </strong>third sonography was performed on day 7 after HCG (D7) to observe LUF syndrome.</p> <p><strong>RESULTS: </strong>There was a significant difference between clomiphene-HMG and letrozole-HMG in LUF (p = 0.021) and pregnancy (p = 0.041). The complete LUF in letrozole-HMG was lower than the alternative group and the pregnancy rate was higher. The patients in the non-LUF group had higher midluteal progesterone and a thicker endometrium compared to LUF cycles (p = 0.039) and (p &lt; 0.001). The results of our multivariate logistic regression indicate that size 18–19.9 mm leads to the complete LUF  less than ≥22 mm [AOR: 0.25, P = 0.005], and  in size 20– 21.9 mm  as well [AOR: 0.17, P = 0.002].</p> <p><strong>CONCLUSION: </strong>Letrozole, with lower incidences of LUF, is more effective than clomiphene citrate for the induction of ovulation in IUI cycles. In our study, we illustrated that larger follicles of ≥22 mm diameter were associated with higher incidences of LUF. We recommend that further studies investigate and focus on the relationship between follicular size and/or full hormonal profiles and LUF.<strong></strong></p>

scholarly journals Effect of nitric oxide donors on uterine and sub-endometrial blood flow in patients with unexplained infertility: a randomized controlled trial

2021 ◽  
Vol 10 (6) ◽  
pp. 2178
Author(s):  
Mohamed A. Abdel Hafeez ◽  
Ashraf M. F. Kortam ◽  
Alaa M. A. Youssef ◽  
Ahmed Reda ◽  
Rehab M. Abdelrahman
Keyword(s):  
Blood Flow ◽  
Uterine Artery ◽  
Endometrial Thickness ◽  
Controlled Trial ◽  
Unexplained Infertility ◽  
Control Group ◽  
Artery Blood Flow ◽  
Randomized Controlled ◽  
Endometrial Blood Flow ◽  
Fertile Women

Background: Impaired sub-endometrial perfusion might reduce endometrial receptivity and possibly contribute to unexplained infertility. A favorable effect on sub-endometrial blood flow has been demonstrated with nitric oxide.Methods: This randomized controlled trial evaluated the effect of nitroglycerine on uterine and sub-endometrial blood flow in women with unexplained infertility. Sixty women were randomized into 2 equal groups. The study group received 5mg nitroglycerine patch daily from day 2 of the cycle till the evaluation day and the control group received no treatment. Independent of the study arms, 30 parous women were included as the fertile group. Six to eight days after detecting luteinizing hormone surge, women were assessed for endometrial thickness, uterine artery blood flow with color Doppler and sub-endometrial blood flow with three-dimensional power Doppler.Results: Compared to fertile women, cases with unexplained infertility (control group) had a significantly thinner endometrium, higher uterine artery Doppler indices and lower sub-endometrial blood flow. Women who received nitroglycerin showed a significant improvement in sub-endometrial blood flow while uterine artery blood flow did not show a significant difference; however, the values were also comparable to fertile women. In addition, no effect on endometrial thickness was found with nitroglycerin treatment. Nitroglycerin treatment side effects were headache, blurring of vision and hypotension. These adverse effects were not significant compared to controls.Conclusions: In women with unexplained infertility, nitroglycerin significantly improved the sub-endometrial blood flow but did not affect the endometrial thickness.

scholarly journals Efficacy and Side Effects of Letrozole Over Clomiphene citrate for Ovulation Induction of the Patients with PCOS: A Randomized Controlled Trial

2021 ◽  
Vol 15 (2) ◽  
pp. 69-73
Author(s):  
Poly Begum ◽  
Dipti Rani Shaha ◽  
Md Kamrul Hassan ◽  
Dilruba Zeba
Keyword(s):  
Side Effects ◽  
Pregnancy Rate ◽  
Endometrial Thickness ◽  
Controlled Trial ◽  
Clomiphene Citrate ◽  
Multiple Pregnancy ◽  
Ovulation Rate ◽  
Medical College ◽  
Drug Of Choice ◽  
Group B

Clomiphene citrate (CC) has been the drug of choice for the treatment of anovulatory subfertility in women with polycystic ovarian syndrome (PCOS) for a long time. Despite high ovulation rate of CC, its pregnancy rate is low. Letrozole, an aromatase inhibitor has been considered as an alternative of CC but its effectiveness is yet controversial. Our aim was to compare the efficacy and side effects of Letrozole over CC. This randomized control clinical trial was conducted in Diabetic Association Medical College and Hospital, Faridpur, Bangladesh from January 2018 to December 2019. A total of 160 women diagnosed as PCOS by Rotterdam criteria seeking treatment of subfertility were included in the study. Participants were randomly divided into two groups. Group A got Letrozole and Group B got CC as treatment. Transvaginal ultrasonogram (TVS) was performed on 12 to 13th day of the cycle to see the details of the follicles and the endometrium. The demographic information of the participants and the side effects of the drugs were recorded. Successful pregnancies were followed up for 12 weeks. Ovulation rate was almost similar among the participants of both of the groups. But monofo licular development and pregnancy rate were significantly higher among the Letrozole group (p = 0.004 and p = 0.008 respectively). Multifo licular development, multiple pregnancy, and abortion rate were significantly higher in the CC group. Patients who took Letrozole had significantly higher endometrial thickness than CC group. Both of the groups reported relatively similar incidence of side effects. Due to the higher pregnancy rate and lower incidence of abortion or multiple pregnancy, Letrozole can be an effective alternative to CC for the treatment of anovulatory subfertility of the PCOS patients. Faridpur Med. Coll. J. 2020;15(2): 69-73

scholarly journals Comparison of Tamoxifen and Clomiphene Citrate for Ovulation Induction in Women with Polycystic Ovarian Syndrome: A Prospective Study

2021 ◽  
Author(s):  
Sangita Sharma ◽  
Manisha Choudhary ◽  
Vikas Swarankar ◽  
Vaibhav Vaishnav
Keyword(s):  
Endometrial Thickness ◽  
Clomiphene Citrate ◽  
P Value ◽  
Ovulatory Cycle ◽  
Chi Square ◽  
Once Daily ◽  
Induction Of Ovulation ◽  
Group A ◽  
Group B ◽  
Estradiol Levels

Background: The purpose of this study was to compare the efficacy of tamoxifen and clomiphene citrate in induction of ovulation in women with PCOS and anovulation. Methods: In this prospective cohort study, 104 women with PCOS and primary infertility were enrolled after fulfilling the inclusion and exclusion criteria. The patients were allocated in two groups; group A (n=54) received tamoxifen 40 mg once daily (Days 3-7) and group B (n=50) received clomiphene citrate 100 mg once daily (Days 3-7). Serial ultrasounds were done till the administration of human chorionic gonadotropin (hCG). The ovulation and pregnancy rates in both groups were compared. The number of dominant follicles, estradiol levels, and endometrial thickness were also studied. Comparison was done using chi-square and student’s t-test and a p-value of less than 0.05 was considered statistically significant. Results: The number of dominant follicles and serum estradiol levels were significantly higher in group B (p<0.05), whereas the endometrial thickness was significantly more in group A (p<0.05). The ovulation rates were similar in both groups (66.6% vs. 70%, p=0.715). Pregnancy rate per treatment cycle and per ovulatory cycle was marginally higher in group A (14.81% and 22.22%, respectively), as compared to group B (14% and 20%, respectively), but the difference was not statistically significant (p>0.05). Conclusion: Tamoxifen and clomiphene citrate are both equally effective in induction of ovulation and achieving a pregnancy in women with PCOS.

scholarly journals Gonadotrophins or clomiphene citrate in women with normogonadotropic anovulation and CC failure: does the endometrium matter?

2020 ◽  
Vol 35 (6) ◽  
pp. 1319-1324
Author(s):  
E M Bordewijk ◽  
N S Weiss ◽  
M J Nahuis ◽  
J Kwee ◽  
A F Lambeek ◽  
...  
Keyword(s):  
Live Birth ◽  
Treatment Effect ◽  
Endometrial Thickness ◽  
Intrauterine Insemination ◽  
Controlled Trial ◽  
Clomiphene Citrate ◽  
Live Birth Rate ◽  
Ovulatory Cycle ◽  
Birth Rates ◽  
Live Birth Rates

Abstract STUDY QUESTION Is endometrial thickness (EMT) a biomarker to select between women who should switch to gonadotropins and those who could continue clomiphene citrate (CC) after six failed ovulatory cycles? SUMMARY ANSWER Using a cut-off of 7 mm for EMT, we can distinguish between women who are better off switching to gonadotropins and those who could continue CC after six earlier failed ovulatory CC cycles. WHAT IS ALREADY KNOWN For women with normogonadotropic anovulation, CC has been a long-standing first-line treatment in conjunction with intercourse or intrauterine insemination (IUI). We recently showed that a switch to gonadotropins increases the chance of live birth by 11% in these women over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. It is unclear whether EMT can be used to identify women who can continue on CC with similar live birth rates without the extra costs of gonadotropins. STUDY DESIGN, SIZE, DURATION Between 8 December 2008 and 16 December 2015, 666 women with CC failure were randomly assigned to receive an additional six cycles with a change to gonadotropins (n = 331) or an additional six cycles continuing with CC (n = 335), both in conjunction with intercourse or IUI. The primary outcome was conception leading to live birth within 8 months after randomisation. EMT was measured mid-cycle before randomisation during their sixth ovulatory CC cycle. The EMT was available in 380 women, of whom 190 were allocated to gonadotropins and 190 were allocated to CC. PARTICIPANTS/MATERIALS, SETTING, METHODS EMT was determined in the sixth CC cycle prior to randomisation. We tested for interaction of EMT with the treatment effect using logistic regression. We performed a spline analysis to evaluate the association of EMT with chance to pregnancy leading to a live birth in the next cycles and to determine the best cut-off point. On the basis of the resulting cut-off point, we calculated the relative risk and 95% CI of live birth for gonadotropins versus CC at EMT values below and above this cut-off point. Finally, we calculated incremental cost-effectiveness ratios (ICER). MAIN RESULTS AND THE ROLE OF CHANCE Mid-cycle EMT in the sixth cycle interacted with treatment effect (P &lt; 0.01). Spline analyses showed a cut-off point of 7 mm. There were 162 women (45%) who had an EMT ≤ 7 mm in the sixth ovulatory cycle and 218 women (55%) who had an EMT &gt; 7 mm. Among the women with EMT ≤ 7 mm, gonadotropins resulted in a live birth in 44 of 79 women (56%), while CC resulted in a live birth in 28 of 83 women (34%) (RR 1.57, 95% CI 1.13–2.19). Per additional live birth with gonadotropins, the ICER was €9709 (95% CI: €5117 to €25 302). Among the women with EMT &gt; 7 mm, gonadotropins resulted in a live birth in 53 of 111 women (48%) while CC resulted in a live birth in 52 of 107 women (49%) (RR 0.98, 95% CI 0.75–1.29). LIMITATIONS, REASONS FOR CAUTION This was a post hoc analysis of a randomised controlled trial (RCT) and therefore mid-cycle EMT measurements before randomisation during their sixth ovulatory CC cycle were not available for all included women. WIDER IMPLICATIONS OF THE FINDINGS In women with six failed ovulatory cycles on CC and an EMT ≤ 7 mm in the sixth cycle, we advise switching to gonadotropins, since it improves live birth rate over continuing treatment with CC at an extra cost of €9709 to achieve one additional live birth. If the EMT &gt; 7 mm, we advise to continue treatment with CC, since live birth rates are similar to those with gonadotropins, without the extra costs. STUDY FUNDING/COMPETING INTEREST(S) The original MOVIN trial received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). C.B.L.A. reports unrestricted grant support from Merck and Ferring. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva, IGENOMIX and Guerbet. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER Netherlands Trial Register, number NTR1449

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