scholarly journals Pregnancy Outcomes of Patients with Low Serum β-hCG Level 14 Days After Fresh Embryo Transfer

2020 ◽  
Author(s):  
Yixuan Wu ◽  
Haiying Liu
Keyword(s):  
Embryo Transfer ◽  
Pregnancy Outcomes ◽  
Roc Curves ◽  
Clinical Pregnancy ◽  
Ongoing Pregnancy ◽  
Fresh Embryo Transfer ◽  
Biochemical Pregnancy ◽  
Β Hcg ◽  
Low Serum ◽  
Day 3 Embryo

Abstract Background: Although previous studies had successfully illustrated different pregnancy outcomes by different serum β-hCG levels after embryo transfer, prognosis of pregnancy outcomes remains elusive when the serum β-hCG level is extremely low (e.g., < 100 mIU/ml 14 days after embryo transfer). Therefore, the purpose of our study is to investigate the pregnancy outcomes of patients with low serum β-hCG level 14 days after day 3 embryo transfer. Methods: A retrospective study was performed with 723 patients with a serum β-hCG level between 5 and 100 mIU/ml 14 days after day 3 fresh embryo transfer. Pregnancy outcomes (ongoing pregnancy, early miscarriage, biochemical pregnancy loss, and ectopic pregnancy) were analyzed according to the female patients’ age. Receiver operating characteristic (ROC) curves were plotted to indicate the threshold for prediction of clinical pregnancy and ongoing pregnancy. Sensitivity and specificity were calculated according the ROC curves as well. Results: Of the 723 patients with serum β-hCG level <100 mIU/mL 14 days after day 3 embryo transfer, 85.6% (619) had biochemical pregnancy, and only 14.4% (104) had clinical pregnancy (including 4.7% with ongoing pregnancy, 3.7% with ectopic pregnancy, and 5.9% with early miscarriage). The rate of ongoing pregnancy was significantly lower in ≥ 38-year group compared with < 38-year group (1.3% vs. 5.6%, P =0.029). The serum β-hCG level to predict clinical pregnancy was 44.7 mIU/ml (sensitivity, 91.3%; specificity, 82.1%; area under the ROC curve (AUROC), 0.908). For ongoing pregnancy, the serum β-hCG level was 53.7 mIU/ml (sensitivity, 94.1%; specificity, 81.4%; AUROC, 0.902). Conclusions: Initially low serum β-hCG level 14 days after day 3 embryo transfer indicated poor prognosis with minimal likelihood of ongoing pregnancy. Keywords: assisted reproductive technology; human chorionic gonadotropin; pregnancy; live birth; embryo transfer

scholarly journals Possibility of Live Birth For Patients With Low Serum β-hCG 14 Days After Blastocyst Transfer

2020 ◽  
Author(s):  
Yixuan Wu ◽  
Haiying Liu
Keyword(s):  
Live Birth ◽  
Roc Curve ◽  
Pregnancy Outcomes ◽  
Luteal Phase ◽  
Clinical Pregnancy ◽  
Blastocyst Transfer ◽  
Biochemical Pregnancy ◽  
Early Miscarriage ◽  
Β Hcg ◽  
Low Serum

Abstract Background: Although many previous study investigated the prediction of pregnancy outcomes by serumβ-hCG levels after blastocyst transfer, no study focused on the pregnancy outcomes of patients with initially low serum β-hCG levels. The purpose of the study was to investigate the pregnancy outcomes of patients with low serum β- level 14 days after blastocyst transfer. Methods: A retrospective study was performed in the Third Affiliated Hospital of Guangzhou Medical University. The purpose was to investigate the patients whose serum β-hCG levels were between 5-299 mIU/ml 14 days after frozen blastocyst transfer. Rates of live birth, early miscarriage, biochemical pregnancy loss and ectopic pregnancy were analyzed according to the female patients’ age by chi-squared test. Receiver operating characteristic (ROC) curves were plotted to explore the threshold for prediction of clinical pregnancy and live birth. Results: A total of 312 patients had serum β-hCG levels <300 mIU/ml 14 days after frozen blastocyst transfer, among which 18.6% were live birth, 47.4% were early miscarriage, 22.8% were biochemical pregnancy and 9.6% were ectopic pregnancy. Pregnancy outcomes were comparable between the patients aged <38 years and ≥38 years. ROC curve analysis showed that the predicted value ofβ-hCG for clinical pregnancy was 58.8 mIU/ml with the AUC of 0.752(95%CI :0.680-0.823), sensitivity of 95.0% and specificity of 53.5%.The threshold for live birth was 108.6mIU/ml with the area under the ROC curve (AUC) of 0.649(95%CI:0.0.583-0.715), sensitivity of 93.1% and specificity of 37.0%.For the β-hCG fold increase over 48 hours, the cut-off for clinical pregnancy was 1.4 with the AUC of 0.899(95%CI :0.801-0.996), sensitivity of 90.3% and specificity of 77.8%; the threshold for live birth was 1.9 with the AUC of 0.808(95%CI :0.724-0.891), sensitivity of 88.5% and specificity of 64.5%. Conclusions: Initially low serum β-hCG level 14 days after frozen blastocyst transfer indicated minimal likelihood of live birth. For patients having initial β-hCG >58.8 mIU/ml, luteal phase support is suggested to continue. Another serum β-hCG test and ultrasound should be performed one week later. If the initial serum β-hCG is < 58.8 mIU/ml, luteal phase support is suggested to discontinue and measurement of serum β-hCG and ultrasound can be arranged one week later.

scholarly journals Luaran Transfer Embrio Simpan Beku pada Pasien Endometriosis Pasca Operasi dan Non Endometriosis yang Menjalani IVF di Klinik Permata Hati RSUP Dr. Sardjito

2020 ◽  
Vol 7 (2) ◽  
pp. 108
Author(s):  
Rina Fatmawati ◽  
Shofwal Widad ◽  
Agung Dewanto
Keyword(s):  
In Vitro Fertilization ◽  
Success Rate ◽  
Embryo Transfer ◽  
Pregnancy Outcomes ◽  
Clinical Pregnancy ◽  
Frozen Embryo Transfer ◽  
Research Subjects ◽  
Vitro Fertilization ◽  
Biochemical Pregnancy

Background: Endometriosis is a chronic condition that is influenced by the hormone estrogen which affects women of childbearing age, and is associated with pelvic pain and infertility. In Vitro Fertilization (IVF) is currently the most efficient assisted reproductive technology and its high success rate is often done for infertility therapy in women associated with endometriosisObjective: The aim of this study is to determine whether postoperative endometriosis affected pregnancy outcomes in patients underwent frozen embryo transfer in IVF / ICSI programs.Method: This Research is done with a retrospective cohort design. The data was taken from medical records, research subjects who met the inclusion and exclusion criteria. The research data was collected, processed and analyzed using SPSS 23. Univariate, bivariate and multivariate data analysis was carried out to determine the effect between variablesResult: There were 458 research subjects in this study. Endometriosis patients were 119 subjects (26%). 57 subjects were categorized as minimum-mild endometriosis (47.9%) and moderate-severe subjects as many as 62 subjects (52.1%). The biochemical pregnancy rate (36.31%) and clinical pregnancy (29.4%) in patients with endometriosis was slightly higher than in non-endometriosis. But statistically it did not affect success rate of achieving biochemical (p = 0.428; RR 0.89; 95% CI: 0.71-1.24) and clinical pregnancy (p = 0.535; RR 0.883; 95% CI: 0.63- 1.22). The rate of miscarriage in postoperative endometriosis patients was higher than non-endometriosis patients (88.6% vs 80.7%) but was not statistically significant (p = 0.294; RR 1.69; 95% CI: 0.61-4.67) . Biochemical and clinical pregnancies were significantly affected by age, infertility, endometrial thickness, embryo age and embryo quality. The incidence of miscarriage was affected by the ovarian stimulation protocol.Conclusion: Endometriosis post operative statistically has no effect on pregnancy outcomes in the IVF / ICSI cycle with frozen embryo transfer compared with another cause of infertility .Keywords:Endometriosis, In Vitro Fertilization, Clinical pregnancy, biochemical pregnancy, miscarriage

scholarly journals Using Deep Learning in a Monocentric Study to Characterize Maternal Immune Environment for Predicting Pregnancy Outcomes in the Recurrent Reproductive Failure Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunyu Huang ◽  
Zheng Xiang ◽  
Yongnu Zhang ◽  
Dao Shen Tan ◽  
Chun Kit Yip ◽  
...  
Keyword(s):  
Pregnancy Outcome ◽  
Live Birth ◽  
Pregnancy Outcomes ◽  
Prediction Models ◽  
Reproductive Failure ◽  
Clinical Pregnancy ◽  
Clinical Samples ◽  
Ongoing Pregnancy ◽  
Biochemical Pregnancy ◽  
Immune Factors

Recurrent reproductive failure (RRF), such as recurrent pregnancy loss and repeated implantation failure, is characterized by complex etiologies and particularly associated with diverse maternal factors. It is currently believed that RRF is closely associated with the maternal environment, which is, in turn, affected by complex immune factors. Without the use of automated tools, it is often difficult to assess the interaction and synergistic effects of the various immune factors on the pregnancy outcome. As a result, the application of Artificial Intelligence (A.I.) has been explored in the field of assisted reproductive technology (ART). In this study, we reviewed studies on the use of A.I. to develop prediction models for pregnancy outcomes of patients who underwent ART treatment. A limited amount of models based on genetic markers or common indices have been established for prediction of pregnancy outcome of patients with RRF. In this study, we applied A.I. to analyze the medical information of patients with RRF, including immune indicators. The entire clinical samples set (561 samples) was divided into two sets: 90% of the set was used for training and 10% for testing. Different data panels were established to predict pregnancy outcomes at four different gestational nodes, including biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth, respectively. The prediction models of pregnancy outcomes were established using sparse coding, based on six data panels: basic patient characteristics, hormone levels, autoantibodies, peripheral immunology, endometrial immunology, and embryo parameters. The six data panels covered 64 variables. In terms of biochemical pregnancy prediction, the area under curve (AUC) using the endometrial immunology panel was the largest (AUC = 0.766, accuracy: 73.0%). The AUC using the autoantibodies panel was the largest in predicting clinical pregnancy (AUC = 0.688, accuracy: 78.4%), ongoing pregnancy (AUC = 0.802, accuracy: 75.0%), and live birth (AUC = 0.909, accuracy: 89.7%). Combining the data panels did not significantly enhance the effect on prediction of all the four pregnancy outcomes. These results give us a new insight on reproductive immunology and establish the basis for assisting clinicians to plan more precise and personalized diagnosis and treatment for patients with RRF.

scholarly journals Possibility of live birth in patients with low serum β-hCG 14 days after blastocyst transfer

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Yixuan Wu ◽  
Haiying Liu
Keyword(s):  
Live Birth ◽  
Roc Curve ◽  
Pregnancy Outcomes ◽  
Luteal Phase ◽  
Clinical Pregnancy ◽  
Blastocyst Transfer ◽  
Luteal Phase Support ◽  
Live Births ◽  
Β Hcg ◽  
Low Serum

Abstract Background Although prior work has attempted to predict pregnancy outcomes by assaying serum β-hCG levels after blastocyst transfer, no study has focused on pregnancy outcomes in those with initially low serum β-hCG levels. This study sought to investigate pregnancy outcomes of patients with low serum β-hCG levels 14 days after blastocyst transfer. Methods A retrospective study was conducted at the Third Affiliated Hospital of Guangzhou Medical University to study patients whose serum β-hCG levels were at 5–299 mIU/ml 14 days after frozen blastocyst transfer. Rates of live birth, early miscarriage, biochemical pregnancy loss and ectopic pregnancy were analyzed according to the female patients’ age by Chi-squared analysis. Receiver operating characteristic (ROC) curves were plotted to explore the threshold of predicting clinical pregnancy and live births. Results 312 patients had serum β-hCG levels < 300 mIU/ml at 14 days after frozen blastocyst transfer, among which, 18.6% were live births, 47.4% were early miscarriages, 22.8% were biochemical pregnancies and 9.6% were ectopic pregnancies. ROC curve analysis showed that a predicted value of β-hCG for clinical pregnancy was 58.8 mIU/ml with an area under the ROC curve (AUC) of 0.752, a sensitivity of 95.0% and specificity of 53.5%. The threshold for live births was 108.6 mIU/ml with an AUC of 0.649, a sensitivity of 93.1% and a specificity of 37.0%. For the β-hCG fold increase over 48 h, the cut-off for clinical pregnancy was 1.4 with an AUC of 0.899, a sensitivity of 90.3% and a specificity of 77.8%. The threshold for live birth was 1.9 with an AUC of 0.808, a sensitivity of 88.5% and specificity of 64.5%. Conclusions Initially low serum β-hCG levels 14 days after frozen blastocyst transfer indicated minimal chances of live birth. For patients having an initial β-hCG > 58.8 mIU/ml, luteal phase support should continue. Another serum β-hCG test and ultrasound should be performed one week later. When an initial serum β-hCG is < 58.8 mIU/ml, luteal phase support should be discontinued and serum β-hCG measured with ultrasound one week later.

scholarly journals Possibility of Live Birth in Patients with Low Serum β-hCG 14 Days After Blastocyst Transfer

2020 ◽  
Author(s):  
Yixuan Wu ◽  
Haiying Liu
Keyword(s):  
Live Birth ◽  
Roc Curve ◽  
Pregnancy Outcomes ◽  
Luteal Phase ◽  
Clinical Pregnancy ◽  
Blastocyst Transfer ◽  
Luteal Phase Support ◽  
Live Births ◽  
Β Hcg ◽  
Low Serum

Abstract Background: Although prior work has attempted to predict pregnancy outcomes by assaying serum β-hCG levels after blastocyst transfer, no study has focused on pregnancy outcomes in those with initially low serum β-hCG levels. This study sought to investigate pregnancy outcomes of patients with low serum β-hCG levels 14 days after blastocyst transfer.Methods: A retrospective study was conducted at the Third Affiliated Hospital of Guangzhou Medical University to study patients whose serum β-hCG levels were at 5-299 mIU/ml 14 days after frozen blastocyst transfer. Rates of live birth, early miscarriage, biochemical pregnancy loss and ectopic pregnancy were analyzed according to the female patients’ age by Chi-squared analysis. Receiver operating characteristic (ROC) curves were plotted to explore the threshold of predicting clinical pregnancy and live births. Results: 312 patients had serum β-hCG levels <300 mIU/ml at 14 days after frozen blastocyst transfer, among which, 18.6% were live births, 47.4% were early miscarriages, 22.8% were biochemical pregnancies and 9.6% were ectopic pregnancies. Live birth rates were higher in the <38 years of age group as compared those > 38 years (19.0% vs.16.6%; P=0.045). ROC curve analysis showed that a predicted value of β-hCG for clinical pregnancy was 58.8 mIU/ml with an area under the ROC curve (AUC) of 0.752, a sensitivity of 95.0% and specificity of 53.5%. The threshold for live births was 108.6 mIU/ml with an AUC of 0.649, a sensitivity of 93.1% and a specificity of 37.0%. For the β-hCG fold increase over 48 hours, the cut-off for clinical pregnancy was 1.4 with an AUC of 0.899, a sensitivity of 90.3% and a specificity of 77.8%. The threshold for live birth was 1.9 with an AUC of 0.808, a sensitivity of 88.5% and specificity of 64.5%.Conclusions: Initially low serum β-hCG levels 14 days after frozen blastocyst transfer indicated minimal chances of live birth. For patients having an initial β-hCG >58.8 mIU/ml, luteal phase support should continue. Another serum β-hCG test and ultrasound should be performed one week later. When an initial serum β-hCG is < 58.8 mIU/ml, luteal phase support should be discontinued and serum β-hCG measured with ultrasound one week later.

scholarly journals Possibility of Live Birth in Patients with Low Serum β -hCG 14 Days After Blastocyst Transfer

2020 ◽  
Author(s):  
Yixuan Wu ◽  
Haiying Liu
Keyword(s):  
Live Birth ◽  
Roc Curve ◽  
Pregnancy Outcomes ◽  
Luteal Phase ◽  
Clinical Pregnancy ◽  
Blastocyst Transfer ◽  
Luteal Phase Support ◽  
Live Births ◽  
Β Hcg ◽  
Low Serum

Abstract Background: Although prior work has attempted to predict pregnancy outcomes by assaying serum β-hCG levels after blastocyst transfer, no study has focused on pregnancy outcomes in those with initially low serum β-hCG levels. This study sought to investigate pregnancy outcomes of patients with low serum β-hCG levels 14 days after blastocyst transfer.Methods: A retrospective study was conducted at the Third Affiliated Hospital of Guangzhou Medical University to study patients whose serum β-hCG levels were at 5-299 mIU/ml 14 days after frozen blastocyst transfer. Rates of live birth, early miscarriage, biochemical pregnancy loss and ectopic pregnancy were analyzed according to the female patients’ age by Chi-squared analysis. Receiver operating characteristic (ROC) curves were plotted to explore the threshold of predicting clinical pregnancy and live births. Results: 312 patients had serum β-hCG levels <300 mIU/ml at 14 days after frozen blastocyst transfer, among which, 18.6% were live births, 47.4% were early miscarriages, 22.8% were biochemical pregnancies and 9.6% were ectopic pregnancies. ROC curve analysis showed that a predicted value of β-hCG for clinical pregnancy was 58.8 mIU/ml with an area under the ROC curve (AUC) of 0.752, a sensitivity of 95.0% and specificity of 53.5%. The threshold for live births was 108.6 mIU/ml with an AUC of 0.649, a sensitivity of 93.1% and a specificity of 37.0%. For the β-hCG fold increase over 48 hours, the cut-off for clinical pregnancy was 1.4 with an AUC of 0.899, a sensitivity of 90.3% and a specificity of 77.8%. The threshold for live birth was 1.9 with an AUC of 0.808, a sensitivity of 88.5% and specificity of 64.5%.Conclusions: Initially low serum β-hCG levels 14 days after frozen blastocyst transfer indicated minimal chances of live birth. For patients having an initial β-hCG >58.8 mIU/ml, luteal phase support should continue. Another serum β-hCG test and ultrasound should be performed one week later. When an initial serum β-hCG is < 58.8 mIU/ml, luteal phase support should be discontinued and serum β-hCG measured with ultrasound one week later.

scholarly journals Does serum progesterone level impact the ongoing pregnancy rate in frozen embryo transfer under artificial preparation with vaginal progesterone? Study protocol for a randomized controlled trial

Trials ◽  
2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Lin Haiyan ◽  
Yang Gang ◽  
Li Yu ◽  
Li Lin ◽  
Chen Xiaoli ◽  
...  
Keyword(s):  
Embryo Transfer ◽  
Clinical Pregnancy ◽  
Frozen Embryo Transfer ◽  
Progesterone Level ◽  
Sufficient Evidence ◽  
Ongoing Pregnancy ◽  
Serum Progesterone ◽  
Randomized Controlled ◽  
Link Type ◽  
Low Serum

Abstract Background In previous retrospective studies, low serum progesterone level on the embryo transfer day is associated with lower clinical pregnancy and ongoing pregnancy rates. Whether adding progesterone in low serum progesterone patients can rescue the outcome, there is no sufficient evidence from randomized controlled studies. Methods This trial is a clinical randomized controlled study (high serum progesterone vs low serum progesterone 1:1, 1:1 randomization ratio of intervention vs the control group with low serum progesterone). The eligible hormone replacement therapy—frozen embryo transfer (HRT-FET) cycles, will be recruited and randomly assigned to two parallel groups when serum progesterone is < 7.24μg/l on the day of embryo transfer for D3. The intervention group will be extrally given intramuscular progesterone 40 mg per day from D3 to 8 weeks of gestation if clinical pregnancy. The primary outcome is the ongoing pregnancy (beyond 12 weeks of gestation) rate. Discussion The findings of this study will provide strong evidence for whether the progesterone addition from the D3 in low serum progesterone patients can improve the outcome in the HRT-FET cycle. Trial registration ClinicalTrials.govNCT04248309. Registered on January 28, 2020

Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study

2021 ◽  
Author(s):  
Manuel Álvarez ◽  
Sofía Gaggiotti-Marre ◽  
Francisca Martínez ◽  
Lluc Coll ◽  
Sandra García ◽  
...  
Keyword(s):  
Pregnancy Rate ◽  
Embryo Transfer ◽  
Pregnancy Outcomes ◽  
Luteal Phase ◽  
Frozen Embryo Transfer ◽  
Ongoing Pregnancy ◽  
Serum Progesterone ◽  
Endometrial Preparation ◽  
Group 2 ◽  
Group 1

Abstract STUDY QUESTION Does an individualised luteal phase support (iLPS), according to serum progesterone (P4) level the day prior to euploid frozen embryo transfer (FET), improve pregnancy outcomes when started on the day previous to embryo transfer? SUMMARY ANSWER Patients with low serum P4 the day prior to euploid FET can benefit from the addition of daily subcutaneous P4 injections (Psc), when started the day prior to FET, and achieve similar reproductive outcomes compared to those with initial adequate P4 levels. WHAT IS KNOWN ALREADY The ratio between FET/IVF has spectacularly increased in the last years mainly thanks to the pursuit of an ovarian hyperstimulation syndrome free clinic and the development of preimplantation genetic testing (PGT). There is currently a big concern regarding the endometrial preparation for FET, especially in relation to serum P4 levels around the time of embryo transfer. Several studies have described impaired pregnancy outcomes in those patients with low P4 levels around the time of FET, considering 10 ng/ml as one of the most accepted reference values. To date, no prospective study has been designed to compare the reproductive outcomes between patients with adequate P4 the day previous to euploid FET and those with low, but restored P4 levels on the transfer day after iLPS through daily Psc started on the day previous to FET. STUDY DESIGN, SIZE, DURATION A prospective observational study was conducted at a university-affiliated fertility centre between November 2018 and January 2020 in patients undergoing PGT for aneuploidies (PGT-A) IVF cycles and a subsequent FET under hormone replacement treatment (HRT). A total of 574 cycles (453 patients) were analysed: 348 cycles (leading to 342 euploid FET) with adequate P4 on the day previous to FET, and 226 cycles (leading to 220 euploid FET) under iLPS after low P4 on the previous day to FET, but restored P4 levels on the transfer day. PARTICIPANTS/MATERIALS, SETTING, METHODS Overall we included 574 HRT FET cycles (453 patients). Standard HRT was used for endometrial preparation. P4 levels were measured the day previous to euploid FET. P4 &gt; 10.6 ng/ml was considered as adequate and euploid FET was performed on the following day (FET Group 1). P4 &lt; 10.6 ng/ml was considered as low, iLPS was added in the form of daily Psc injections, and a new P4 analysis was performed on the following day. FET was only performed on the same day when a restored P4 &gt; 10.6 ng/ml was achieved (98.2% of cases) (FET Group 2). MAIN RESULTS AND THE ROLE OF CHANCE Patient’s demographics and cycle parameters were comparable between both euploid FET groups (FET Group 1 and FET Group 2) in terms of age, weight, oestradiol and P4 levels and number of embryos transferred. No statistically significant differences were found in terms of clinical pregnancy rate (56.4% vs 59.1%: rate difference (RD) −2.7%, 95% CI [−11.4; 6.0]), ongoing pregnancy rate (49.4% vs 53.6%: RD −4.2%, 95% CI [−13.1; 4.7]) or live birth rate (49.1% vs 52.3%: RD −3.2%, 95% CI [−12; 5.7]). No significant differences were also found according to miscarriage rate (12.4% vs 9.2%: RD 3.2%, 95% CI [−4.3; 10.7]). LIMITATIONS, REASONS FOR CAUTION Only iLPS through daily Psc was evaluated. The time for Psc injection was not stated and no serum P4 determinations were performed once the pregnancy was achieved. WIDER IMPLICATIONS OF THE FINDINGS Our study provides information regarding an ‘opportunity window’ for improved ongoing pregnancy rates and miscarriage rates through a daily Psc injection in cases of inadequate P4 levels the day previous to FET (P4 &lt; 10.6 ng/ml) and restored values the day of FET (P4 &gt; 10.6 ng/ml). Only euploid FET under HRT were considered, avoiding one of the main reasons of miscarriage and implantation failure and overcoming confounding factors such as female age, embryo quality or ovarian stimulation protocols. STUDY FUNDING/COMPETING INTEREST(S) No external funding was received. B.C. reports personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, IBSA and Gedeon Richter outside the submitted work. N.P. reports grants and personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, Theramex and Besins International and personal fees from IBSA and Gedeon Richter outside the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER NCT03740568.

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