72 EFFECT OF PROGESTERONE SUPPLEMENTATION ON DAY 4 AFTER TIMED ARTIFICIAL INSEMINATION ON PREGNANCY RATE OF LACTATING DAIRY COWS

2017 ◽  
Vol 29 (1) ◽  
pp. 143
Author(s):  
G. Tortorelli ◽  
A. J. Azrak ◽  
V. da Costa Andrade ◽  
R. dos Santos Ramos ◽  
A. S. Moraes ◽  
...  

Progesterone plays an important role in the maintenance of pregnancy. It is hypothesised that insufficient progesterone early in pregnancy may result in embryonic loss, and that supplemental progesterone would decrease pregnancy loss in dairy cows. The aim of this study was to compare the effect of progesterone supplementation after timed AI on pregnancy rate of dairy cows. The experiment was conducted in a single commercial herd, in Sao Paulo State (Brazil), during a period of 1 year (January–December 2016). The cows were assigned at a nonpregnancy diagnosis 32 ± 3 days after AI to 1 to 6 resynchronization treatments. They were submitted to the same fixed time AI protocol: Day 0, 0.1 mg of gonadorelin, 2 mg of oestradiol benzoate, and an intravaginal device of 1.9 g of progesterone; Day 7, 25 mg of dinoprost tromethamine; Day 8, 25 mg of dinoprost tromethamine, 1 mg of oestradiol cipionate, and device withdrawal; Day 10, AI. At Day 14, the cows were alternately arranged in 2 groups. Group 1 received a 900-mg progesterone supplementation IM injection, and Group 2 did not receive progesterone supplementation. Then, 32 ± 3 days after insemination, pregnancy diagnosis was performed by transrectal ultrasonography, and the data were tabulated. Full statistical analysis will be done at the end of the study, when more than 500 cows will be allocated to the 2 groups. From January until April 2016, 230 lactating dairy cows were submitted to the experiment. Both groups had similar average days in lactation (166), average number of lactations (1.95), and average number of inseminations (4.3). Group 1 had a pregnancy rate of 25% (29/116), and group 2 had a pregnancy rate of 15.8% (18/114) (P = 0.01, one-way ANOVA). Based on these preliminary data, pregnancy rates of lactating dairy cows may be improved with progesterone supplementation on Day 4 after insemination. These results need to be confirmed on larger numbers of cows.

2013 ◽  
Vol 25 (1) ◽  
pp. 156
Author(s):  
D. Romero ◽  
G. Romero ◽  
G. Veneranda ◽  
L. Filippi ◽  
D. Racca ◽  
...  

An experiment was designed to compare pregnancy rates in lactating dairy cows synchronized with a 7-day CIDR-Synch or a 5-day CIDR-Synch program and to determine if the addition of a second prostaglandin F2α (PGF) injection to the 7-day CIDR-Synch program would improve pregnancy rates following fixed-time AI (FTAI). The experiments were performed on 2 dairy farms in Argentina, with year-round calving and a mixed feeding system (35% grazing plus 65% corn silage and grain). Cows (n = 621) were 39.3 ± 6.5 days in milk (DIM, mean ± SD) when they were enrolled in the program, had 2.4 ± 1.5 lactations and a body condition score (BCS) of 3.1 ± 0.2 (range: 2.7 to 4.0). All cows received a pre-synchronization treatment with 2 doses of prostaglandin (PGF, 25 mg of dinoprost, Lutalyse, Pfizer Animal Health, Argentina) 14 days apart, and 11 days after the second PGF (Day 0) received 10 µg of Buserelin (GnRH, Receptal, MSD-Intervet, Argentina) and a CIDR device (1.9 g of progesterone, Pfizer Animal Health). Cows were randomly allocated to 1 of 3 groups. The CIDR devices were removed and PGF was administered to cows in Groups 1 and 2 on Day 7. A second GnRH was given 56 h later and cows experienced FTAI 16 h after gonadotropin-releasing hormone (GnRH) injection (i.e. 72 h after CIDR removal). Cows in Group 2 also received a second PGF injection on the afternoon of Day 7. Cows in Group 3 had the CIDR removed and received 2 PGF injections 12 h apart on Day 5. A second dose of GnRH was given and FTAI was performed at the same time, on Day 8 (i.e. 72 h after CIDR removal). All cows were examined by ultrasonography (Aloka 500V, Aloka, Tokyo, Japan) on the day of the first PGF injection and at CIDR removal to determine the presence and number of corpora lutea (CL), and 30 days after FTAI to determine pregnancy status. Data were analyzed by logistic regression to determine the effects of treatment, parity, days postpartum, milk production, BCS, presence of a CL at enrollment, and number of CL at the time of CIDR removal on pregnancy rates. Overall pregnancy rates did not differ among groups: 32.9% (68/207), 38.2% (78/204), and 38.3% (80/209) for Groups 1, 2, and 3, respectively (P = 0.2). Although the number of CL present at CIDR removal did not significantly affect pregnancy rates (P = 0.4), pregnancy rates in cows with 1 CL in Groups 1 and 2 tended to differ [29.0% (11/38) v. 48.9% (21/43); P < 0.07], but neither differed from that in Group 3 [37.2% (16/43)]. No differences were detected among groups in cows without a CL at CIDR removal [overall pregnancy rate: 29.4% (5/17)] and those with ≥2 CL [overall pregnancy rate: 36.1% (173/479)]. Among the other variables evaluated, first-parity cows had 1.96 (1.38–2.78) times more chance of getting pregnant than second-or-more-parity cows (P = 0.002) and cows with BCS >3 had 1.63 (1.16–2.28) times more chance of getting pregnant than those with BCS <3 (P = 0.003). Finally, herd, days postpartum, milk production, and presence of a CL at enrollment did not significantly affect pregnancy rates. We concluded that the 3 treatments resulted in similar pregnancy rates for lactating dairy cows and that the benefit of adding a second PGF injection to the 7-day protocol was only marginal in cows with 1 CL at CIDR removal.


2005 ◽  
Vol 17 (2) ◽  
pp. 231
Author(s):  
J. Lagioia ◽  
M. Panarace ◽  
M. Marfil ◽  
M. Basualdo ◽  
J. Gutierrez ◽  
...  

The most important factor in bovine embryo transfer programs is the low efficiency in the utilization of the recipients; this low efficiency is associated with low response to synchronization protocols and failures in estrus detection. It has been shown that cows transferred at fixed time with in vivo-derived embryos resulted in high rates of recipients selected for transfer and high overall pregnancy rates (recipients pregnant/recipients treated) (Tribulo et al. 2002 Theriogenology 57, 563). An experiment was designed to evaluate the pregnancy rate in recipients transferred with in vivo (fresh and frozen), IVF, and cloned-derived embryos without estrus detection. A total of 1555 non-lactating Bos Taurus crossbred beef cows was divided into two groups. Cows from group 1 (n = 421) were synchronized with a progesterone intravaginal releasing device (1 g P4; DIB, Syntex®, Buenos Aires, Argentina) plus 2 mg of estradiol benzoate (EB) i.m. (Syntex®) on Day 0. On Day 5, they received 400 IU of eCG (Novormon 5000, Syntex®) i.m. and 150 μg of D-Cloprostenol (PGF2α) (Bioprost-D, Biotay®, Buenos Aires, Argentina). The DIB devices were removed on Day 8 and on Day 9, 1 mg of EB was injected. Day 10 was arbitrarily considered as the day of estrus. Cows from group 2 (n = 1134) received 2 doses of PGF2α 14 days apart and were checked for heat during 5 days after the second PGF2α dose. Cows of both groups were examined 7 days after estrus by ultrasonography (Pie Medical Scanner 200®) and those with a corpus luteum >10 mm of diameter were transferred nonsurgically with in vivo (fresh and frozen), IVF, and cloned-derived embryos. In group 1, 360 cows were transferred, and in group 2, 726 cows were transferred (Table 1). Pregnancy was diagnosed 23 days later by ultrasonography (Pie Medical Scanner 200®). The pregnancy rates were compared statistically between groups 1 and 2 by analysis of variance (Infostat, LSD Fisher). There was no significant statistic difference (P > 0.05) between pregnancy rate in group 1 and 2 with in vivo (fresh), IVF, and cloned-derived embryos. However, pregnancy rate of frozen in vivo-derived embryos was lower in group 1 than in group 2 (P < 0.05). Results showed that treatment using DIB combined with EB, PGF2α, and eCG associated with embryo transfer without estrus detection (group 1) had no difference in pregnancy rate when compared with the treatment where synchronization with PGF2α and heat detection were used (group 2). Another important advantage is the use the group 1 treatment for increasing the flexibility and efficiency in the management of the recipients of in vivo, IVF, and cloned-derived embryo transfer programs. Table 1. Comparison of pregnancy rates between group 1 (embryo transfer at fixed time) and group 2 (embryo transfer 7 days after estrus detection)


2006 ◽  
Vol 18 (2) ◽  
pp. 118 ◽  
Author(s):  
G. Veneranda ◽  
L. Filippi ◽  
D. Racca ◽  
G. Romero ◽  
E. Balla ◽  
...  

Two experiments were designed to evaluate the effect of different treatments for the synchronization of ovulation on pregnancy rates following fixed-time AI (FTAI) of lactating dairy cows. In Experiment 1, 394 Holstein cows that were 61.7 � 13.6 days postpartum (range 35 to 94 days), with a milk yield of 30.7 � 6.8 liters per day (range 12.0 to 52.4 liters) and a body condition score (BCS) between 2.5 to 3.5 out of 5, were used. Cows were blocked by days postpartum and milk yield and randomly assigned to one of four treatment groups. Cows in P4+EB treatment groups received an intravaginal DIB device (1 g P4; Syntex, Argentina) and 2 mg of estradiol benzoate (EB; Syntex) i.m. on Day 0. On Day 8, DIB devices were removed, and cows received PGF (150 �g D+cloprostenol: Ciclase; Syntex), and were subdivided to receive 400 IU eCG (Novormon 5000, Syntex) i.m. or no further treatment at that time. On Day 9, all cows received 1 mg of EB and were FTAI 60 h after DIB removal. Cows in P4-Synch groups received a DIB device and 50 �g of GnRH (Lecirelina, Gonasyn; Syntex) i.m. on Day 0. On Day 7, DIB devices were removed; cows received PGF and were divided to receive 400 IU eCG i.m. or no further treatment. On Day 9, all cows received a second GnRH treatment and were FTAI 60 h after DIB removal. Blood samples were taken on Days -10 and 0 to determine plasma P4 concentrations; 93% of the cows had >1 ng/mL P4 in at least one sample. In Experiment 2, 200 lactating cows from the same farm were treated with the P4+EB+eCG and P4-Synch without eCG treatments with either a DIB or a CIDR-B (1.9 g P4; Pfizer Animal Health, Groton, CT, USA) in a 2 � 2 factorial design. Cows were examined by rectal palpation 50 days after FTAI to determine pregnancy status, and data were analyzed by chi-square Mantel-Haenszel test. There was an EB/GnRH by eCG interaction (P < 0.05) which was attributed to a higher pregnancy rate in the P4+EB+eCG group (44/98; 44.9%) than in the P4+EB without eCG group (30/100; 30.0%) and P4-Synch+eCG group (30/98; 30.6%); the P4-Synch without eCG group had an intermediate pregnancy rate that did not differ from the other treatment groups (37/98; 38.8%). In Experiment 2, no significant differences (P = 0.40) in pregnancy rates were detected between cows treated with DIB (51/100; 51.0%) or CIDR-B (42/100; 42.0%), and there was no difference (P = 0.18) between P4+EB+eCG (52/100; 52.0%) and P4-Synch without eCG (41/100; 41.0%) treated groups. Results suggest that the addition of eCG will improve pregnancy rates following FTAI in lactating dairy cows treated with EB but not in those treated with GnRH at the time of insertion and after removal of a P4 releasing device. Although treatment with P4+EB+eCG resulted in numerically higher pregnancy rates, results were not different from those obtained in the GnRH-based treatment, without the addition of eCG.


2020 ◽  
Vol 76 (10) ◽  
pp. 6451-2020
Author(s):  
MUSHAP KURU ◽  
CIHAN KACAR ◽  
HASAN ORAL ◽  
SEMRA KAYA ◽  
NEBI CETIN ◽  
...  

The aim of the present study was to determine the effects of one or two doses of prostaglandin F2α (PGF) on the pregnancy rate (PR) in Simmental cows subjected to the Ovsynch or Ovsynch + Controlled internal drug release (CIDR) protocols. On d 0, 100 µg gonadorelin diacetate tetrahydrate (GnRH) was injected into cows in group 1 (n = 50) and group 2 (n = 40) and CIDR was intravaginally inserted. On d 7, 25 mg dinoprost tromethamine (PGF2α, PGF) was administered, and GnRH was injected 56 h later. Fixed-time artificial insemination (TAI) was performed 16 h after GnRH injection. In group 3 (n = 62) and group 4 (n = 63), PGF was administered 7 d following GnRH treatment, and GnRH was injected 56 h later. TAI was performed 16 h after GnRH injection. In groups 2 and 4, a second dose of PGF was injected 24 h after the first dose. Pregnancy was determined by transrectal ultrasonography on d 30 and 60 post-TAI. The pregnancy rate (PR) on d 30 post-TAI was significantly different among the groups: 46%, 55%, 29%, and 36.5%, in groups 1, 2, 3, and 4, respectively (P = 0.048). In addition, the PR was 36.3% and 43.7% in the single PGF and double PGF injection groups, respectively. There was no statistical difference in the PR on d 60 post-TAI (P > 0.05). Pregnancy loss was between 4.34% and 11.11% (P > 0.05). The highest PR in the primiparous cows was observed in group 3 (57.7%). The PR was not significantly different among multiparous cows (P > 0.05). In conclusion, two injections of PGF administered 24 h apart in Simmental cows may increase the PR in the Ovsynch or Ovsynch + CIDR protocols.


2008 ◽  
Vol 20 (1) ◽  
pp. 91 ◽  
Author(s):  
G. Veneranda ◽  
L. Filippi ◽  
D. Racca ◽  
L. Cutaia ◽  
G. A. Bo

We have previously shown that the addition of eCG improved pregnancy rates following fixed-time artificial insemination (FTAI) in lactating dairy cows treated with estradiol benzoate (EB) and progesterone releasing devices (Veneranda et al. 2006 Reprod. Fertil. Dev. 18, 118). An experiment was designed to compare pregnancy rates in lactating dairy cows treated with progesterone-releasing devices and EB plus eCG with different gonadotropin-releasing hormone (GnRH)-based protocols. Five-hundred lactating dairy cows between 30 and 51 days postpartum (when prostaglandin F (PGF) treatments were given in the Pre-Synch groups), with a milk yield of 29.5 � 7.0 kg per day (range 13.0 to 46.0 kg) and a body condition score (BCS) between 2.5 to 3.5 out of 5 were used. Cows were blocked by days postpartum and randomly assigned to five treatment groups. Cows in the Pre-Synch group received PGF 28 and 14 days prior to the insertion of a DIB device (1 g progesterone, Syntex SA, Buenos Aires, Argentina) and the administration of 50 µg of Lecirelin (GnRH, Ovusin, Syntex SA) IM (Day 0). On Day 7, DIB were removed and cows received PGF (0.5 mg cloprostenol, Ciclase, Syntex SA). On Day 9, cows received a second GnRH treatment and were FTAI 16 h later (60 h after device removal). Cows in the Modified Pre-Synch group were treated similarly except that they received a DIB for 7 days prior to the second PGF injection and no DIB at the time of the first GnRH. Cows in the P4-Synch group were treated as those in the Pre-synch group but did not receive the two doses of PGF 28 and 14 days earlier. Cows in the P4 + EB + eCG groups received a DIB for 8 days, 2 mg of EB at DIB insertion (Day 0), and PGF and 400 IU eCG (Novormon, Syntex SA) IM at DIB removal (Day 8); they were subdivided to receive 1 mg of EB on Day 9 (P4 + EB + eCG + EB group) or GnRH on Day 10 (P4 + EB + eCG + GnRH group). Cows in these latter two groups were also FTAI 60 h after device removal. Pregnancy was determined by rectal palpation 50 days after FTAI and data were analyzed by logistic regression. Pregnancy rates were not affected by BCS, days postpartum, or milk yield (P > 0.5). However, there was a significant group effect due to a higher (P < 0.05) pregnancy rate in the P4 + EB + eCG + EB (49%) and P4 + EB + eCG + GnRH (44%) treatment groups than in those in the Modified Pre-Synch group (30%). Pregnancy rate in the P4-Synch group (39%) was lower (P < 0.05) than those in the P4 + EB + eCG + EB group but not different from the others. Finally, pregnancy rate in Pre-Synch group (41%) was intermediate and not different from the other treatment groups. Results of these experiments suggest that treatments with progesterone-releasing devices, EB, and eCG result in pregnancy rates that are comparable to or better than those obtained in GnRH-based protocols in lactating dairy cows. Further studies are needed to investigate whether eCG could increase pregnancy rates in cows treated with GnRH and progesterone-releasing devices. The authors thank Syntex SA for providing the hormones used in the study.


Author(s):  
D. Berean ◽  
O. Ergene ◽  
A. Blaga-Petrean ◽  
I. Bogdan ◽  
S. Ciupe ◽  
...  

Backgroung: Seasonal anestrus in ewes reduces reproductive efficiency and hinders productivity. Exogenous hormones can be used to facilitate the induction and synchronization of estrus in the anestrus period. The aim of this study was to evaluate the pregnancy rate in ewes after the treatment with different hormones and fixed time artificial insemination. Methods: The ewes were randomly divided in 4 (n=4) groups: Melatonin group (Group 1), Melatonin and Medroxyprogesterone group (Group 2), Medroxyprogesterone group (Group 3) and control group (Group 4). Pregnancy rate, estrus induction rate and litter size were determined and compared. Result: The estrus induction rate in our study was 100% for the first 3 groups and 6.25% for the 4th group. The pregnancy rate was between 4.16% (group 4) and 95.83% (group 2). For the others groups the values were 89.58% for the first group and 91.67%, for the 3rd group. The prolificacy rate was between 1 (control group) and 1.71 (2nd group), with intermediate values for the other 2 groups: 1.21 for 1st group and 1.27 for the 3rd group.


2021 ◽  
Vol 25 (1) ◽  
pp. 77-90
Author(s):  
Al-Timimi I. H. ◽  
Khammas D. J. ◽  
Al-Hamedawi T. M.

Repeated breeder dairy cows (96) were used in this study. They were diagnosed clinically as cases of delayed ovulation and divided into five groups according to type of treatment used post insemination. Group one which includes 28 cow (1=28) treated with 1 vial of fertagyl, (2=22) treated with 2 vials of fertagyl, (3=19) treated with 5 ml of chorionic gonadotropin, (4=17) treated with 1 vial of Nymfalom and (5=10) treated with 1 vial of chorulon. Results showed that the number of cows which did not return to estrus (responded) were 16(57.14%), 12(54.54%), 9(47.47%), 12(70.6%) and 4(40%) respectively. Treatment and insemination were repeated to a number of unresponded cows and their results revealed response of 3 cows (27.27%) from group (1=11), response of 4 cows (50%) from group (2=8), response of 3 cows (42.85%) from group (3=7), response of 1 cow (20%) from group (4=5) and response of 2 (50%) from group (5=4). Data concerning the number, type, sex and viability of the offspring born from the treated cows were included in this study. Finally we may conclude that Nymfalon showed better result in treating cases of delayed ovulation and in improving their conception and pregnancy rate. The remaining treatments were also advisable in the absence of Nymfalon. The use of the same treatment again was also beneficial in some unresponded cases.


Animals ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 257 ◽  
Author(s):  
Cheryl O’Connor ◽  
Suzanne Dowling ◽  
Vanessa Cave ◽  
Jim Webster

Bedding quality and cow lying time were measured during five weeks in a normal farm practice (NFP) off-paddock system with no bedding refreshment. Two groups of 100 non-lactating dairy cows were compared to groups of 8 cows with fresh bedding (FB). The cows were on a woodchip pad for 18 h/d at a space allowance of 5.4 m2/cow, with 6 h/d on pasture for 5 weeks. Lying times were recorded continuously for 60 cows per group using accelerometers. Bedding moisture content was measured weekly. Data for each NFP group were analysed and compared with those of their respective FB group using repeated measures. The lying time declined over five weeks from 11.6 h/day during the first week to 5.6 h/day during the fifth week (SED = 0.3; F1,25 = 351.56; p < 0.001). The moisture content of the bedding increased over the five weeks and was significantly higher for both NFP groups (NFP Group 1: F5,59 = 8.33; p < 0.001; NFP Group 2: F5,61 = 5.54; p < 0.001) than those of the respective FB groups. The percentage of total time lying when in the paddock increased for the NFP groups, reaching 15% in the last week of the trial. During five weeks on a stand-off pad, bedding quality deteriorated, and cows lay down less, to such an extent that welfare was compromised.


2021 ◽  
Author(s):  
Manuel Álvarez ◽  
Sofía Gaggiotti-Marre ◽  
Francisca Martínez ◽  
Lluc Coll ◽  
Sandra García ◽  
...  

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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