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Meta-Analysis
. 2020 Nov 4;15(11):e0241044.
doi: 10.1371/journal.pone.0241044. eCollection 2020.

Dydrogesterone as an oral alternative to vaginal progesterone for IVF luteal phase support: A systematic review and individual participant data meta-analysis

Georg Griesinger  1 , Christophe Blockeel  2 , Elke Kahler  3 , Claire Pexman-Fieth  4 , Jan I Olofsson  5   6 , Stefan Driessen  7 , Herman Tournaye  2
Affiliations
Free PMC article
Meta-Analysis

Dydrogesterone as an oral alternative to vaginal progesterone for IVF luteal phase support: A systematic review and individual participant data meta-analysis

Georg Griesinger et al. PLoS One. .
Free PMC article

Abstract

The aim of this systematic review and meta-analysis was to conduct a comprehensive assessment of the evidence on the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) for luteal phase support. Embase and MEDLINE were searched for studies that evaluated the effect of luteal phase support with daily administration of oral dydrogesterone (20 to 40 mg) versus MVP capsules (600 to 800 mg) or gel (90 mg) on pregnancy or live birth rates in women undergoing fresh-cycle IVF (protocol registered at PROSPERO [CRD42018105949]). Individual participant data (IPD) were extracted for the primary analysis where available and aggregate data were extracted for the secondary analysis. Nine studies were eligible for inclusion; two studies had suitable IPD (full analysis sample: n = 1957). In the meta-analysis of IPD, oral dydrogesterone was associated with a significantly higher chance of ongoing pregnancy at 12 weeks of gestation (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.08 to 1.61; P = 0.0075) and live birth (OR, 1.28; 95% CI, 1.04 to 1.57; P = 0.0214) compared to MVP. A meta-analysis combining IPD and aggregate data for all nine studies also demonstrated a statistically significant difference between oral dydrogesterone and MVP (pregnancy: OR, 1.16; 95% CI, 1.01 to 1.34; P = 0.04; live birth: OR, 1.19; 95% CI, 1.03 to 1.38; P = 0.02). Safety parameters were similar between the two groups. Collectively, this study indicates that a higher pregnancy rate and live birth rate may be obtained in women receiving oral dydrogesterone versus MVP for luteal phase support.

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Conflict of interest statement

G.G.'s institution has received investigator fees from Abbott during the conduct of the Lotus I and Lotus II studies. Outside of this submitted work, G.G. has received nonfinancial support from MSD, Ferring, Merck Serono, IBSA, Finox, TEVA, Glycotope and Gedeon Richter, as well as personal fees from MSD, Ferring, Merck Serono, IBSA, Finox, TEVA, Glycotope, Vitrolife, NMC Healthcare, ReprodWissen, Biosilu, Gedeon Richter and ZIVA. C.B.’s institution has received investigator fees from Abbott during the conduct of the Lotus I and Lotus II studies. C.B. is the President of the Belgian Society of Reproductive Medicine (unpaid) and Section Editor of Reproductive BioMedicine Online. C.B. has received grants from Ferring, participated in an MSD-sponsored trial and has received consultancy fees from Ferring, MSD, BioMérieux, Abbott and Merck. E.K. is an employee of Abbott Laboratories GmbH, Hannover, Germany and owns shares of Abbott. C.P.-F. is an employee of Abbott GmbH & Co. KG, Wiesbaden, Germany and owns shares in Abbott. J.I.O. is an employee of Abbott Products Operations AG, Allschwil, Switzerland. S.D. is an employee of Abbott Healthcare Products BV, Weesp, The Netherlands and owns shares in Abbott. H.T.'s institution has received investigator fees from Abbott during the conduct of the Lotus I and Lotus II studies. H.T.’s institution has received grants from Merck, MSD, Goodlife, Cook, Roche, CooperSurgical, Besins, Ferring and Allergan. H.T. has received consultancy fees from Gedeon Richter, Merck, Ferring, Abbott and ObsEva. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Flow diagram of the process of selecting and excluding studies for the meta-analyses.
IPD, individual participant data; IVF, in vitro fertilization.
Fig 2
Fig 2. Risk of bias for the eligible studies.
Risk of bias legend: A = random sequence generation; B = allocation concealment; C = blinding of participants and personnel; D = blinding of outcome data; E = incomplete data; F = selective reporting; G = other bias. ahigh risk of bias was expected for the assessment of adverse events; the risk of bias was lower for efficacy outcomes due to the objective methods of assessment. bA high risk of bias was expected for the reporting of adverse events. cStudy contained a larger proportion of women > 40 years of age in the oral dydrogesterone group. dSingle-blind study. eDouble-blind study, but patients were aware of the treatment arm due to the different routes of administration and the lack of use of a placebo dummy. fOpen-label study. g10.3% participants were excluded after randomization, and the numbers lost to follow-up were unbalanced between treatment groups. hDouble-blind, double-dummy study.
Fig 3
Fig 3. Meta-analysis of IPD: Influence of significant predictor variables (including treatment) on ongoing pregnancy and live birth (FAS).
CI, confidence interval; DYD, dydrogesterone; FAS, full analysis sample; IPD, individual participant data; MVP, micronized vaginal progesterone; NA, not applicable; OR, odds ratio. aAdjusted for age, study site, and day of embryo transfer. bAt 12 weeks of gestation. c75 sites in the dataset, resulting in 74 ORs and 95% CIs.
Fig 4
Fig 4
Fixed effect and random effects model meta-analysis of IPD and aggregate data: odds ratio for (A) pregnancy rate and (B) live birth rate (oral dydrogesterone versus MVP). CI, confidence interval; DYD, dydrogesterone; MVP, micronized vaginal progesterone; OR, odds ratio.
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Publication types

Grants and funding

The authors declare that the study was supported by Abbott and that one or more of the authors have an affiliation to the company. G.G., H.T. and C.B.’s institution has received investigator fees from Abbott during the conduct of the Lotus I and Lotus II studies. Editorial assistance was provided by Josh Lilly of Alpharmaxim Healthcare Communications, funded by Abbott Established Pharmaceuticals. The funder provided support in the form of salaries for several authors (E.K., C.P.-F., J.I.O., S.D.) but did not have any additional role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The specific roles of the authors are articulated in the ‘author contributions’ section.