To the content
4 . 2022

A critical appraisal of safety data on dydrogesterone for the support of early pregnancy: a scoping review and meta-analysis

Abstract

No data support the suggestion that first-trimester dydrogesterone use increases the risk of fetal abnormalities; however, two low-quality retrospective studies (one retracted by the journal) have suggested such a link.

A scoping review and meta-analysis were carried out to address this discrepancy. The literature was reviewed but it was not possible to identify any evidence of a plausible mechanism for potential causality between dydrogesterone and fetal abnormalities. To investigate whether any evidence existed, a preliminary meta-analysis was undertaken of clinical studies published since 2005 on first-trimester dydrogesterone use with assessment of fetal abnormalities.

A fixed effects model was used to determine pooled odds ratios with 95% confidence intervals (CI). From 83 articles identified, six randomized controlled trials were included.

Pooled risk ratios (RR) for maternal dydrogesterone use and fetal abnormalities gave a RR approaching 1 (RR 0.96; 95% CI 0.57–1.62), confirming previous conclusions of no causal association between fetal abnormalities and first-trimester dydrogesterone use. Physicians, scientists and journal reviewers should exercise due diligence to prevent promulgation of retracted data. We are confident in using dydrogesterone, if indicated, in the treatment of threatened or recurrent miscarriage, and believe that its favourable safety profile should extend to its appropriate use in assisted reproductive technologies.

Keywords:congenital abnormality; dydrogesterone; meta-analysis; miscarriage; progestogen

Katalinic A., Shulman L.P., Strauss J.F., Garcia-Velasco J.A., van den Anker J.N. A critical appraisal of safety data on dydrogesterone for the support of early pregnancy: a scoping review and meta-analysis. Reprod Biomed Online. 2022; 45 (2):365–73. DOI: https://doi.org/10.1016/j.rbmo.2022.03.032

References

- Babalioglu R., Varol F.G., Ilhan R., Yalcin O., Cizmecioglu F. Progesterone profiles in luteal-phase defects associated with recurrent spontaneous abortions. J Assist Reprod Genet. 1996; 13: 306–9. DOI: https://doi.org/10.1007/BF02070143

- Boughton S.L., Wilkinson J., Bero L. When beauty is but skin deep: dealing with problematic studies in systematic reviews. Cochrane Database Syst Rev. 2021; 6: ED000152. DOI: https://doi.org/10.1002/14651858.ED000152

- Brent R.L. Nongenital malformations following exposure to progestational drugs: the last chapter of an erroneous allegation. Birth Defects Res A Clin Mol Teratol. 2005; 73: 906–18. DOI: https://doi.org/10.1002/bdra.20184

- Broekmans F., Humaidan P., Lainas G., Toyli M., Le Clef N., Vermeulen N. Reply: Questionable recommendation for LPS for IVF/ICSI in ESHRE guideline 2019: ovarian stimulation for IVF/ICSI. Hum Reprod Open. 2021; 2021: hoab006. DOI: https://doi.org/10.1093/hropen/hoab006

- Carp H.J.A. Progestogens and pregnancy loss. Climacteric. 2018; 21: 380–4. DOI: https://doi.org/10.1080Z13697137.2018.1436166

- Chakravarty B.N., Shirazee H.H., Dam P., Goswami S.K., Chatterjee R., Ghosh S. Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study. J Steroid Biochem Mol Biol. 2005; 97: 416–20. DOI: https://doi.org/10.1016/j.jsbmb.2005.08.012

- Chan D.M.K., Cheung K.W., Ko J.K.Y., Yung S.S.F., Lai S.F., Lam M.T., et al. Use of oral progestogen in women with threatened miscarriage in the first trimester: a randomized double-blind controlled trial. Hum Reprod. 2021; 36: 587–95. DOI: https://doi.org/10.1093/humrep/deaa327

- Coomarasamy A., Williams H., Truchanowicz E., Seed P.T., Small R., Quenby S., et al. PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages – a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. Health Technol Assess. 2016; 20: 1–92. DOI: https://doi.org/10.3310/hta20410

- Coomarasamy A., Harb H.M., Devall A.J., Cheed V., Roberts T.E., Goranitis I., et al. Progesterone to prevent miscarriage in women with early pregnancy bleeding: the PRISM RCT. Health Technol. Assess. 2020; 24: 1–70. DOI: https://doi.org/10.3310/hta24330

- Coomarasamy A., Gallos I.D., Papadopoulou A., Dhillon-Smith R.K., Al-Me- mar M., Brewin J., et al. Sporadic miscarriage: evidence to provide effective care. Lancet. 2021; 397: 1668–74. DOI: https://doi.org/10.1016/S0140-6736(21)-00683-8

- Csapo A.I., Pulkkinen M.O., Ruttner B., Sauvage J.P., Wiest W.G. The significance of the human corpus luteum in pregnancy maintenance. I. Preliminary studies. Am J Obstet Gynecol. 1972; 112: 1061–7. DOI: https://doi.org/10.1016/0002-9378(72)90181-0

- Devall A.J., Papadopoulou A., Podesek M., Haas D.M., Price M.J., Coomarasamy A., et al. Progestogens for preventing miscarriage: a network meta-analysis. Cochrane Database Syst Rev. 2021; 4: CD013792.

- Donovan M.F., Cascella M. Embryology, weeks 6–8. In: StatPearls. NCBI Bookshelf 2020. 2021. URL: https://www.ncbi.nlm.nih.gov/books/NBK563181/ (date of access 05, 2021)

- El-Zibdeh M.Y. Dydrogesterone in the reduction of recurrent spontaneous abortion. J Steroid Biochem Mol Biol. 2005; 97: 431–4. DOI: https://doi.org/10.1016/j.jsbmb.2005.08.007

- El-Zibdeh M.Y., Yousef L.T. Dydrogesterone support in threatened miscarriage. Maturitas. 2009; 65 (suppl 1): S43–6. DOI: https://doi.org/10.1016/j.maturitas.2009.11.013

- ESHRE Reproductive Endocrinology Guideline Group. Ovarian Stimulation for IVF/ICSI. Guideline of the ESHRE. Oct 2019. URL: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Ovarian-Stimulation-in-IVF-ICSI (date of access December 12, 2021)

- European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, 2021. URL: https://www.enepp.eu/encepp/vιewResourcehtm?ιd=44304 (date of access December, 2021)

- Food and Drug Administration. Federal Register. 2017; 82: 171. URL: https://www.govinfo.gov/content/pkg/FR-2017-09-06/pdf/2017-18816.pdf (date of access March, 2022)

- Garg D., Ng S.S.M., Baig K.M., Driggers P., Segars J. Progesterone-mediated non-classical signaling. Trends Endocrinol Metab. 2017; 28: 656–8. DOI: https://doi.org/111016/j.tem.2017.05.006

- Griesinger G., Blockeel C., Sukhikh G.T., Patki A., Dhorepatil B., Yang D.Z., et al. Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial. Hum Reprod. 2018; 33: 2212–21. DOI: https://doi.org/10.1093/humrep/dey306

- Griesinger G., Tournaye H., Macklon N., Petraglia F., Arck P., Blockeel C., et al. Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online. 2019; 38: 249–59. DOI: https://doi.org/10.1016/j.rbmo.2018.11.017

- Griesinger G., Blockeel C., Kahler E., Pexman-Fieth C., Olofsson J.I., Driessen S., et al. Dydrogesterone as an oral alternative to vaginal progesterone for IVF luteal phase support: a systematic review and individual participant data meta-analysis. PLoS One. 2020; 15: e0241044. DOI: https://doi.org/10.1371/journal.pone.0241044

- Health Products Regulatory Authority. Summary of Product Characteristics Duphaston. 23 November 2020. URL: https://www.hpra.ie/img/uploaded/swedocuments/Licence_PA2010-010-001_23112020124149.pdf (date of access June 17, 2021)

- Heine P., Sellar L., Whitten S., Bajaj P. A questionnaire-based audit to assess overall experience and convenience among patients using vaginal progesterone tablets (Lutigest®) for luteal phase support during IVF treatment. Patient Relat Outcome Meas. 2017; 8: 169–79. DOI: https://doi.org/10.2147/PROM.S140678

- Hodgson J., McClaren B.J. Parental experiences after prenatal diagnosis of fetal abnormality. Semin Fetal Neonatal Med. 2018; 23: 150–4. DOI: https://doi.org/10.1016/j.siny.2017.11.009

- Huang J., Xie Q., Lin J., Lu X., Wang N., Gao H., et al. Neonatal outcomes and congenital malformations in children born after dydrogesterone application in progestin-primed ovarian stimulation protocol for IVF: a retrospective cohort study. Drug Des Devel Ther. 2019; 13: 2553–63. DOI: https://doi.org/10.2147/DDDT.S210228

- Koren G., Gilboa D. Dydrogesterone exposure in the first trimester of pregnancy and fetal malformations. Motherisk Int J. 2020; 1: 11.

- Koren G., Gilboa D., Katz R. Expression of concern to: Fetal safety of dydrogesterone exposure in the first trimester of pregnancy. Clin Drug Investig. 2020; 40: 681. DOI: https://doi.org/10.1007/s40261-019-00884-4

- Li T.C., Spuijbroek M.D., Tuckerman E., Anstie B., Loxley M., Laird S. Endocrinological and endometrial factors in recurrent miscarriage. BJOG. 2000; 107: 1471–9. DOI: https://doi.org/10.1111/j.1471-0528.2000.tb11670.x

- Lobo I., Zhaurova K. Birth defects: causes and statistics. 2008. URL: https://www.nature.com/scitable/topicpage/birth-defects-causes-and-statistics-863/ (date of access April 16, 2021)

- Mirza F.G., Patki A., Pexman-Fieth C. Dydrogesterone use in early pregnancy. Gynecol Endocrinol. 2016; 32: 97–106. DOI: https://doi.org/10.3109/09513590.2015.1121982

- Mor G., Aldo P., Alvero A.B. The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol. 2017; 17: 469–82. DOI: https://doi.org/10.1038/nri.2017.64

- Munn Z., Peters M.D.J., Stern C., Tufanaru C., McArthur A., Aromataris E. Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC Med Res Methodol. 2018; 18: 143.

- Nadarajah R., Rajesh H., Wong K.Y., Faisal F., Yu S.L. Live birth rates and safety profile using dydrogesterone for luteal phase support in assisted reproductive techniques. Singapore Med J. 2017; 58: 294–7. DOI: https://doi.org/10.11622/smedj.2016080

- Neumann K., Masuch A., Vonthein R., Depenbusch M., Schultze-Mosgau A., Eggersmann T.K., et al. Dydrogesterone and 20α-dihydrodydrogesterone plasma levels on day of embryo transfer and clinical outcome in an anovulatory programmed frozen-thawed embryo transfer cycle: a prospective cohort study. Hum Reprod. 2022; 37 (6): 1183–93. DOI: https://doi.org/10.1093/humrep/deac045

- Northen A.T., Norman G.S., Anderson K., Moseley L., Divito M., Cotroneo M., et al.; National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol. 2007; 110: 865–72. DOI: https://doi.org/10.1097/01.AOG.0000281348.51499.bc

- Pandian R.U. Dydrogesterone in threatened miscarriage: a Malaysian experience. Maturitas. 2009; 65 (suppl 1): S47–50. DOI: https://doi.org/10.1016/j.maturitas.2009.11.016

- Piette P.C.M. Questionable recommendation for LPS for IVF/ICSI in ESHRE guideline 2019: ovarian stimulation for IVF/ICSI. Hum Reprod Open. 2021; 2021: hoab005. DOI: https://doi.org/10.1093/hropen/hoab005

- Queisser-Luft A. Dydrogesterone use during pregnancy: overview of birth defects reported since 1977. Early Hum Dev. 2009; 85: 375–7. DOI: https://doi.org/10.1016/j.earlhumdev.2008.12.016

- Quenby S., Gallos I.D., Dhillon-Smith R.K., Podesek M., Stephenson M.D., Fisher J., et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021; 397: 1658–67. DOI: https://doi.org/10.1016/S0140-6736(21)00682-6

- Rizner T.L., Brožič P., Doucette C., Turek-Etienne T., Müller-Vieira U., Sonne- veld E., et al. Selectivity and potency of the retroprogesterone dydrogesterone in vitro. Steroids. 2011; 76: 607–15. DOI: https://doi.org/10.1016/j.steroids.2011.02.043

- Saccone G., Schoen C., Franasiak J.M., Scott R.T. Jr, Berghella V. Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials. Fertil Steril. 2017; 107: 430–8.e3. DOI: https://doi.org/10.1016/j.fertnstert.2016.10.031

- Schindler A.E. Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium. Maturitas. 2009; 65 (suppl 1): S3–11. DOI: https://doi.org/10.1016/j.maturitas.2009.10.011

- Schindler A.E., Campagnoli C., Druckmann R., Huber J., Pasqualini J.R., Schweppe K.W., et al. Classification and pharmacology of progestins. Maturitas. 2008; 61: 171–80. DOI: https://doi.org/10.1016/j.maturitas.2008.11.013

- Tournaye H., Sukhikh G.T., Kahler E., Griesinger G. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum. Reprod. 2017; 32: 1019–27. DOI: https://doi.org/10.1093/humrep/dex023 Erratum in Hum Reprod. 2017; 32: 2152. DOI: https://doi.org/10.1093/humrep/dex266

- van der Horst H.J., de Wall L.L. Hypospadias, all there is to know. Eur J Pediatr. 2017; 176: 435–41. DOI: https://doi.org/10.1007/s00431-017-2864-5

- Vuong L.N., Pham T.D., Le K.T.Q., Ly T.T., Le H.L., Nguyen D.T.N., et al. Micronized progesterone plus dydrogesterone versus micronized progesterone alone for luteal phase support in frozen-thawed cycles (MIDRONE): a prospective cohort study. Hum Reprod. 2021; 36: 1821–31. DOI: https://doi.org/10.1093/humrep/deab093

- Wang X.X., Luo Q., Bai W.P. Efficacy of progesterone on threatened miscarriage: difference in drug types. J Obstet Gynaecol Res. 2019; 45: 794–802. DOI: https://doi.org/10.1111/jog.13909

- World Health Organization (WHO). URL. https://www.who.int/news-room/fact-sheets/detail/congenital-anomalies (date of access May, 2021)

- Xu H., Zhang X.Q., Zhu X.L., Weng H.N., Xu L.Q., Huang L., et al. Comparison of vaginal progesterone gel combined with oral dydrogesterone versus intramuscular progesterone for luteal support in hormone replacement therapy-frozen embryo transfer cycle. J Gynecol Obstet Hum Reprod. 2021; 50: 102110. DOI: https://doi.org/10.1016/j.jogoh.2021.102110

- Yang D.Z., Griesinger G., Wang W., Gong F., Liang X., Zhang H., et al. A Phase III randomized controlled trial of oral dydrogesterone versus intravaginal progesterone gel for luteal phase support in in vitro fertilization (Lotus II): results from the Chinese mainland subpopulation. Gynecol Endocrinol. 2020; 36: 175–83. DOI: https://doi.org/10.1080/09513590.2019.1645110

- Zaqout M., Aslem E., Abuqamar M., Abughazza O., Panzer J., De Wolf D. The impact of oral intake of dydrogesterone on fetal heart development during early pregnancy. Pediatr Cardiol. 2015; 36: 1483–8. DOI: https://doi.org/10.1007/s00246-015-1190-9

- Zhao H., He W., Yang Z. A pairwise and network meta-analysis comparing the efficacy and safety of progestogens in threatened abortion. Int J Gynaecol Obstet. 2022; 156 (3): 383–93. DOI: https://doi.org/10.1002/ijgo.13707

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)

CHIEF EDITORS
CHIEF EDITOR
Sukhikh Gennadii Tikhonovich
Academician of the Russian Academy of Medical Sciences, V.I. Kulakov Obstetrics, Gynecology and Perinatology National Medical Research Center of Ministry of Healthсаre of the Russian Federation, Moscow
CHIEF EDITOR
Kurtser Mark Arkadievich
Academician of the Russian Academy of Sciences, MD, Professor, Head of the Obstetrics and Gynecology Subdepartment of the Pediatric Department, N.I. Pirogov Russian National Scientific Research Medical University, Ministry of Health of the Russian Federation
CHIEF EDITOR
Radzinsky Viktor Evseevich
Corresponding Member of the Russian Academy of Sciences, MD, Professor, Head of the Subdepartment of Obstetrics and Gynecology with a Course of Perinatology of the Medical Department in the Russian People?s Friendship University

Journals of «GEOTAR-Media»