No additional risk of congenital anomalies after first-trimester dydrogesterone use: a systematic review and meta-analysis

• Katalinic A.
• Noftz M.R.
• Garcia-Velasco J.A.
• Shulman L.P.
• van den Anker J.N.
• Strauss J.F. III

Abstract

Study question. Is exposure to dydrogesterone a risk factor for congenital anomalies when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in assisted reproductive technology (ART)?

Summary answer. Dydrogesterone, when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in ART, is not a relevant additional risk factor for congenital anomalies.

What is known already. Despite large clinical trials and meta-analyses that show no association between dydrogesterone and congenital anomalies, some recently retracted publications have postulated an association with teratogenicity. Dydrogesterone is also often rated as less safe than bioidentical progestins.

Study design, size, duration. A systematic review was conducted according to a pre-specified protocol with searches on Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov. The search was limited to human studies, with no restrictions on language, geographical region, or date. The search algorithm used a PICO (Population, Intervention, Comparison, Outcome)-style approach combining both simple search terms and medical subject heading terms. As congenital anomalies are mostly reported as secondary outcomes, the search term ‘safety’ was added.

Participants/materials, setting, methods. Interventional study and observational study (OS) designs were eligible for inclusion. Inclusion criteria were: women >17 years old treated for threatened miscarriage, recurrent pregnancy loss, and/or ART; the use of dydrogesterone in the first trimester compared with placebo, no treatment or other interventions; and reporting of congenital anomalies in newborns or infants 12 months old (primary outcome). Two authors (K.А., N.M.R.) independently extracted the following

data: general study information, study population details, intervention and comparator(s), and frequencies of congenital anomalies (classification, time of determination, and type). Risk of bias focused on the reporting of congenital malformations and was assessed using the Cochrane Risk of Bias Tool Version 2 or the ROBINS-I tool. The GRADEproGDT platform was used to generate the GRADE summary of findings table.

Main results and the role of chance. Of the 897 records retrieved during the literature search, 47 were assessed for eligibility. 9 studies were included in the final analysis: six randomized controlled trials (RCTs) and three OSs. Among the RCTs, three had a low risk and three a high risk of bias. Two of the OSs were considered to have a serious risk of bias and one with critical risk of bias and was excluded for the evidence syntheses. The eight remaining studies included a total of 5070 participants and 2680 live births from 16 countries. In the meta-analysis of RCTs only, the overall risk ratio (RR) was 0.92 [95% CI 0.55–1.55] with low certainty. When the two OSs were included, the overall RR was 1.11 [95% CI 0.73–1.68] with low certainty.

Limitations, reasons for caution. The studies included in the analysis do not report congenital anomalies as the primary outcome; reporting of congenital anomalies was often not standardized.

Wider implications of the findings. This systematic literature review and meta-analysis provide clear reassurance to both clinicians and patients that dydrogesterone is not associated with congenital anomalies above the rate that might be expected due to environmental and genetic factors. The results of this work represent the highest current level of evidence for the question of congenital anomalies, which removes the existing uncertainty caused by poor quality and retracted studies.

Trial registration number: PROSPERO 2022 CRD42022356977.

Keywords:progesterone; meta-analysis; congenital abnormality; recurrent miscarriage; miscarriage; ART

REFERENCES

• Almohammadi A., Raveendran A., Black M., Maheshwari A. The optimal route of progesterone administration for luteal phase support in a frozen embryo transfer: a systematic review. Arch Gynecol Obstet. 2022; 308: 341–50.
• Babalioğlu R., Varol F.G., Ilhan R., Yalçin O., Cizmecioglu F. Progesterone profiles in luteal-phase defects associated with recurrent spontaneous abortions. J Assist Reprod Genet. 1996; 13: 306–9.
• Barbosa M.W., Silva L.R., Navarro P.A., Ferriani R.A., Nastri C.O., Martins W.P. Dydrogesterone vs progesterone for luteal-phase support: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol. 2016; 48: 161–70.
• Baron J., Holzman G.B., Schulkin J. Attitudes of obstetricians and gynecologists toward hormone replacement therapy. Med Decis Making 1998; 18: 406–11.
• Carp H.J.A. Progestogens and pregnancy loss. Climacteric. 2018; 21: 380–4.
• 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.
• Czajkowski K., Sienko J., Mogilinski M., Bros M., Szczecina R., Czajkowska A. Uteroplacental circulation in early pregnancy complicated by threatened abortion supplemented with vaginal micronized progesterone or oral dydrogesterone. Fertil Steril. 2007; 87: 613–8.
• 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.
• El-Zibdeh M.Y. Dydrogesterone in the reduction of recurrent spontaneous abortion. J Steroid Biochem Mol Biol. 2005; 97: 431–4.
• El-Zibdeh M.Y., Yousef L.T. Dydrogesterone support in threatened miscarriage. Maturitas. 2009; 65: S43–6.
• ESHRE. Recurrent Pregnancy Loss. Guideline of European Society of Human Reproduction and Embryology, 2022. URL: https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Recurrent-pregnancy-loss (date of access June, 2023).
• EUROCAT. European Network of Population-Based Registries for the Epidemiological Surveillance of Congenital Anomalies, 2023. URL: https://eu-rd-platform.jrc.ec.europa.eu/eurocat/eurocat-data/prevalence_en (date of access July, 2023).
• 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.
• 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.
• Ji L.J., Lappas C.M., Wang X.Q., Meier B.P. The naturalness bias influences drug and vaccine decisions across cultures. Med Decis Making. 2023; 43: 252–62.
• 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 metaanalysis. Reprod Biomed Online. 2022; 45: 365–73.

• Li H., Cao Y. For the love of nature: people who prefer natural versus synthetic drugs are higher in nature connectedness. J Environ Psychol. 2020; 71: 101496. URL: https://www.sciencedirect.com/science/article/abs/pii/S0272494420306617
• 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.
• Licciardi F.L., Kwiatkowski A., Noyes N.L., Berkeley A.S., Krey L.L., Grifo J.A. Oral versus intramuscular progesterone for in vitro fertilization: a prospective randomized study. Fertil Steril. 1999; 71: 614–8.
• Moorthie S., Blencowe H., Darlison M.W., Lawn J., Morris J.K., Modell B., et al.; Congenital Disorders Expert Group. Estimating the birth prevalence and pregnancy outcomes of congenital malformations worldwide. J Community Genet. 2018; 9: 387–96.
• Mount Sinai Health Library, 2023. URL: https://www.mountsinai.org/health-library/herb/wild-yam (date of access June, 2023).
• Ovarian Stimulation TEGGO; Bosch E., Broer S., Griesinger G., Grynberg M., Humaidan P., Kolibianakis E., et al. ESHRE guideline: ovarian stimulation for IVF/ICSIf. Hum Reprod Open 2020; 2020: hoaa009.
• Page M.J., McKenzie J.E., Bossuyt P.M., Boutron I., Hoffmann T.C., Mulrow C.D., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71.
• Pandian R.U. Dydrogesterone in threatened miscarriage: a Malaysian experience. Maturitas. 2009; 65: S47–50.
• Parveen R., Khakwani M., Tabassum S., Masood S. Oral versus vaginal micronized progesterone for the treatment of threatened miscarriage. Pak J Med Sci. 2021; 37: 628–32.
• Retraction Watch Database, n.d. URL: http://retractiondatabase.org/RetractionSearch.aspx#?auth%3dKoren (date of access July, 2023).
• Rižner T.L., Brožič P., Doucette C., Turek-Etienne T., Müller-Vieira U., Sonneveld E., et al. Selectivity and potency of the retroprogesterone dydrogesterone in vitro. Steroids. 2011; 76: 607–15.
• Schindler A.E. Progestational effects of dydrogesterone in vitro, in vivo and on the human endometrium. Maturitas. 2009; 65: S3–11.
• 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.
• Shoham G., Leong M., Weissman A. A 10-year follow-up on the practice of luteal phase support using worldwide web-based surveys. Reprod Biol Endocrinol. 2021; 19: 15.
• Sterne J.A., Hernan M.A., Reeves B.C., Savovic J., Berkman N.D., Viswanathan M., et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016; 355: i4919.
• Sterne J.A.C., Savovic J., Page M.J., Elbers R.G., Blencowe N.S., Boutron I., et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019; 366: l4898.
• Sterne J.A., Sutton A.J., Ioannidis J.P., Terrin N., Jones D.R., Lau J., et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011; 343: d4002.
• The GRADE Working Group; Schünemann H., Brozek J., Guyatt G., Oxman A. (eds). GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations, 2013. URL: https://gdt.gradepro.org/app/handbook/handbook.html (date of access June, 2023).

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