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Impact of progestin ovarian stimulation on newborn outcomes: a meta-analysis

  • Assisted Reproduction Technologies
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Abstract

Objectives

To compare progestin ovarian stimulation protocols with gonadotropin-releasing hormone analogue (agonists and antagonists) protocols on newborn outcomes.

Methods

The PubMed, Embase, Cochrane Central Register of Controlled Trials, and BioMed Central databases were searched for studies comparing progestin prime ovarian stimulation (PPOS) protocols with gonadotropin-releasing hormone analogues. Data were pooled by meta-analysis using a random effects model.

Main outcome measures

Primary endpoint was the risk of newborn congenital malformations.

Results

A total of 4 studies involving 9274 live-born infants were included. No important harm was observed with PPOS in terms of congenital malformations (OR 0.92; 95% CI 0.63–1.34; p = 0.65) (very low quality of evidence (QOE)) and low birth weight (OR 1.06; 95% CI 0.95–1.18; p = 0.29) (very low QOE) as compared with GnRH-a short protocols. In addition, a trend to a lower risk of preterm birth (OR 0.90; 95% CI 0.80–1.02; p = 0.10) (very low QOE) was found among patients treated with a PPOS protocol.

Conclusions

PPOS protocols, compared with GnRH-a protocols, are associated with a similar congenital malformation risk profile. Therefore, PPOS might represent a safe and appealing treatment option for infertile patients.

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References

  1. von Wolff M, Thaler CJ, Frambach T, Zeeb C, Lawrenz B, Popovici RM, et al. Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil Steril Elsevier. 2009;92:1360–5.

    Article  CAS  Google Scholar 

  2. Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, et al. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril. 2015;104:62–70.e3.

    Article  CAS  PubMed  Google Scholar 

  3. Soules MR, Steiner RA, Clifton DK, Cohen NL, Aksel S, Bremner WJ. Progesterone modulation of pulsatile luteinizing hormone secretion in normal women. J Clin Endocrinol Metab Narnia. 1984;58:378–83.

    Article  CAS  PubMed  Google Scholar 

  4. Harris TG, Dye S, Robinson JE, Skinner DC, Evans NP. Progesterone can block transmission of the estradiol-induced signal for luteinizing hormone surge generation during a specific period of time immediately after activation of the gonadotropin-releasing hormone surge-generating system. Endocrinology Narnia. 1999;140:827–34.

    Article  CAS  PubMed  Google Scholar 

  5. Zhu X, Ye H, Fu Y. Use of Utrogestan during controlled ovarian hyperstimulation in normally ovulating women undergoing in vitro fertilization or intracytoplasmic sperm injection treatments in combination with a “freeze all” strategy: a randomized controlled dose-finding study of 100 mg versus 200 mg. Fertil Steril. 2017;107:379–386.e4.

    Article  CAS  PubMed  Google Scholar 

  6. Wang Y, Chen Q, Wang N, Chen H, Lyu Q, Kuang Y. Controlled ovarian stimulation using medroxyprogesterone acetate and hMG in patients with polycystic ovary syndrome treated for IVF. Medicine (Baltimore). 2016;95:e2939.

    Article  CAS  Google Scholar 

  7. Huang C-Y, Chen G-Y, Shieh M-L, Li H-Y. An extremely patient-friendly and efficient stimulation protocol for assisted reproductive technology in normal and high responders. Reprod Biol Endocrinol. 2018;16:18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang J, Mao X, Wang Y, Chen Q, Lu X, Hong Q, et al. Neonatal outcomes and congenital malformations in children born after human menopausal gonadotropin and medroxyprogesterone acetate treatment cycles. Arch Gynecol Obstet. 2017;296:1207–17.

    Article  CAS  PubMed  Google Scholar 

  9. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Iorio A, Spencer FA, Falavigna M, Alba C, Lang E, Burnand B, et al. Use of GRADE for assessment of evidence about prognosis: rating confidence in estimates of event rates in broad categories of patients. BMJ Br Med J Publishing Group. 2015;350.

  12. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010;1:97–111.

    Article  PubMed  Google Scholar 

  13. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhu X, Ye H, Fu Y. Comparison of neonatal outcomes following progesterone use during ovarian stimulation with frozen-thawed embryo transfer. Sci Rep. 2017;7:7835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang N, Lin J, Zhu Q, Fan Y, Wang Y, Fu Y, et al. Comparison of neonatal outcomes and live-birth defects after progestin-primed ovarian stimulation versus conventional ovarian stimulation for in vitro fertilization. Medicine (Baltimore). 2018;97:e11906.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. La Marca A, Capuzzo M. Use of progestins to inhibit spontaneous ovulation during ovarian stimulation: the beginning of a new era? Reprod BioMed Online. 2019;39:321–31.

    Article  CAS  PubMed  Google Scholar 

  18. Massin N. New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF. Hum Reprod Update. 2017;23:211–20.

    CAS  PubMed  Google Scholar 

  19. Wang A, Santistevan A, Hunter Cohn K, Copperman A, Nulsen J, Miller BT, et al. Freeze-only versus fresh embryo transfer in a multicenter matched cohort study: contribution of progesterone and maternal age to success rates. Fertil Steril. 2017;108:254–261.e4.

    Article  CAS  PubMed  Google Scholar 

  20. Jin XY, Zhao LJ, Luo DH, Liu L, Dai YD, Hu XX, et al. Pinopode score around the time of implantation is predictive of successful implantation following frozen embryo transfer in hormone replacement cycles. Hum Reprod. 2017;32:2394–403.

    Article  CAS  PubMed  Google Scholar 

  21. Silva CC, Knight PG. Effects of androgens, progesterone and their antagonists on the developmental competence of in vitro matured bovine oocytes. J Reprod Fertil. 2000;119:261–9.

    Article  CAS  PubMed  Google Scholar 

  22. Carter F, Rings F, Mamo S, Holker M, Kuzmany A, Besenfelder U, et al. Effect of elevated circulating progesterone concentration on bovine blastocyst development and global transcriptome following endoscopic transfer of in vitro produced embryos to the bovine oviduct. Biol Reprod. 2010;83:707–19.

    Article  CAS  PubMed  Google Scholar 

  23. Willingham-Rocky LA, Hinrichs K, Westhusin ME, Kraemer DC. Effects of stage of oestrous cycle and progesterone supplementation during culture on maturation of canine oocytes in vitro. Reproduction. 2003;126:501–8.

    Article  CAS  PubMed  Google Scholar 

  24. Vannucchi CI, de Oliveira CM, Marques MG, Assumpção MEOÁ, Visintin JA. In vitro canine oocyte nuclear maturation in homologous oviductal cell co-culture with hormone-supplemented media. Theriogenology. 2006;66:1677–81.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang X, Armstrong DT. Effects of follicle-stimulating hormone and ovarian steroids during vitro meiotic maturation on fertilization of rat oocytes. Gamete Res. 1989;23:267–77.

    Article  CAS  PubMed  Google Scholar 

  26. Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS, Lammer EJ. Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med. American Medical Association. 2005;159:957.

    Article  PubMed  Google Scholar 

  27. Giorlandino C, Cignini P, Padula F, Giannarelli D, d’Emidio L, Aloisi A, et al. Effects of exogenous progesterone on fetal nuchal translucency: an observational prospective study. Am J Obstet Gynecol. 2015;212:335.e1–7.

    Article  CAS  Google Scholar 

  28. De Santis M, Cavaliere AF, Straface G, Carducci B, Caruso A. Failure of the emergency contraceptive levonorgestrel and the risk of adverse effects in pregnancy and on fetal development: an observational cohort study. Fertil Steril. 2005;84:296–9.

    Article  CAS  PubMed  Google Scholar 

  29. Murthy YS, Arronet GH, Parekh MC. Luteal phase inadequacy. Its significance in infertility. Obstet Gynecol. 1970;36:758–61.

    CAS  PubMed  Google Scholar 

  30. Norman JE, Marlow N, Messow C-M, Shennan A, Bennett PR, Thornton S, et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016;387:2106–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Romero R, Conde-Agudelo A, Da Fonseca E, O’Brien JM, Cetingoz E, Creasy GW, et al. Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data. Am J Obstet Gynecol. 2018;218:161–80.

    Article  CAS  PubMed  Google Scholar 

  32. Romero R, Nicolaides KH, Conde-Agudelo A, O’Brien JM, Cetingoz E, Da Fonseca E, et al. Vaginal progesterone decreases preterm birth ≤ 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet Gynecol Wiley-Blackwell. 2016;48:308–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Word R, Li X-H, Hnat M, Carrick K. Dynamics of cervical remodeling during pregnancy and parturition: mechanisms and current concepts. Semin Reprod Med. 2007;25:069–79.

    Article  CAS  Google Scholar 

  34. Giacalone PL, Daurés JP, Faure JM, Boulot P, Hedon B, Laffargue F. The effects of mifepristone on uterine sensitivity to oxytocin and on fetal heart rate patterns. Eur J Obstet Gynecol Reprod Biol. 2001;97:30–4.

    Article  CAS  PubMed  Google Scholar 

  35. Xiao Z, Peng J, Yang J, Xu W. Flexible GnRH antagonist protocol versus progestin-primed ovarian stimulation (PPOS) protocol in patients with polycystic ovary syndrome: comparison of clinical outcomes and ovarian response. Curr Med Sci. 2019;39:431–6.

    Article  CAS  PubMed  Google Scholar 

  36. Yildiz S, Turkgeldi E, Angun B, Eraslan A, Urman B, Ata B. Comparison of a novel flexible progestin primed ovarian stimulation protocol and the flexible gonadotropin-releasing hormone antagonist protocol for assisted reproductive technology. Fertil Steril. 2019;112:677–83.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Irene Zolfaroli.

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Zolfaroli, I., Ferriol, G.A., Mora, JJ.H. et al. Impact of progestin ovarian stimulation on newborn outcomes: a meta-analysis. J Assist Reprod Genet 37, 1203–1212 (2020). https://doi.org/10.1007/s10815-020-01755-0

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  • DOI: https://doi.org/10.1007/s10815-020-01755-0

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