Метааналізи та рандомізовані контрольовані дослідження: що повинні знати клініцисти для профілактики звичних і спонтанних викиднів нез’ясованого ґенезу?

Paul Piette

doi:10.18370/2309-4117.2021.61.39-44

Authors

Paul Piette Besins Healthcare Global, Belgium https://orcid.org/0000-0001-8186-7287

DOI:

https://doi.org/10.18370/2309-4117.2021.61.39-44

Keywords:

recurrent miscarriage, vaginal micronized progesterone, dydrogesterone, research

Abstract

The etiopathology of recurrent miscarriage is a combination of various factors, including chromosomal defects, genetic or structural abnormalities, endocrine abnormalities, infections, immune dysfunction, thrombophilia disorders, antiphospholipid syndrome, and unexplained causes.
It has long been known that progesterone is needed to maintain pregnancy and its physiological development. Insufficient progesterone secretion and its low level in the blood serum in early pregnancy is associated with the threat of miscarriage and loss of pregnancy at a later stage – up to 16 weeks of gestation. The effectiveness of the vaginal micronized progesterone (VMP) at a dose of 400 mg twice a day in the first trimester of pregnancy was evaluated in two recent large high-quality multicenter placebo-controlled studies, one of which included pregnant women with recurrent miscarriages of unexplained origin (PROMISE Trial), and the other study included women with early pregnancy loss (PRISM Trial). A key finding, pioneered in the PROMISE study and later confirmed in the PRISM study, was that VMP treatment associated with an increase in live births in line with the number of previous miscarriages.
It has been shown that there is no evidence regarding safety concerns with natural micronized progesterone. Treatment with an VMP should be recommended for women with bleeding in early pregnancy and a history of one or more miscarriages. The recommended treatment regimen is 400 mg 2 times a day (800 mg/day) intravaginal, starting from the moment bleeding is detected up to 16 weeks of pregnancy.
In the future, there remains uncertainty effectiveness and safety of alternative progestogens (dydrogesterone) for the treatment of women at high risk of threatened abortion and recurrent miscarriage. It is important that dydrogesterone is a synthetic progestin, its structure is significantly different from natural progesterone, and therefore it is necessary to unequivocally prove the short- and long-term safety of this drug before considering its use in clinical practice.

Author Biography

Paul Piette, Besins Healthcare Global

PharmD, Scientific & Medical Affairs Director, Senior Research Fellow, Clinique Antonie Depage, Senior Research Fellow and Consultant

References

Coomarasamy, A., Williams, H., Truchanowicz, E., et al. “A randomized trial of progesterone in women with recurrent miscarriages.” N Engl J Med 373.22 (2015): 2141–8.
Coomarasamy, A., Devall, A.J., Cheed, V., et al. “A randomized trial of progesterone in women with bleeding in early pregnancy.” N Engl J Med 380.19 (2019): 1815–24.
Coomarasamy, A., Devall, A.J., Brosens, J.J., et al. “Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence.” Am J Obstet Gynecol 223.2 (2020): 167–76. DOI: 10.1016/j.ajog.2019.12.006
Devall, A.J., Gallos, I.D., Khalaf, Y., et al. “Effect of progestogen for women with threatened miscarriage: a systematic review and meta-analysis.” BJOG 127 (2020): 1303–04.
Devall, A.J., Papadopoulou, A., Podesek, M., et al. “Progestogens for preventing miscarriage: a network meta-analysis.” Cochrane Library 4.4 (2021): CD013792. DOI: 10.1002/14651858.CD013792.pub2
Di Renzo, G.C., Giardina, I., Clerici, G., et al. “The role of progesterone in maternal and fetal medicine.” Gynecol Endocrinol 28.11 (2012): 925–32.
Di Renzo, G.C., Fonseca, E. “Effect of progestogen for women with threatened miscarriage: a systematic review and meta-analysis.” BJOG 127 (2020): 1304–05.
El-Zibdeh, M.Y., Yousef, L.T. “Dydrogesterone support in threatened miscarriage.” Maturitas 65 (2009): S43–6.
Koren, G., Barer, Y., Kaplan, Y.C. “Fetal safety of medications used in treating Infertility.” Expert Rev Clin Pharmacol 13.9 (2020): 991–1000.
Ku, C.W., Allen, J.C.Jr., Lek, S.M., et al. “Serum progesterone distribution in normal pregnancies compared to pregnancies complicated by threatened miscarriage from 5 to 13 weeks gestation: a prospective cohort study.” BMC Pregnancy Childbirth 18.1 (2018): 360–6.
Li, L., Zhang, Y., Tan, H., et al. “Effect of progestogen for women with threatened miscarriage: a systematic review and meta-analysis.” BJOG 127 (2020): 1055–63.
Ogasawara, M., Aoki, K., Okada, S., Suzumori, K. “Embryonic karyotype of abortuses in relation to the number of previous miscarriages.” Fertil Steril 73.2 (2000): 300–4. DOI: 10.1016/s0015-0282(99)00495-1
Okeke Ogwulu, C.B., et al. “The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial.” BJOG 127.6 (2020): 757–67.
Pandian, R.U. “Dydrogesterone in threatened miscarriage: a Malaysian experience.” Maturitas 65 (2009): S47–50.
Piette, P. “The pharmacodynamics and safety of progesterone.” Best Pract Res Clin Obstet Gynaecol 69 (2020): 13–29.
Rai, R., Regan, L. “Recurrent miscarriage.” Lancet 368.9535 (2006): 601–11.
Wahabi, H.A., Fayed, A.A., Esmaeil, S.A., Bahkali, K.H. “Progestogen for treating threatened miscarriage.” Cochrane Database Syst Rev 8 (2018): CD005943.
Zaqout, M., Aslem, E., Abuqamar, M., et al. “The impact of oral intake of dydrogesterone on fetal heart development during early pregnancy.” Pediatr Cardiol 36.7 (2015): 1483–8.
Zaqout, M., Aslem, E., Abuqamar, M., et al. “Association between oral intake of dydrogesterone during early pregnancy and congenital heart disease: a case-control study.” Lancet 390.2 (2017): S8.
Coomarasamy, A., et al. “Sporadic miscarriage: evidence to provide effective care.” Lancet 397.10285 (2021): 1668–74.