Early pregnancy bleeding, also known as ‘threatened miscarriage’, refers to any vaginal bleeding occurring prior to 20 weeks’ gestation.¹ It occurs in almost 1 in 4 pregnancies.²

While two-thirds of women with early pregnancy bleeding will go on to have a healthy baby, approximately 1 in 3 will suffer a miscarriage.² In fact, early pregnancy bleeding is associated with a 2.6 times increased risk of miscarriage later in the same pregnancy, compared to women without bleeding.¹ Risk of miscarriage is also increased in women with a history of previous miscarriages.³

References: 1. Breeze C. Aus Fam Phys 2016;45(5):283–86. 2. Victoria State Government, Department of Health, Better Health Channel. Pregnancy – bleeding problems. Available at https://www.betterhealth.vic.gov.au/health/healthyliving/pregnancy-bleeding-problems. Accessed December 2022. 3. Coomarasamy A et al. Am J Obstet Gynaecol 2020;223(2):167–76.

Miscarriage can be considered as aneuploid and euploid.¹

Aneuploid miscarriage is thought to occur on a random basis, due to numeric chromosome errors. Due to its random nature, the risk of subsequent miscarriage is not increased with each aneuploid miscarriage (see figure below).¹

In contrast, euploid miscarriage is often mediated by progesterone, whereby low progesterone levels may have an impact on the maintenance of early pregnancy. The risk of euploid miscarriage increases with an increasing number of previous miscarriages (see figure below), suggesting a biological role for progesterone supplementation in women with a history of previous miscarriages.¹

Risk of miscarriage by the number of previous miscarriages.
Adapted from Coomarasamy et al.¹ and Ogasawara et al.²

References: 1. Coomarasamy A et al. Am J Obstet Gynaecol 2020;223(2):167–76. 2. Ogasawara M et al. Fertil Steril 2000;73:300–304.

The efficacy of Utrogestan for the treatment of early pregnancy bleeding (threatened miscarriage) was examined in a pre-specified subgroup analysis of the PRISM trial; the largest randomised trial evaluating progesterone in women with early pregnancy bleeding.^1,2

In this study, Utrogestan 400 mg administered vaginally twice daily was initiated at the first sign of vaginal bleeding and continued until the 16th week of gestation, compared to placebo.^1,2 Analysis revealed a biological gradient, whereby women with 1 or 2 previous miscarriages gained some benefit and those with ³3 previous miscarriages received a considerably significant benefit from treatment with Utrogestan (see figure below).¹

In women with early pregnancy bleeding and a history of 1 or more miscarriage(s), the number needed to treat for 1 additional live birth was 20. In women with a history of 3 or more previous miscarriages, the number needed to treat for 1 additional live birth was 8.^1,2

Adapted from Utrogestan Product Information¹ and Coomarasamy et al.²

References: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022.  2. Coomarasamy A et al. N Engl J Med 2019;380:1815–24.

Utrogestan is indicated for the treatment of unexplained early pregnancy bleeding (threatened miscarriage) in women with bleeding in the current pregnancy and a history of at least three or more previous miscarriages.¹

Use in women with less than three miscarriages may be warranted in those with reduced chances of future pregnancy such as those undergoing IVF treatment with limited viable egg and/or embryo availability or advanced fertility age. However, the benefit of treatment in clinical trials was limited to women with three or more miscarriages.¹

Most women can safely take Utrogestan. Utrogestan should not be used in women with: a known hypersensitivity to progesterone (or to any of the ingredients in Utrogestan); severe hepatic dysfunction; undiagnosed vaginal bleeding; known missed abortion or ectopic pregnancy; mammary or genital tract carcinoma; thromboembolic or thrombophlebitis disorders; cerebral haemorrhage; porphyria.¹

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022.

Utrogestan is administered as a soft vaginal capsule. The usual dose for treatment of early pregnancy bleeding (threatened miscarriage) is 400 mg twice a day, morning and night.¹

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022.

For the treatment of early pregnancy bleeding (threatened miscarriage) in women with a history of miscarriage, Utrogestan should be initiated at the first sign of vaginal bleeding during the first trimester of pregnancy and should continue to at least the 16th week of gestation.¹

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022.

Most women can take Utrogestan without side effects. Some women may experience side effects including vaginal burning, vaginal itching and vaginal discharge, however the incidence of these side effects is very rare (<1/10,000).^1,2

In the PRISM trial, the incidence of adverse neonatal outcomes and serious maternal adverse events were low, comparable to placebo in the 1st and 2nd trimesters. Furthermore, the adverse event profile remained unchanged regardless of the timing or duration of treatment during pregnancy with beneficial effects of progesterone expected to increase the number of live births in women with threatened miscarriage or a history of recurrent miscarriage.¹

Of note, Utrogestan is metabolised primarily by the liver. Caution should be taken with drugs that are P450 enzyme inducers and inhibitors.¹

Refer to the Product Information for a full list of adverse events, special warnings and precautions, and for more information about potential interactions with other medicines.

References: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022. 2. Utrogestan (micronised progesterone) Consumer Medicine Information. Last updated February 2022.

Utrogestan is available for the treatment of threatened miscarriage on private prescription; it is not yet listed on the Pharmaceutical Benefits Scheme (PBS).¹

Reference: 1. Pharmaceutical Benefits Scheme (PBS). Available at www.pbs.gov.au; Accessed December 2022.

One in twelve Australian babies are born preterm, defined as babies born alive before 37 weeks of pregnancy are completed.^1,2 Most preterm births occur spontaneously.²

Preterm babies are at higher risk of adverse neonatal outcomes compared to babies born at term, including low birthweight, extended time in hospital, a higher likelihood of needing specialised care and worse perinatal mortality.¹ Pre-term birth can also have longer-term consequences, including neurodevelopmental delay, hearing and visual loss, cerebral palsy, and learning and behavioural problems.³

A short cervix, conventionally defined as a transvaginal sonographic cervical length ≤25 mm in the midtrimester of pregnancy, is a powerful risk factor for spontaneous preterm birth.⁴

References: 1. Australian Institute of Health and Welfare. Australia’s mothers and babies 2020. Available at https://www.aihw.gov.au/reports/mothers-babies/australias-mothers-babies/contents/about. Accessed December 2022. 2. World Health Organization. Preterm birth. Available at https://www.who.int/news-room/fact-sheets/detail/preterm-birth. Accessed December 2022. 3. Newnham JP et al. Am J Obstet Gynaecol 2017;216(5):434–42. 4. Romero R et al. Am J Obstet Gynaecol 2018;218(2):161-80.

Progesterone plays a central role in maintaining pregnancy.^1,2

In the latter half of pregnancy, progesterone is postulated to contribute to pregnancy maintenance by limiting the production of stimulatory prostaglandins, and inhibiting the expression of contraction-associated protein genes within the myometrium.³

The onset of labour is associated with a withdrawal of progesterone activity in the uterus, providing rationale for the use of progesterone supplementation for preterm birth prevention.³

References: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022. 2. Romero R et al. Am J Obstet Gynaecol 2018;218(2):161-80. 3. Norwitz ER et al. Rev Obstet Gynecol 2011;4(2):60–72.

The efficacy of vaginal progesterone for preterm birth prevention in women with a short midtrimester cervix was initially reported in the New England Journal of Medicine in 2017. In this study, daily administration of Utrogestan 200 mg from 24 to 34 weeks of gestation significantly reduced the risk of preterm birth (<34 weeks) by 43% compared to placebo (RR 0.57; 95% CI 0.35–0.92; p=0.02).^1,4

These findings were confirmed in a systematic review and meta-analysis of 974 women from 5 high-quality clinical trials.^1-7 In women with a singleton pregnancy and a midtrimester short cervix (≤25 mm), vaginal progesterone significantly and consistently reduced the risk of preterm birth from <28 to <36 weeks of gestation, compared to placebo. The primary outcome – preterm birth <33 weeks of gestation – saw a significant 38% reduction in preterm birth with vaginal progesterone over placebo (RR 0.62, p=0.0006; see figure below).²

In addition, vaginal progesterone resulted in significant improvements in perinatal outcomes, including reduced risk of respiratory distress syndrome (RR 0.47, p=0.007), low birthweight <2500g (RR 0.82, p=0.03), NICU admission (RR 0.68, p=0.003) and neonatal morbidity and mortality (RR0.59, 0.02).²

Adapted from Romero R et al. 2018.²

Note: Vaginal progesterone preparations included Utrogestan® micronised progesterone capsules,^3,4 micronised progesterone gel,^5,6 and a compounded progesterone suppository.⁷

RR, risk reduction. References: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022. 2. Romero R et al. Am J Obstet Gynaecol 2018;218(2):161-80. 3. Norman JE et al. Lancet 2016;387:2106-16. 4. Fonseca EB et al. N Engl J Med 2007;357:462-9. 5. O’Brien JM et al. Ultrasound Obstet Gynecol 2007;30:687-96. 6. Hassan SS et al. Ultrasound Obstet Gynecol 2011;38:18-31. 7. Cetingoz E et al. Arch Gynecol Obstet 2011;283:423-9.

Utrogestan is indicated for prevention of preterm birth in women with singleton pregnancy who have a short cervix (midtrimester sonographic cervix ≤25 mm) and/or a history of spontaneous preterm birth.¹

Most women can safely take Utrogestan. Utrogestan should not be used in women with: a known hypersensitivity to progesterone (or to any of the ingredients in Utrogestan); severe hepatic dysfunction; undiagnosed vaginal bleeding; known missed abortion or ectopic pregnancy; mammary or genital tract carcinoma; thromboembolic or thrombophlebitis disorders; cerebral haemorrhage; porphyria.¹

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022.

Utrogestan is administered as a soft vaginal capsule. The usual dose for prevention of preterm birth is 200 mg per day, recommended at bedtime.¹

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022.

For the prevention of preterm birth, Utrogestan can be initiated during the second trimester (16-24 weeks gestation) and is to be continued to the end of the 36th week of gestation or until delivery.¹

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022.

Most women can take Utrogestan without side effects. Some women may experience side effects including vaginal burning, vaginal itching and vaginal discharge, however the incidence of these side effects is very rare (<1/10,000).^1,2

No significant safety concerns for the mother or for the foetus were identified with vaginally administered Utrogestan during pregnancy. Maternal outcomes were unaffected. Treatment-related adverse effects were generally mild and transient, and the incidence was no greater than those reported for placebo or no treatment. The beneficial effects of progesterone to prevent preterm birth in women with a short cervix and/or a history of preterm birth is expected to improve neonatal outcomes. There is no evidence that fetal progesterone exposure in the 2nd and 3rd trimester adversely affects childhood neurodevelopmental outcomes.¹

Of note, Utrogestan is metabolised primarily by the liver. Caution should be taken with drugs that are P450 enzyme inducers and inhibitors.¹

Refer to the Product Information for a full list of adverse events, special warnings and precautions, and for more information about potential interactions with other medicines.

References: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022. 2. Utrogestan (micronised progesterone) Consumer Medicine Information. Last updated February 2022.

Utrogestan is listed on the Pharmaceutical Benefits Scheme (PBS) for prevention of preterm birth, under an Authority Required listing (PBS item 12598C) with the following clinical criteria:¹

• Patient must have a singleton pregnancy, AND
• Patient must have at least one of: (i) short cervix (mid-trimester sonographic cervix no greater than 25 mm), (ii) a history of spontaneous preterm birth, AND
• The treatment must be administered no earlier than at 16 weeks gestation.

Reference: 1. Pharmaceutical Benefits Scheme (PBS). Available at www.pbs.gov.au; Accessed December 2022.

The ‘luteal phase’ refers to the time between ovulation and either pregnancy or menstruation. During this time, progesterone is responsible for preparing the endometrium for implantation and maintenance of early pregnancy.¹

During ART, use of gonadotrophin-releasing hormones may impair progesterone production leading to luteal phase defect and unsuccessful assisted reproduction or miscarriage. Thus, progesterone supplementation can be beneficial during ART.¹

Reference: 1. Shah D & Nagarajan N. Ind J Endocrinol Metab 2013;17(1):44–49.

The use of Utrogestan for luteal phase support of ART cycles is well established, supported by data from more than 27 clinical trials in over 6,700 patients, across fresh and frozen cycles.^1-27

References: 1. Smitz J et al. Rev Fr Gynecol Obstet 1992;87(10):507-16. 2. Chillik C et al. Assisted Reprod Rev 1997; 7: 29:33. 3.Friedler S et al. Hum Reprod 1999;14(8):1944-8. 4. Williams SC et al. Fertil Steril 2001;76(6):1140-43. 5. Ludwig M et al. Eur J Obstet Gynecol Reprod Biol 2002;103(1):48-52. 6. Gorkemli H et al. Gynecol Obstet Invest 2004;58(3):140-4. 7. Kleinstein J et al. Fertil Steril 2005;83(6):1641-9. 8. Fatemi HM et al. Hum Reprod 2006;21(10):2628-32. 9. Simunic V et al. Fertil Steril 2007;87(1):83-7. 10. Geber S et al. Reprod Biomed Online 2007;14(2):155-8. 11. Lam PM et al. Gynecol Endocrinol 2008;24(12):674-80. 12. Wang L-J et al. Taiwan J Obstet Gynecol 2009;48(4):375-9. 13. Ganesh A et al. Fertil Steril 2011;95(6):1961-5. 14. Bergh C et al. Hum Reprod 2012;27(12):3467-73. 15. Devroey P et al. Fertil Steril 2012;97(3):561-71. 16. Kohls G et al. Fertil Steril 2012;98(4):858-62. 17. Tournaye H et al. Hum Reprod 2017;32(5):1019-27. 18. Labarta E et al. Hum Reprod 2017;32(12):2437-42. 19. Lightman A et al. Hum Reprod 1999;14(10):2596-9. 20. Lan VTN et al. Fertil Steril 2007;88(1):S164. 21. Chang EM et al. J Assist Reprod Genet 2011;28(4):369-74. 22. Bjuresten K et al. Fertil Steril 2011;95(2):534-7. 23. van de Vijver A et al. Hum Reprod 2016;31(5):1097-104. 24. Schwartz E et al. J Gynecol Obstet Hum Reprod 2019;48(2):95-98. 25. Gaggiotti-Marre S et al. Gynecol Endocrinol 2019;35(5):439-42. 26. Cedrin-Durnerin I et al. Reprod Biomed Online 2019;38(3):472-80. 27. Enatsu Y et al. Reprod Med Biol 2018;17(3):242-48. 28. Kleinstein J. Fertil Steril 2005;83:1641-49.

Utrogestan is indicated for luteal phase support of assisted reproductive technology cycles.¹

Most women can safely take Utrogestan. Utrogestan should not be used in women with: a known hypersensitivity to progesterone (or to any of the ingredients in Utrogestan); severe hepatic dysfunction; undiagnosed vaginal bleeding; known missed abortion or ectopic pregnancy; mammary or genital tract carcinoma; thromboembolic or thrombophlebitis disorders; cerebral haemorrhage; porphyria.¹

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022.

Utrogestan is administered as a soft vaginal capsule. The recommended dose for luteal phase support of ART cycles is 600 mg/day, in three divided doses.¹

Of note, Utrogestan has been used at higher doses of up to 1200 mg/day in clinical trials;^1-6 while the recommended dose for luteal phase support is 600 mg/day, this may be increased depending on the patient’s response.¹

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022. 2. Chillik C et al. Assisted Reprod Rev 1997; 7: 29:33 3. Wang L-J et al. Taiwan J Obstet Gynecol 2009;48(4):375-9. 4. Bjuresten K et al. Fertil Steril 2011;95(2):534-7. 5. Labarta E et al. Hum Reprod 2017;32(12):2437-42. 6. Enatsu Y et al. Reprod Med Biol 2018;17(3):242-48.

For luteal phase support of ART cycles, Utrogestan should be administered from the day of embryo transfer until at least the 7^th week of pregnancy, and not later than the 12^th week of pregnancy.¹

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022.

Utrogestan is generally well tolerated as luteal phase support of ART cycles, with low rates of vaginal discharge, no major local tolerance issues and no systemic side effects reported in clinical trials at the recommended dose.^1,2 Over 90% of patients and physicians rate the tolerability and acceptance of therapy as ‘good’ or ‘very good’.²

In a head-to-head trial vs progesterone 8% gel, Utrogestan resulted in significantly lower rates of bleeding (52% vs 38%, p<0.0001).³

Reference: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022. 2. Kleinstein J. Fertil Steril 2005;83:1641-49. 3. Child T et al. Reprod Biomed Online 2018;36:630-45.

Most women can take Utrogestan without side effects. Some women may experience side effects including vaginal burning, vaginal itching and vaginal discharge, however the incidence of these side effects is very rare (<1/10,000).^1,2

No significant safety concerns for the mother or for the foetus were identified with vaginally administered Utrogestan during pregnancy. Maternal outcomes were unaffected. Treatment-related adverse effects were generally mild and transient, and the incidence was no greater than those reported for placebo or no treatment.¹

Of note, Utrogestan is metabolised primarily by the liver. Caution should be taken with drugs that are P450 enzyme inducers and inhibitors.¹

Refer to the Product Information for a full list of adverse events, special warnings and precautions, and for more information about potential interactions with other medicines.

References: 1. Utrogestan (micronised progesterone) Product Information. Last updated 22 February 2022. 2. Utrogestan (micronised progesterone) Consumer Medicine Information. Last updated February 2022.

Utrogestan is listed on the Pharmaceutical Benefits Scheme (PBS) for assisted reproductive technology, under an Authority Required listing (PBS item 10930G) with the following clinical criteria:¹

• The treatment must be for luteal phase support as part of an assisted reproductive technology (ART) treatment cycle for infertile women, AND
• Patient must be receiving medical services as described in items 13200 or 13201 of the Medicare Benefits Schedule.

The luteal phase is defined as the time span from embryo transfer until implantation confirmed by positive B-hCG measurement.

Reference: 1. Pharmaceutical Benefits Scheme (PBS). Available at www.pbs.gov.au; Accessed December 2022.