Resources and information to help you manage your patients with Threatened Miscarriage1 (Early Pregnancy Bleeding) and Preterm Birth.1

Threatened Miscarriage (Early Pregnancy Bleeding)

Threatened miscarriage and premature labour – the role of the GP

Professor Bill Ledger discusses new developments in the treatment of Threatened Miscarriage.

Prevention and Management of Miscarriage: Facts and Myths with Prof. Gian Carlo Di Renzo.

Professor Bill Ledger discusses Early Pregnancy Bleeding in the Healthed Product Explainer.

Preterm Birth

Dr Chris Lehner, from the Australian Preterm Birth Prevention Alliance, discusses the single greatest cause of death in young children in Australia.

HOW TO INSERT UTROGESTAN

  • Practise good hygiene and wash your hands before and after inserting the Utrogestan vaginal capsule.
  • Take one Utrogestan 200 mg vaginal capsule from the blister pack.
  • Place the Utrogestan capsule on the tip of your finger and
  • insert deep into the vagina. No applicator is needed.
  • Sometimes there may be some leakage from the dissolved capsule. This is normal.
  • You do not need to lie flat following insertion of Utrogestan.

You can also watch a video on how to insert the Utrogestan capsule below.

DOWNLOADS

PATIENT BOOKLET PRETERM BIRTH

PATIENT BOOKLET – EARLY PREGNANCY BLEEDING (THREATENED MISCARRIAGE)

CONSUMER MEDICINE INFORMATION

Utrogestan for the treatment of Threatened Miscarriage (Early Pregnancy Bleeding)

How common is early pregnancy bleeding, and what are the risks?

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.

How can progesterone play a role in preventing miscarriage?

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.

What is the clinical data supporting the use of Utrogestan for early pregnancy bleeding?

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 3 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.

Who is suitable for Utrogestan in an early pregnancy bleeding setting?

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

 

What is the recommended dose of Utrogestan for early pregnancy bleeding?

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 (2 x 200 mg soft vaginal capsules), morning and night.1

 

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

When should Utrogestan be used for early pregnancy bleeding, and for how long?

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.

Are there any risks or side effects to be aware of?

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.

How can I access Utrogestan for early pregnancy bleeding (threatened miscarriage)?

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.

Utrogestan for prevention of Preterm Birth

How common is preterm birth, and what are the risks?

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.

How can progesterone play a role in preventing preterm birth?

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.

What is the clinical data supporting the use of Utrogestan for preterm birth prevention?

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.

Who is suitable for Utrogestan in the preterm birth setting?

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.

What is the recommended dose of Utrogestan for preterm birth prevention?

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.

When should Utrogestan be used for preterm birth prevention, and for how long?

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.

Are there any risks or side effects to be aware of?

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.

How can I access Utrogestan for preterm birth prevention?

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.

Pregnancy Support (TM)

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy.

Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence.

The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM trial.

Serum progesterone distribution in normal pregnancies compared to pregnancies complicated by threatened miscarriage from 5 to 13 weeks gestation: a prospective cohort study.

Pregnancy Support (PTB)

Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials.

Vaginal progesterone for the prevention of preterm birth: who can benefit and who cannot? Evidence-based recommendations for clinical use.

Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.

Reducing preterm birth by a statewide multifaceted program: an implementation study.

Progesterone and the risk of preterm birth among women with a short cervix.

For additional information on Threatened Miscarriage (Early Pregnancy Bleeding) and Preterm Birth, please visit the organisations below.

Women & Infants Research Foundation
https://wirf.com.au/

References: 1. Utrogestan® (micronised progesterone) Product Information, last updated 2022.