When can it be prescribed and what does the evidence say

Pregnant women concerned about risk of miscarriage or preterm birth will often ask their GP about progesterone. Dr Anneliese Perkins, Adelaide obstetrician and sonologist, says there are some specific presentations where it can help.

Bleeding in early pregnancy is common. “We see it in around one in four pregnancies and the vast majority of these will go on to have a normal live birth,” Dr Perkins says.

But roughly one third of those who experience bleeding will miscarry, and the risk increases with the number of previous miscarriages.

Risk factors for recurrent miscarriage include:

1. increasing maternal age (especially ≥ 35)
2. increasing paternal age (especially ≥ 40)
3. environmental factors (such as alcohol and smoking)
4. antiphospholipid syndrome
5. parental chromosomal rearrangements
6. uterine malformations
7. cervical weakness
8. poorly controlled endocrine disorders such as thyroid disease or diabetes
9. thrombophilias

Dr Perkins recommends referring couples with recurrent miscarriage to a specialised clinic for investigation to look for potential underlying causes, such as problems with uterine anatomy, thyroid disorders, or issues with sperm, among others. But in many cases no ‘reason’ can be found.

“Unfortunately a good 50-75% of recurrent pregnancy loss, we don’t know why,” she says.

“We know that progesterone is necessary for successful implantation and maintenance of a pregnancy,” Dr Perkins says. It protects the foetus by modulating maternal immune response, improving uteroplacental circulation and maintaining cervical integrity, among other things.

So it’s not surprising that there has been significant interest in progesterone supplementation to reduce miscarriage risk, especially for women who have had unexplained recurrent miscarriage.

What is the evidence for progesterone use to prevent miscarriage?

Results from two large randomised controlled trials were initially disappointing.

The PROMISE trial found that using progesterone in the first trimester was no more beneficial than placebo in asymptomatic women with a history of unexplained recurrent miscarriage. In other words, progesterone does not protect from recurrent miscarriage if there is no bleeding in the current pregnancy.

The PRISM trial found that overall, 16 weeks of vaginal progesterone use (400mg, twice a day) in confirmed pregnancies with early bleeding did not increase the incidence of live birth.

However, sub-group analysis of the PRISM trial found some groups did get some benefit.

Specifically, women with previous miscarriage who had bleeding in their current pregnancy were more likely to have a live birth. The benefit was small for those who’d had one or two previous miscarriages, just reaching statistical significance. But it was much more pronounced for women who’d had three or more miscarriages.

Prescribing progesterone pessaries for unexplained threatened miscarriage

Following this evidence, the TGA revised its guidelines in February 2022 to allow prescription of intravaginal progesterone for current bleeding in pregnancy with a history of three or more previous miscarriages. It may also be used with one to two prior miscarriages if there is reduced chance of further pregnancy (e.g. undergoing IVF with limited viable egg or embryos or advanced maternal age). It can be started at the first sign of bleeding after intrauterine pregnancy is confirmed.

“It’s not yet PBS-approved, so it is still a private script, costing the patient around $9 per day,” Dr Perkins says.