Clinical overview
Progesterone is the hormone of pregnancy maintenance, and the question of exogenous progesterone supplementation runs through almost every chapter of complicated obstetrics — threatened and recurrent miscarriage, the prevention of spontaneous preterm birth, luteal-phase support after assisted reproduction, and the long-discarded fashion of using it to "rescue" any bleeding early pregnancy. The registrar must be able to separate the evidence-based, guideline-endorsed indications from the historical and the speculative, because progesterone is cheap, widely available, perceived as harmless, and therefore heavily over-prescribed. It is one of the commonest "just-in-case" prescriptions handed out in early-pregnancy units and antenatal clinics, often with no clear indication and no defined stopping point.
The contemporary picture, anchored by the PRISM and PROMISE trials and the large preterm-birth literature, is more disciplined than the prescribing habit. There are now two reasonably well-defined situations in which vaginal progesterone earns its place — selected women with early-pregnancy bleeding and a history of miscarriage, and women with a short cervix or a prior spontaneous preterm birth — and a much larger penumbra of uses that are either unsupported or actively negative (for example, in unselected threatened miscarriage, or in multiple pregnancy for preterm-birth prevention). This chapter describes those uses in turn, weighting the discussion toward the mechanisms and the indications because the objective verb is "describe the use of." In the South African setting, where the National Integrated Maternal and Perinatal Care Guideline (NDoH, 2024) governs antenatal practice across the district–regional–tertiary network, the practical message is to reserve progesterone for evidence-based indications and to avoid it as a reflexive response to a positive pregnancy test and a little bleeding.
Core knowledge
Physiology — what progesterone actually does in pregnancy
Progesterone (literally "pro-gestational steroid") is secreted first by the corpus luteum and, from roughly the 7th–9th week, increasingly by the placental syncytiotrophoblast, which then becomes the dominant source for the remainder of pregnancy. This handover is the luteoplacental shift: before it, the pregnancy is dependent on luteal progesterone (hence luteal-phase support after IVF, and the rationale for progesterone where corpus-luteum function might be impaired); after it, the placenta autonomously produces large quantities and exogenous supplementation has a weaker physiological rationale.
Its actions relevant to pregnancy maintenance:
- Myometrial quiescence — progesterone promotes uterine relaxation and opposes the contractile, pro-inflammatory effects of oestrogen and prostaglandins. The "progesterone withdrawal" concept (functional withdrawal in humans, via altered progesterone-receptor isoform expression, rather than a fall in serum level) is part of the cascade toward labour. This underpins the preterm-birth-prevention hypothesis.
- Decidualisation and endometrial receptivity — progesterone transforms the endometrium into secretory decidua that supports implantation and early placentation.
- Immunomodulation — it favours a maternal-tolerance (broadly Th2-skewed) immune environment at the materno-fetal interface; this is the proposed mechanism behind any benefit in recurrent miscarriage.
- Cervical competence — progesterone is thought to maintain cervical integrity and reduce the inflammatory remodelling that precedes cervical shortening.
Preparations and routes
The agent used in obstetrics is micronised natural progesterone (bio-identical), not the synthetic progestogens of contraception.
- Vaginal micronised progesterone is the route with the best obstetric evidence (pessary/gel/capsule), achieving high local uterine concentrations via a "first uterine pass" with relatively low systemic levels. This is the form used in the PRISM/PROMISE early-pregnancy work and in short-cervix preterm-birth prevention.
- Oral preparations (including dydrogesterone, an orally active retroprogesterone) are also used, particularly for threatened/recurrent miscarriage in some guidelines; dydrogesterone featured in the LOTUS luteal-support and some miscarriage literature.
- Intramuscular 17-hydroxyprogesterone caproate (17-OHPC) was historically used for preterm-birth prevention after a prior preterm birth but its efficacy has been seriously undermined (see below).
A typical regimen described in the PRISM/PROMISE programme is vaginal micronised progesterone 400 mg twice daily, started in early pregnancy and continued to around 16 weeks; for short-cervix preterm prophylaxis a commonly described dose is vaginal progesterone ~200 mg daily continued into the early-mid third trimester (around 34–36 weeks). These doses are widely-cited standard regimens; confirm against the current product label and local protocol before prescribing — flagged in notes.
Figure J14.1 — Luteoplacental progesterone handover, major pregnancy-maintenance actions and obstetric route choices, with the serum-level pitfall highlighted.
The evidence-defined indications
1. Early-pregnancy bleeding with a previous miscarriage. The PRISM trial (vaginal progesterone in women with early-pregnancy bleeding) found no significant benefit in the overall population, but a pre-specified subgroup signal: a graded benefit in live-birth rate that increased with the number of previous miscarriages, becoming clinically meaningful in women with three or more prior losses. This nuanced result — "no for everyone, modest yes for the woman who is both bleeding and has recurrent loss" — is the single most examinable progesterone fact and is reflected in NICE NG126 (ectopic pregnancy and miscarriage), which supports offering vaginal micronised progesterone to women with bleeding in early pregnancy and a history of miscarriage.
2. Recurrent miscarriage without bleeding. The PROMISE trial tested first-trimester vaginal progesterone in women with unexplained recurrent miscarriage and found no improvement in live-birth rate. So progesterone is not indicated for recurrent miscarriage per se in the absence of current bleeding — a distinction PRISM and PROMISE together draw sharply. ESHRE's recurrent pregnancy loss guidance reflects this cautious position.
3. Prevention of spontaneous preterm birth. Two populations matter — a short cervix on transvaginal ultrasound (commonly cited threshold ≤25 mm), and a prior spontaneous preterm birth. Vaginal progesterone reduces preterm birth and improves perinatal outcomes in singleton pregnancies with a short cervix. In multiple pregnancy, vaginal progesterone has not shown benefit for preterm-birth prevention and should not be used for that purpose. This is closely tied to cervical-cerclage and to the broader preterm-birth-and-pprom management pathway.
4. Luteal-phase support after assisted reproduction. In IVF cycles the corpus luteum is functionally impaired by the stimulation/down-regulation protocol, so progesterone (usually vaginal) is standard luteal support — this is a reproductive-medicine indication rather than a complicated-obstetrics one, but registrars should recognise it.
Assessment
Because progesterone is so freely prescribed, the registrar's main task is disciplined patient selection — establishing whether a real, evidence-based indication exists before reaching for a prescription.
History
- Obstetric history is decisive. Count and characterise previous pregnancy losses (number, gestation, whether spontaneous), and previous spontaneous preterm births (gestation, whether following spontaneous labour or PPROM, as opposed to iatrogenic/indicated delivery). The PRISM benefit is graded on the number of prior miscarriages; the preterm indication rests on a spontaneous prior preterm birth.
- Current presentation — for the early-pregnancy bleeding indication, document the bleeding (onset, amount, pain) and confirm an intrauterine pregnancy. Progesterone has no role in, and must never delay the diagnosis of, an ectopic pregnancy (ectopic-pregnancy-management) or in evacuating an established non-viable pregnancy.
- Mode of conception (spontaneous vs IVF — luteal support).
- Risk factors for preterm birth — prior cervical surgery (LLETZ/cone), uterine anomaly, prior PPROM.
Examination and investigations
- Confirm viability and location with transvaginal ultrasound before treating early-pregnancy bleeding; a spontaneous-miscarriage that is already non-viable does not benefit from progesterone.
- Transvaginal cervical length is the investigation that defines the short-cervix indication — measured in the mid-trimester, with the commonly cited treatment threshold of ≤25 mm. Treat the threshold as standard teaching and confirm against the local/NDoH protocol — flagged in notes.
- Serum progesterone levels do not guide therapy. There is no validated threshold for "low progesterone needing replacement," and checking a level to justify supplementation is not evidence-based — a common pitfall.
Selection rule to memorise. Progesterone earns its place in only a few clear situations: (i) early-pregnancy bleeding plus previous miscarriage(s); (ii) singleton with a short cervix (≤25 mm) or a prior spontaneous preterm birth; (iii) luteal support after ART. Outside these, the default is no progesterone.
Management
This objective is about use, so the management section is about how and when to prescribe, and equally when not to. Always practise within the South African levels-of-care framework: most early-pregnancy bleeding and antenatal preterm-risk assessment is managed at district/regional level per the NDoH Maternity Guideline (NDoH, 2024), with referral to a regional/tertiary unit where cervical length surveillance, cerclage, or specialist fetal-medicine input is needed.
Early-pregnancy bleeding with prior miscarriage
- First, exclude ectopic and confirm an intrauterine pregnancy by TVS and, where needed, serial βhCG. Resuscitate and refer any haemodynamically unstable or ectopic-suspicious woman — progesterone is irrelevant to that emergency.
- If the woman has early-pregnancy bleeding and one or more previous miscarriages, offer vaginal micronised progesterone (PRISM-regimen, commonly 400 mg twice daily) and continue to around 16 weeks of gestation if the pregnancy is ongoing, in line with NICE NG126. Counsel honestly that the absolute benefit is modest and greatest in those with several prior losses.
- Do not offer progesterone for threatened miscarriage in a woman with no prior miscarriage — PRISM showed no benefit in that group.
- Provide standard early-pregnancy support, clear safety-netting about heavy bleeding or pain, and follow-up scanning. Link with recurrent-pregnancy-loss for the woman with multiple losses, who needs a fuller work-up rather than progesterone alone.
Recurrent miscarriage (not currently bleeding)
- Progesterone is not recommended as a treatment for unexplained recurrent miscarriage on the strength of PROMISE. Investigate and manage per the recurrent-loss pathway (antiphospholipid screen, uterine assessment, etc.) rather than reflexively prescribing progesterone — see recurrent-pregnancy-loss.
Preterm-birth prevention
- Singleton, short cervix (≤25 mm) on mid-trimester TVS: offer vaginal progesterone (commonly ~200 mg daily) and continue into the early third trimester (around 34–36 weeks). This is integrated with the decision about cervical-cerclage, and managed alongside the wider preterm-birth-and-pprom pathway.
- Singleton with a prior spontaneous preterm birth: vaginal progesterone is offered as prophylaxis; cervical-length surveillance helps stratify who also needs cerclage. Note the major caveat below regarding 17-OHPC.
- Multiple pregnancy: vaginal progesterone is not recommended for preterm-birth prevention — it has not shown benefit in twins/higher-order pregnancies. Manage multiple-pregnancy preterm risk through the dedicated pathway, not progesterone.
- 17-OHPC (intramuscular): the PROLONG trial failed to confirm the benefit previously attributed to 17-OHPC for recurrent preterm-birth prevention; the FDA subsequently moved to withdraw it. Vaginal micronised progesterone is the preferred agent where progesterone is indicated. This reflects the current direction of evidence; confirm the local regulatory/formulary position — flagged in notes.
South African / resource context
- Practise within the NDoH Maternity Guideline (NDoH, 2024) and refer along the district → regional → tertiary chain for cervical-length surveillance and cerclage where these are not available locally. Confirm whether your facility/EML stocks vaginal micronised progesterone and at what dose form before promising therapy.
- Cost-conscious prescribing matters. Progesterone is inexpensive but not free, and over-prescription for unproven indications diverts resources and gives false reassurance. The discipline of only treating the evidence-based indications above is itself good stewardship.
- HIV. Progesterone has no specific interaction that changes ART, and HIV status does not create a progesterone indication; manage HIV per the SA HIV/ART consolidated guidelines and hiv-in-pregnancy independently. Do not let a focus on progesterone distract from the core antenatal priorities of HIV, hypertension and haemorrhage that dominate Saving Mothers (NCCEMD) maternal-death data.
- Safety in pregnancy. Micronised natural progesterone is regarded as safe in pregnancy; it is not one of the contraceptive synthetic progestogens. Reassure women accordingly, while being honest about limited efficacy.
Figure J14.2 — Evidence-defined progesterone prescribing algorithm, separating PRISM-supported early bleeding, PROMISE-negative recurrent loss, preterm-birth indications, ART support and key "do not" branches.
Red flags / pitfalls
- Do not let progesterone delay or replace the diagnosis of ectopic pregnancy. A woman with bleeding and pain needs her pregnancy located first — a "treat the bleeding with progesterone" reflex can mask a tubal ectopic until it ruptures. Always exclude ectopic before treating early-pregnancy bleeding (ectopic-pregnancy-management).
- Do not prescribe progesterone for threatened miscarriage in a woman with no previous miscarriage — PRISM showed no benefit, and prescribing here is unsupported.
- Do not use progesterone for unexplained recurrent miscarriage in the absence of current bleeding — PROMISE was negative.
- Do not use vaginal progesterone for preterm-birth prevention in multiple pregnancy — no demonstrated benefit.
- Do not measure serum progesterone to decide on supplementation — there is no validated replacement threshold; it is a meaningless investigation in this context.
- Do not assume 17-OHPC works — the PROLONG data and subsequent regulatory action undermine it; prefer vaginal micronised progesterone where progesterone is indicated.
- Do not continue progesterone indefinitely. Each indication has a stopping point (around 16 weeks for the early-pregnancy/PRISM indication; early third trimester for the preterm indication). Open-ended prescriptions reflect unclear thinking.
- Do not let progesterone substitute for the real preterm-risk work-up — cervical length, cerclage decision, and the broader pathway in preterm-birth-and-pprom and cervical-cerclage.
- Never present progesterone as a guaranteed "pregnancy-saver." Counsel honestly: even in the best-supported subgroup the absolute benefit is modest. Over-promising erodes trust and ignores the high background rate of spontaneous miscarriage being driven by chromosomal causes that no hormone can fix.
Evidence anchors
- NICE NG126 — Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management (2019). Supports offering vaginal micronised progesterone to women with early-pregnancy bleeding and a history of miscarriage; basis for the PRISM-informed practice.
- PRISM trial (vaginal progesterone in women with early-pregnancy bleeding) — overall negative, with a pre-specified graded benefit in women with previous miscarriage(s), strongest in those with ≥3 prior losses. Trial named in standard teaching; specifics summarised cautiously — flagged in notes.
- PROMISE trial (first-trimester vaginal progesterone in unexplained recurrent miscarriage) — negative for live-birth improvement. As above.
- ESHRE Guideline: Recurrent Pregnancy Loss (2022 update). Cautious position on progesterone for recurrent loss.
- RCOG GTG 17 — Recurrent Miscarriage — recurrent-loss evaluation framework into which the progesterone evidence fits.
- RCOG GTG 75 — Cervical Cerclage and RCOG GTG 73 — PPROM (≥24 weeks) — preterm-birth context within which short-cervix vaginal progesterone is positioned.
- PROLONG trial — failed to confirm 17-OHPC efficacy for recurrent preterm-birth prevention; underpins the shift away from 17-OHPC. Trial named in standard teaching — flagged in notes.
- South African National Integrated Maternal and Perinatal Care Guideline (NDoH, 2024) — the SA obstetric source of truth for antenatal practice, levels of care and referral; consult for the local position on progesterone availability and protocols.
- South African Saving Mothers Report (NCCEMD) — context for prioritising the major maternal-death causes (haemorrhage, hypertension, HIV-related infection) over unproven progesterone use.