Version July 2025
INTRODUCTION —
Preterm birth (delivery prior to 37+0 weeks or 259 days of gestation) complicates 9 to 12 percent of births worldwide and is the leading cause of newborn morbidity and mortality [1]. Approximately 40 to 45 percent of preterm births follow preterm labor and another 25 to 30 percent follow preterm prelabor rupture of membranes (PPROM) [2]. Prophylactic and therapeutic tocolytic medications have been largely unsuccessful in preventing preterm birth; thus, other strategies, such as progesterone supplementation, have been investigated.
The efficacy of progesterone supplementation for preventing preterm birth depends primarily on appropriate patient selection, which remains controversial. The specific pathogenic pathway leading to spontaneous preterm birth is likely to be important as well [3-5]. Since spontaneous preterm birth is the final common pathway of several pathogenic processes, many of which involve reduction in the expression or activity of the progesterone receptor, a single intervention such as progesterone supplementation is unlikely to benefit all patients at risk or achieve the same degree of risk reduction in all patient populations. In vitro and animal research suggests that the type of progestin, formulation, dose, route of administration, and plasma concentration (which varies among patients receiving progestins) also impact efficacy [6-8].
Guidance regarding progesterone supplementation to reduce the risk of spontaneous preterm birth has undergone significant revision in recent years, and is discussed in this topic. Risk factors for preterm birth and other potential interventions for reducing risk are reviewed separately. (See "Spontaneous preterm birth: Overview of risk factors and prognosis" and "Spontaneous preterm birth: Overview of interventions for risk reduction".)
RATIONALE FOR PROGESTERONE SUPPLEMENTATION —
The hypothesis that exogenous progesterone supplementation may prevent spontaneous preterm birth is based on the effects of endogenous progesterone production during pregnancy:
●Corpus luteum progesterone production is essential for maintaining pregnancy until the placenta takes over this function at 7 to 9 weeks of gestation. Removing the corpus luteum [9] or administering a progesterone receptor antagonist [10] before 7 weeks (49 days) of gestation readily induces abortion.
●Progesterone appears to suppress myometrial contractility [11-13]. Functional withdrawal of progesterone activity at the level of the uterus appears to occur proximate to the onset of labor both at term and preterm [11-18].
●Progesterone has immune modulating effects, which may counter proinflammatory pathways, both systemic and intrinsic to the uterus, that lead to preterm labor and birth [19-22].
●In vitro, progesterone prevents apoptosis in fetal membrane explants under both basal and proinflammatory conditions [23-25] and thus may protect from PPROM and, in turn, preterm labor and birth.
●Progesterone may affect cervical remodeling and the rate at which the cervix shortens throughout the course of pregnancy [26-28].
However, circulating levels of endogenous progesterone in the second and third trimesters are already very high, sufficient to saturate progesterone receptors, do not decrease before labor, and do not increase with exogenous progesterone administration, so it is unclear why or how exogenous supplementation might have biologic effects. In addition, idiopathic and stress-associated preterm and term labor are associated with an increase in reproductive tract nuclear progesterone metabolizing enzymes and a net reduction in progesterone receptor transcriptional activity; therefore, increasing local progesterone levels should have no or minimal effects.
CLINICAL SETTINGS WHERE PROGESTERONE SUPPLEMENTATION MAY BE EFFECTIVE
Patients with no prior spontaneous preterm birth who develop a short cervix — For patients with a singleton pregnancy, no symptoms of preterm labor, and no prior spontaneous preterm birth who are found to have a cervical length (CL) ≤25 mm on midtrimester transvaginal ultrasound examination, we suggest vaginal progesterone supplementation to reduce the risk of preterm birth. Guidance from selected organizations worldwide regarding use of vaginal progesterone in pregnant patients with a short cervix is summarized in the table (table 1).
Cerclage does not appear to be useful in this population.
Evidence
●Progesterone versus no progesterone – In a 2018 meta-analysis of individual participant data, asymptomatic patients with a singleton pregnancy and midtrimester short CL (≤25 mm) benefited from vaginal progesterone supplementation (five high-quality randomized trials, 974 participants) [29]. The majority of participants had no previous spontaneous preterm birth.
Compared with placebo, daily vaginal progesterone administration reduced:
•Spontaneous preterm birth:
-<34 weeks (15 versus 20 percent; relative risk [RR] 0.72, 95% CI 0.55-0.95)
-<33 weeks (12 versus 17 percent; RR 0.70, 95% CI 0.51-0.95)
•All preterm birth (spontaneous and indicated):
-<34 weeks (17 versus 26 percent; RR 0.65, 95% CI 0.51-0.83)
-<28 weeks (8 versus 11 percent; RR 0.67, 95% CI 0.45-0.99)
•Composite neonatal morbidity and mortality:
-Respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, proven neonatal sepsis, or neonatal death (8 versus 14 percent; RR 0.59, 95% CI 0.38-0.91)
•Respiratory distress syndrome (5 versus 10 percent; RR 0.47, 95% CI 0.27-0.81)
•Low birth weight: <1500 g (10 versus 16 percent; RR 0.62, 95% CI 0.44-0.86) and <2500 g (29 versus 36 percent; RR 0.82, 95% CI 0.68-0.98)
•Neonatal intensive care unit admission (17 versus 25 percent; RR 0.68, 95% CI 0.53-0.88).
However, it is unclear whether these reductions translate into an improvement in long-term outcome for either the mother or offspring. The analysis found that neonatal death may be reduced, but the wide confidence interval precludes a definitive conclusion (RR 0.44, 95% CI 0.18-1.07). Maternal adverse events as well as congenital anomalies and adverse neurodevelopmental and health outcomes at two years of age did not differ between groups.
The daily dose of vaginal progesterone used in the trials varied from 90 to 200 mg. Treatment was initiated at 18 to 25 weeks of gestation and continued through 34 to 36 weeks. Subgroup analysis suggested these variables did not significantly affect the results. Limitations of the analysis were that one trial was stopped early due to low enrollment, another trial lacked data on respiratory distress syndrome and use of mechanical ventilation, many of the subgroup analyses had small sample sizes, and lack of stratification by whether the patient had a previous spontaneous preterm birth.
●Cerclage versus no cerclage – In a meta-analysis of five randomized trials including 419 asymptomatic singleton gestations with CL <25 mm and no prior spontaneous preterm birth, patients assigned to cerclage placement had similar rates of preterm birth <35, <34, <32, <28, and <24 weeks; rates of PPROM; gestational age at delivery; and neonatal outcomes as those who did not receive a cerclage [30].
CLINICAL SETTINGS WHERE THE BENEFIT OF PROGESTOGEN SUPPLEMENTATION IS UNPROVEN
Patients with a prior preterm birth
●Vaginal progesterone – We suggest not using vaginal progesterone supplementation to reduce the risk of recurrent preterm birth in asymptomatic pregnant people who are at high risk of preterm birth by past or current pregnancy history and who do not have a short cervix. Our approach is based on the evidence described below and prospective observational data from a large study of inner-city pregnant patients in the United States [31]. Patients with a prior spontaneous preterm birth who develop a short cervix are diagnosed with ultrasound-based cervical insufficiency and managed with cerclage. These data are reviewed separately. (See "Cervical insufficiency", section on 'Ultrasound-based diagnosis of cervical insufficiency' and "Cervical insufficiency", section on 'Ultrasound-based interventions for possible cervical insufficiency'.)
In 2023 the American College of Obstetricians and Gynecologists (ACOG) recommended against use of vaginal progesterone to prevent recurrent preterm birth in patients who do not have a short cervix [32].
The Society for Maternal-Fetal Medicine (SMFM) recommends a shared decision-making process regarding use of vaginal progesterone for primary prevention of recurrent preterm birth without input of cervical length (CL) or in those with a CL ≥25 mm [33]. Factors to consider in shared decision-making include the gestational age of previous spontaneous preterm birth, use of progesterone in a previous pregnancy, number of previous spontaneous preterm births, number of term births, and outcome of most recent pregnancy (ie, preterm versus term).
•Evidence – In a 2022 meta-analysis limited to assessing the efficacy and safety of vaginal progesterone to prevent recurrent preterm birth and adverse perinatal outcomes in singleton gestations with a history of spontaneous preterm birth (seven small and three large trials, 2958 participants), vaginal progesterone reduced the risk of preterm birth <37 weeks (32.0 versus 37.8 percent; RR 0.64, 95% CI 0.50-0.81, very low-quality evidence) and <34 weeks (13.5 versus 17.0 percent; RR 0.62, 95% CI 0.42-0.92, very low-quality evidence) [34]. However, none of the reductions in preterm birth remained statistically significant after restriction to trials at low risk of bias and adjustment for small-study effects (<37 weeks: RR 0.96, 95% CI 0.84-1.09; <34 weeks: RR 0.90, 95% CI 0.71-1.15). The authors concluded that there was no convincing evidence to support use of vaginal progesterone to prevent recurrent preterm birth or improve perinatal outcomes in singleton gestations with a history of spontaneous preterm birth. We agree with this interpretation of these data.
In another 2022 meta-analysis of patients with singleton gestations and previous spontaneous preterm birth (seven trials, 1910 participants), vaginal progesterone reduced preterm birth <37 and <34 weeks compared with hydroxyprogesterone caproate (17-OHPC; <37 weeks: 36.0 versus 46.6 percent; RR 0.76, 95% CI 0.69-0.85; <34 weeks: 14.7 versus 19.9 percent; RR 0.74, 95% CI 0.57-0.96); however, the difference at <34 weeks was not statistically significant when sensitivity analysis was restricted to trials at low risk of bias (12.2 versus 13.9 percent; RR 0.87, 95% CI 0.57-1.32) [35].
●Hydroxyprogesterone caproate — Hydroxyprogesterone caproate (17-OHPC) is a synthetic progestogen formulated specifically for prevention of recurrent preterm birth (irrespective of CL) and previously marketed in the United States and elsewhere as Makena. Makena is no longer commercially available because of lack of efficacy. Both ACOG [32] and SMFM [36] recommend not prescribing 17-OHPC, including compounded formulations, for this indication; we agree with their recommendations.
This is the history of the development, approval, and withdrawal of Makena:
•In 2003, Meis and coinvestigators randomly assigned 459 patients with a documented history of spontaneous singleton preterm birth <37 completed weeks to weekly intramuscular injections of 17-OHPC or placebo beginning at 16 to 20 weeks of gestation and continuing until 36 weeks [37]. Active prophylaxis significantly reduced the risk of preterm birth at all gestational ages studied.
•In February 2011, based on this single randomized trial and after delaying approval on two separate occasions to seek additional studies and documentation, the United States Food and Drug Administration (FDA) approved 17-OHPC (Makena) for the primary prevention of spontaneous preterm birth under their Accelerated Approval Program [38]. The Accelerated Approval Program (Subpart H of the Code of Federal Regulations) was instituted by the FDA in 1992 (amended in 1999) to allow for earlier approval of drugs that: (i) treat serious conditions, (ii) fill an unmet medical need, and (iii) demonstrate safety and efficacy based on a surrogate endpoint (ie, a marker that is thought to predict clinical benefit but is not itself a measure of clinical benefit). In this case, the FDA determined that the sponsor had demonstrated a favorable effect on an acceptable surrogate endpoint (ie, recurrent spontaneous preterm birth) that was reasonably likely to predict clinical benefit (ie, a favorable effect on neonatal morbidity and mortality resulting from complications of spontaneous preterm birth). This benefit of the Accelerated Approval Program is that it can considerably shorten the time required to receive FDA approval, but it comes with caveats. The approval is temporary and sponsors are mandated to conduct postmarket follow-up studies to confirm the anticipated clinical benefit (and safety) suggested by the surrogate endpoint. The FDA has the right and the responsibility to revisit approval if such trials are either not performed or are unfavorable.
•In 2020, results of the FDA-mandated, follow-up, randomized placebo-controlled multicenter international trial (PROLONG) were published. The trial assessed the safety and efficacy of 17-OHPC in over 1700 patients with a singleton gestation and past history of preterm birth. It did not include US sites since the drug was already being widely used and was considered "standard of care." Although no safety concerns were identified, the trial found that the intervention did not significantly reduce preterm birth <35 weeks or fetal/early infant death [39].
•In April 2023, additional analysis of the data from these two trials, other randomized trials, and observational studies led the FDA to conclude that use of Makena, the only commercially available 17-OHPC medication for prevention of recurrent preterm birth, was not supported by available evidence and withdrew its approval of the medication [40,41]. The decision to withdraw marketing approval was based on lack of evidence of benefit, not a safety concern.
Other clinical settings at increased risk for spontaneous preterm birth — Progesterone supplementation has not been proven to be effective in any of these settings.
●Positive fetal fibronectin (fFN) test – Although a positive cervicovaginal fFN test in asymptomatic pregnant patients is a risk factor for spontaneous preterm birth, minimal information on use of progesterone supplementation in such pregnancies is available. In the OPPTIMUM trial, patients with a positive fFN test and risk factors for preterm birth were included in the study population [42]. Vaginal progesterone supplementation did not improve obstetric, neonatal, or childhood outcomes in this trial.
●Uterine anomaly – Patients with some uterine anomalies appear to be at increased risk of preterm birth from a variety of mechanisms. The effectiveness of progesterone therapy for prevention of spontaneous preterm birth in these patients is unknown [43]. (See "Congenital uterine anomalies: Overview".)
●Pregnancies conceived with assisted reproductive technology – Patients who conceive with assisted reproductive technology appear to be at increased risk of preterm birth from a variety of mechanisms. The effectiveness of progesterone therapy for prevention of spontaneous preterm birth in these patients is unknown [43]. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
●After PPROM – No trials have evaluated vaginal progesterone in patients with PPROM. 17-OHPC was ineffective at prolonging gestation in a 2018 meta-analysis of randomized trials (six trials, 545 participants) [44]. (See "Preterm prelabor rupture of membranes: Management and outcome", section on 'Supplemental progesterone'.)
●Threatened or established preterm labor – A 2014 meta-analysis of randomized trials of progesterone supplementation for treatment of threatened or established preterm labor found no significant reduction in preterm birth <34 weeks (RR 0.62, 95% CI 0.30-1.27; one trial, 62 participants) or newborn birthweight <2500 g (RR 1.08, 95% CI 0.59-1.97; one trial, 105 participants) [45]. 17-OHPC was the progestin used in both trials. No trials have evaluated use of vaginal progesterone. (See "Inhibition of acute preterm labor", section on 'Progesterone supplementation'.)
●Maintenance therapy after threatened preterm labor – In a 2023 meta-analysis of randomized trials (13 trials, 1722 pregnancies), progestogen maintenance therapy (any type) after an episode of preterm labor increased latency by 4.32 days compared with untreated controls (mean difference [MD] 4.32, 95% CI 0.40-8.24) and neonates had a higher birthweight (MD 124.25 g, 95% CI 8.99-239.51), but other perinatal outcomes (eg, preterm birth <37 and <34 weeks, NICU admission, respiratory distress syndrome, intraventricular hemorrhage) were not significantly different [46]. In a 2022 meta-analysis of randomized trials of vaginal progesterone after an episode of arrested preterm labor, the risk of preterm birth <37 weeks was similar in the progesterone and control groups (pooled RR 1.06, 95% CI 0.83-1.35) [47]. (See "Management of pregnancy after resolution of an episode of acute idiopathic preterm labor", section on 'Initiation of progesterone supplementation'.)
●Multiple gestation – In a 2021 meta-analysis of individual participant data from randomized trials, vaginal progesterone in unselected twin pregnancies did not reduce preterm birth before 34 weeks (RR 1.01, 95% CI 0.84-1.20; eight trials, 2046 participants) [48].
PROGESTOGEN PREPARATIONS
Natural or micronized progesterone — Natural progesterone is typically administered vaginally. The advantage of vaginal progesterone is its high uterine bioavailability since uterine exposure occurs before the first pass through the liver. It has few systemic side effects, but vaginal irritation can be bothersome, and the drug needs to be administered daily. Doses of 90 to 400 mg are used, beginning as early as 18 weeks of gestation. Commonly, 100 mg is administered vaginally each evening; however, in some areas, a 200 mg suppository may be more readily available and less costly. A vaginal suppository can be prepared by a compounding pharmacy utilizing commercially available standardized kits.
Other options include a 100 mg micronized progesterone vaginal tablet or an 8 percent vaginal gel containing 90 mg micronized progesterone per dose. Both preparations are commercially available in the US and widely used, although not approved by the United States Food and Drug Administration (FDA) for the indication prevention of preterm birth. (See 'Patients with no prior spontaneous preterm birth who develop a short cervix' above.)
Oral progesterone — An oral micronized preparation of natural progesterone also exists. In an individual patient data meta-analysis, preterm birth <34 weeks was reduced by 40 percent (relative risk [RR] 0.60, 95% CI 0.41-0.90), but data were limited to two trials with a total of 181 patients [48]. A daily dose of 400 mg is common [49,50], although doses have varied widely. Reported side effects, which are less than with synthetic progesterone, include sleepiness and fatigue [51,52]. The author of this topic does not use oral progesterone for preterm birth prevention and we found no guidelines that suggest its use.
Hydroxyprogesterone caproate — Hydroxyprogesterone caproate (17-OHPC) is a synthetic progestogen with minimal to no androgenic activity. The commercial preparation, which is administered intramuscularly, is no longer available for prevention of preterm birth because data do not support its efficacy, as discussed above.
Physicians may request a licensed pharmacist to compound a 17-OHPC preparation tailored to an individual patient's particular medical needs, but should be aware of regulations and spectrum of quality concerns related to this practice and the FDA's determination that the drug is not effective for reducing recurrent spontaneous preterm birth [40,53-57]. The American College of Obstetricians and Gynecologists (ACOG) does not endorse use of compounded 17-OHPC preparation for prevention of recurrent preterm birth [32].
SAFETY, SIDE EFFECTS, AND ADVERSE EFFECTS —
Only vaginal progesterone is currently used for supplementation. Vaginal progesterone supplementation in pregnancy is probably not harmful.
●Composite risk data – In a 2021 meta-analysis of individual participant data from randomized trials evaluating progestins for preventing preterm birth (30 trials, >11,600 participants), there was a nonsignificant increase in composite maternal complications (gestational hypertension, preeclampsia, gestational diabetes, maternal infection including chorioamnionitis) with progesterone supplementation (vaginal progesterone: relative risk [RR] 1.14, 95% CI 0.93-1.40) compared with no supplementation, mostly as a result of increased gestational hypertension and maternal infection events; however, individual outcomes were uncertain [48]. The OPPTIMUM trial of vaginal progesterone prophylaxis for preterm birth, a large trial with the longest duration of follow-up (children at two years of age), found no increase in risk of any major complication in mothers or offspring up to two years of age [42].
●Risk of developing gestational diabetes – Both diabetogenic and antidiabetogenic effects have been attributed to progesterone; the net effect on risk of developing gestational diabetes in exposed pregnancies is unclear. In a 2019 meta-analysis (seven observational studies, four randomized trials) evaluating the risk of glucose intolerance in pregnant people who received a progestin for prevention of preterm birth, vaginal progesterone was not associated with an increased risk of developing gestational diabetes mellitus (6.5 versus 7.4 percent, RR 0.82, 95% CI 0.50-1.12) [58]. A statistically significant difference was not reported in any of the randomized trials, but a meta-analysis of these trials alone was not performed. Moderate heterogeneity may have accounted for the statistical difference in glucose tolerance noted in the overall analysis.
●Risk of developing venous thrombosis – There is no clinical evidence that vaginal progesterone or hydroxyprogesterone caproate (17-OHPC) are associated with an increased risk of venous thrombosis. As such, the author of this topic does not regard this concern as an absolute contraindication to progesterone supplementation in pregnancy. The package inserts of all progesterone preparations and progestins in the US carry a warning that a history of or current thrombophlebitis or venous thromboembolic disorders is a contraindication to use. The US Food and Drug Administration (FDA) requires this warning because estrogen-progestin contraceptives are associated with an increased risk of venous thrombosis and they believe there is inadequate information to determine whether specific progesterone preparations or progestins used alone are also associated with an increased risk.
●Local side effects – Minor side effects are related to the route of administration and include vaginal irritation or discharge for vaginal progesterone.
●Risk of teratogenesis – Initiation of progesterone supplementation begins at 16 weeks, which is well past the period of embryogenesis. No significant teratogenic effects have been reported.
●Long-term risk of developmental effects – A meta-analysis of two trials (890 children) found no increased risk of impaired neurodevelopment in children aged six months to eight years exposed to vaginal progesterone during the second or third trimester of pregnancy [59]. Mental health, sexual or gender orientation, and pubertal development were not evaluated.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Preterm labor and birth".)
SUMMARY AND RECOMMENDATIONS
●Asymptomatic patients with no prior spontaneous preterm birth who develop a short cervix – For asymptomatic patients with a singleton pregnancy, no prior spontaneous preterm birth, and cervical length (CL) ≤25 mm on midtrimester transvaginal ultrasound examination, we suggest vaginal progesterone supplementation rather than no supplementation (Grade 2B). The absolute reductions in preterm birth and neonatal morbidity may be small but no serious short-term safety concerns have been identified. (See 'Clinical settings where progesterone supplementation may be effective' above and 'Safety, side effects, and adverse effects' above.)
●Asymptomatic patients with a prior spontaneous preterm birth
•CL >25 mm – For asymptomatic patients with a singleton pregnancy and prior spontaneous preterm birth who do not have a short CL in the current pregnancy, the use of vaginal progesterone to prevent recurrent spontaneous preterm birth is controversial. The author and section editor of this topic do not use it for this indication but another UpToDate section editor does offer it. The American College of Obstetricians and Gynecologists (ACOG) recommends against use of vaginal progesterone to prevent recurrent preterm birth. The Society for Maternal-Fetal Medicine (SMFM) recommends a shared decision-making process. (See 'Patients with a prior preterm birth' above.)
•CL ≤25 mm – Asymptomatic patients with a singleton pregnancy and prior spontaneous preterm birth who develop a short CL on midtrimester ultrasound in the current pregnancy are given an ultrasound-based diagnosis of cervical insufficiency. Cervical cerclage is the preferred treatment. The management of these patients and supporting evidence are reviewed separately. (See "Cervical insufficiency", section on 'Ultrasound-based diagnosis of cervical insufficiency' and "Cervical insufficiency", section on 'Ultrasound-based interventions for possible cervical insufficiency'.)
●Other scenarios – Routine progesterone supplementation does not appear to be useful for preventing preterm birth in the setting of preterm prelabor rupture of membranes (PPROM) or after an episode of arrested preterm labor. There is no information on efficacy in patients with a positive fetal fibronectin (fFN) test. The effect in patients with a cerclage is unclear. (See 'Other clinical settings at increased risk for spontaneous preterm birth' above.)
