Progesterone supplementation to reduce the risk of spontaneous preterm labor and birth

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]. A common reason for preterm birth is the occurrence of spontaneous preterm labor. Because tocolysis of preterm labor has been largely unsuccessful in preventing preterm birth, attention has focused on preventive strategies, such as progesterone supplementation. Progesterone supplementation may be effective in some high-risk patients (short cervix), but it is not a panacea because prophylaxis has limited efficacy and many spontaneous preterm births occur in patients without this high risk factor [2-5].

This topic will discuss issues related to progesterone supplementation to reduce the risk of spontaneous preterm birth. However, progesterone supplementation is only one component of risk reduction. Risk factors for preterm birth and other potential interventions for reducing risk are discussed 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 rationale for progesterone supplementation is that endogenous progesterone contributes to pregnancy maintenance in several ways; therefore, exogenous progesterone supplementation may enhance these actions [6].

Progesterone effects on pregnancy include:

●Corpus luteum progesterone production is critical for maintaining the pregnancy until the placenta takes over this function at seven to nine weeks of gestation. Removing the corpus luteum [7] or administering a progesterone receptor antagonist [8] readily induces abortion before seven weeks (49 days) of gestation.

●Subsequently, placental progesterone production maintains uterine quiescence [9-11]. 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, without a significant change in serum progesterone levels in the weeks preceding labor [9-16].

●Progesterone-related immune modulation may act to counter pro-inflammatory pathways, both systemic and intrinsic to the uterus, thereby protecting against preterm labor and birth [17].

●In vitro, progesterone prevents apoptosis in fetal membrane explants under both basal and proinflammatory conditions [18,19] and thus may protect from preterm prelabor rupture of membranes and, in turn, preterm labor and birth.

However, circulating levels of endogenous progesterone in the third trimester are already very high, are sufficient to saturate progesterone receptors, and do not increase with exogenous progesterone administration, so it is unclear why 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; therefore, increasing local progesterone levels should have no or minimal effects. One theory to explain possible efficacy in some clinical scenarios is that exogenous vaginal progesterone may directly alter the vaginal microbiome or alter the inflammatory response to aberrant microbial states by its effects on local glucocorticoid receptors.

CANDIDATES FOR PROGESTERONE SUPPLEMENTATION — The existing literature suggests that 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 [20-22]. 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 have 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 [23-25].

Singleton pregnancy with a short cervix — In asymptomatic patients with a singleton pregnancy and midtrimester short cervical length (≤25 mm), vaginal progesterone supplementation reduces the rate of spontaneous preterm birth and improves neonatal outcome. (See "Spontaneous preterm birth: Overview of risk factors and prognosis", section on 'Obstetric history' and "Short cervix before 24 weeks: Screening and management in singleton pregnancies", section on 'Rationale for measuring cervical length'.)

In a meta-analysis of individual participant data from five high-quality randomized trials including a total of 974 participants, compared with the placebo, daily vaginal progesterone administration resulted in statistically significant reductions in [26]:

●Preterm birth <33 weeks of gestation (14.1 versus 22.5 percent; relative risk [RR] 0.62; 95% CI 0.47-0.81)

●Preterm birth <36 weeks (28 versus 35 percent; RR 0.80), <35 weeks (21 versus 30 percent; RR 0.72), <34 weeks (17 versus 26 percent; RR 0.65), <32 weeks (12 versus 19 percent; RR 0.64), <30 weeks (10 versus 14 percent; RR 0.70), and <28 weeks (8 versus 11 percent; RR 0.67)

●Spontaneous preterm birth <33 weeks (12 versus 17 percent; RR 0.70) and <34 weeks (15 versus 20 percent; RR 0.72)

●Respiratory distress syndrome (5 versus 10 percent; RR 0.47, 95% CI 0.27-0.81)

●Composite neonatal morbidity and mortality (8 versus 14 percent; RR 0.59, 95% CI 0.38-0.91)

●Birthweight <1500 (10 versus 16 percent; RR 0.62) and <2500 g (29 versus 36 percent; RR 0.82)

●Neonatal intensive care unit admission (17 versus 25 percent; RR 0.68).

●Neonatal deaths were also reduced, but the confidence interval crossed 1.0 (7 in 498 [1 percent] versus 15 in 476 [3 percent]; RR 0.44, 95% CI 0.18- 1.07).

●Maternal adverse events, 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.

The American College of Obstetricians and Gynecologists (ACOG) recommends vaginal progesterone for asymptomatic patients with a singleton pregnancy with a short cervix without a previous history of preterm birth [27]. ACOG also considers it an option for asymptomatic patients with a singleton pregnancy with a short cervix and a previous history of preterm birth but also considers cerclage an option for these patients. We agree with this recommendation.

Twin pregnany with a short cervix — A meta-analysis of individual patient data from six randomized trials including 95 patients with twin gestations and midtrimester cervical length ≤25 mm found that vaginal progesterone reduced preterm birth <33 weeks and a composite of neonatal morbidity and mortality [28]. These data and recommendations for pregnancy monitoring and management are reviewed separately. (See "Twin pregnancy: Management of pregnancy complications", section on 'Approach to patients with a short cervix'.)

PREGNANCIES WHERE THE BENEFIT OF PROGESTERONE SUPPLEMENTATION IS UNPROVEN — The benefit of progesterone supplementation in pregnant people at high risk of preterm birth, but without a short cervix, is not supported by strong evidence. Some of these clinical scenarios are reviewed below.

Singleton pregnancy with prior preterm birth

●Vaginal progesterone – 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 patients), vaginal progesterone reduced the risk of preterm birth <37 weeks (RR 0.64, 95% CI 0.50-0.81, very low-quality evidence) and <34 weeks (RR 0.62, 95% CI 0.42-0.92, very low-quality evidence); however, the reductions were not statistically significant after restriction to trials at low risk of bias and adjustment for small-study effects [29]. Based on these findings and prospective observational data from a large study of inner-city pregnant patients in the US [30], ACOG recommends against use of vaginal progesterone to prevent recurrent preterm birth [27]. The author and section editor of this topic agree with this recommendation.

The Society for Maternal-Fetal Medicine recommends a shared decision-making process regarding use of vaginal progesterone for primary prevention of recurrent preterm birth without input of cervical length (including those with a cervical length ≥25 mm), especially if a progesterone formulation for preterm birth prevention was used in a previous pregnancy [31].

The use of progesterone to prevent recurrent spontaneous preterm birth remains controversial and another UpToDate section editor does offer vaginal progesterone to these patients [32]. The 2022 meta-analysis discussed above did show a benefit from vaginal progesterone before restriction to trials at low risk of bias and adjustment for small-study effects [29]. Another meta-analysis of randomized trials in patients with singleton gestations and previous spontaneous preterm birth found that vaginal progesterone reduced preterm birth <34 and <37 weeks compared with 17-OHPC, although 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) [33]. In addition, secondary analysis of data from a randomized trial suggests that vaginal progesterone is associated with reduced cervical shortening and rates of cervical shortening in patients with singleton pregnancies and a previous singleton spontaneous preterm birth [34]. Lastly, translational data suggest that vaginal progesterone prevents cervical remodeling, uterine contractility, inflammation-induced pathology, and immune activation [32].

●Hydroxyprogesterone caproate (17-OHPC) – 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 [4]. Active prophylaxis significantly reduced the risk of preterm birth at all gestational ages studied.

However, in 2020, a randomized placebo-controlled multicenter international trial (PROLONG) that assessed the safety and efficacy of 17-OHPC in over 1700 patients with a singleton gestation and past history of preterm birth found that the intervention did not significantly reduce preterm birth <35 weeks or fetal/early infant death [35].

In 2023, additional analysis of the data from these two trials, other randomized trials, and observational studies led the United States Food and Drug Administration (FDA) to conclude that use of Makena, the only commercially available 17-OHPC medication for prevention of recurrent preterm birth, is not supported by available evidence and withdrew its approval of the medication [36]. The American College of Obstetricians and Gynecologists (ACOG) concurred with this assessment [27].

Positive fetal fibronectin test — Although a positive cervicovaginal fetal fibronectin (fFN) test 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 [37]. Vaginal progesterone supplementation did not improve obstetric, neonatal, or childhood outcomes in this trial.

Uterine anomaly or assisted reproductive technology — Patients with some uterine anomalies and those 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 [38]. (See "Assisted reproductive technology: Pregnancy and maternal outcomes" and "Congenital uterine anomalies: Clinical manifestations and diagnosis".)

Unselected twin pregnancies — (See "Twin pregnancy: Management of pregnancy complications", section on 'Overview'.)

After preterm prelabor rupture of membranes — (See "Preterm prelabor rupture of membranes: Management and outcome", section on 'Supplemental progesterone'.)

Threatened or established preterm labor — (See "Inhibition of acute preterm labor", section on 'Progesterone supplementation'.)

Maintenance therapy after threatened preterm labor — (See "Management of pregnancy after resolution of an episode of acute idiopathic preterm labor", section on 'Initiation of progesterone supplementation'.)

SAFETY, SIDE EFFECTS, AND ADVERSE EFFECTS

●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; hydroxyprogesterone caproate [17-OHPC]: RR 1.17, 0.97-1.42) compared with no supplementation, mostly as a result of increased gestational hypertension and maternal infection events; however, individual outcomes were uncertain [39]. 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 [37].

●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, 17-OHPC was associated with an increased risk of developing gestational diabetes mellitus (11.9 versus 6.6 percent, risk ratio 1.73, 95% CI 1.32-2.28) while vaginal progesterone was not (6.5 versus 7.4 percent, risk ratio 0.82, 95% CI 0.50-1.12) [40]. 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 – As there is no clinical evidence that vaginal progesterone or 17-OHPC are associated with an increased risk of venous thrombosis, we use these drugs to reduce the risk of spontaneous preterm birth, when indicated, in patients with a history of venous thrombosis. The package inserts of all progesterone preparations and progestins in the United States 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 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 injection site reactions for 17-OHPC and 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 progesterone during the second or third trimester of pregnancy [41]. Mental health, sexual or gender orientation, and pubertal development were not evaluated.

●Risk of cancer in offspring – A retrospective population-based cohort study of >18,000 mother-child dyads reported a possible small absolute increase in cancer among 234 offspring of mothers who received 17-OHPC during pregnancy between 1959 and 1966; 70 percent received treatment in the first trimester (41 percent for threatened abortion) [42]. At 60-years follow-up, 23 cancers had been diagnosed in 17-OHPC-exposed offspring. First-trimester exposure was associated with an increased risk of any cancer in offspring (incidence rate 29.6 versus 13.7 per 100,000 persons; adjusted hazard ratio 2.57, 95% CI 1.59-4.15). The highest risk was for colorectal, prostate, and pediatric brain cancers, with no increase in breast cancer risk. No comparison was made between risk of cancer in offspring and risk in the mother (or father), an approach that could have helped adjust for numerous confounding demographic, social, environmental, and genetic factors. Whether this association is germane to the current use of 17-OHPC to prevent preterm birth, in which treatment is initiated at 16 to 20 weeks, is not known.

PROGESTERONE 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 have been effective, beginning as early as 18 weeks of gestation. We use 100 mg 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 United States but not approved for prevention of preterm birth in cervical shortening. In 2012, the US Food and Drug Administration (FDA) concluded the data in the manufacturer's application did not sufficiently support the efficacy of progesterone 8 percent gel compared with placebo in reducing the risk of preterm births before 33 completed weeks of gestation among pregnant people with a short cervical length, but the drug was safe in this population [43]. The FDA was critical of the statistical methods used in the key trial and noted that most of the apparent treatment benefit occurred in non-United States centers. Since 2012, an additional trial and meta-analysis have supported the efficacy of vaginal progesterone in singleton pregnancies with a short cervical length and it is widely used off-label for this indication. (See 'Singleton pregnancy with 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 [39]. A daily dose of 400 mg is common [44,45], although doses have varied widely. Reported side effects, which are less than with synthetic progesterone, include sleepiness and fatigue [46,47]. The author of this topic does not use oral progesterone for preterm birth prevention.

Hydroxyprogesterone caproate — Hydroxyprogesterone caproate (17-OHPC) is a synthetic progestogen with minimal to no androgenic activity.

Makena (United States brand name) is a 17-OHPC preparation approved in 2011 by the FDA to reduce the risk of recurrent preterm birth in pregnant people with a singleton pregnancy who have a history of a prior spontaneous preterm delivery [48]. However, in October 2020 and October 2022, FDA advisors voted to withdraw Makena from the market based in part on findings of the international PROLONG trial in which administration of 17-OHPC to patients with a previous spontaneous preterm birth did not reduce the risk for recurrent PTB (spontaneous or indicated) [35,49,50]. In March 2023, the manufacturer announced plans to voluntarily withdraw it from the market in the coming months [51]. On April 5, 2023, the FDA withdrew its approval of Makena because a postmarketing confirmatory trial and studies did not show a clinical benefit [36]. The FDA found no clinically significant benefit when analyzed by race (Black versus non-Black), region (US versus non-US), by history of spontaneous preterm birth (one versus more than one previous spontaneous preterm birth), and by composite risk level (no risk factor versus at least one risk factor versus at least two risk factors). Clinicians should discuss these issues with patients who are currently taking Makena and offer them the choice of continuing treatment until 37 weeks or immediately discontinuing treatment. The FDA did not identify any harms from continuing or discontinuing treatment. However, medication supply may be limited.  

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 [36,52-56]. ACOG does not endorse use of compounded 17-OHPC preparation for prevention of recurrent preterm birth [27].

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

●Singleton gestation

•Short cervical length –For pregnant people with a singleton pregnancy with a short cervix on ultrasound examination, we discuss vaginal progesterone supplementation. Uncertainty regarding risk reduction and its magnitude exists, so not administering supplemental progesterone is also reasonable. Providers should discuss the option of prophylactic progesterone supplementation with patients, highlighting uncertainty regarding benefit but lack of serious short-term safety concerns. (See 'Candidates for progesterone supplementation' above and 'Safety, side effects, and adverse effects' above.)

•Prior spontaneous preterm birth – The use of progesterone to prevent recurrent spontaneous preterm birth regardless of cervical length remains controversial. The author and section editor of this topic do not use it for this indication but another UpToDate section editor does offer it. ACOG recommends against use of vaginal progesterone to prevent recurrent preterm birth. The Society for Maternal-Fetal Medicine recommends a shared decision-making process. (See 'Singleton pregnancy with prior preterm birth' above.)

•Other scenarios – Routine progesterone supplementation does not appear to be useful for preventing preterm birth in the setting of preterm prelabor rupture of membranes or after an episode of arrested preterm labor. There is no information on efficacy in patients with a positive fetal fibronectin test. The effect in patients with a cerclage is unclear. (See 'After preterm prelabor rupture of membranes' above and 'Positive fetal fibronectin test' above and 'Threatened or established preterm labor' above.)

●Multiple gestation – Treating twin pregnancies with a short cervix with vaginal progesterone may be beneficial for prolonging gestation. Cerclage is another option. (See "Twin pregnancy: Management of pregnancy complications", section on 'Approach to patients with a short cervix'.).