INTRODUCTION — Preterm birth (delivery prior to 37 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 for delaying delivery in patients experiencing spontaneous preterm labor has been largely unsuccessful, attention has focused on preventive strategies, such as progesterone supplementation (the name is derived from its function: progestational steroidal ketone).

Although progesterone supplementation may be effective in preventing spontaneous preterm labor and birth in some high-risk patients, it is not a panacea. For example, even if all pregnant patients in the United States with a history of spontaneous preterm birth receive progesterone prophylaxis, it has been estimated that spontaneous preterm birth would be reduced by no more than 20 percent and the absolute preterm birth rate would be reduced by no more than 0.01 percent because most spontaneous preterm births are not recurrences and prophylaxis has limited efficacy [2-5]. If patients with a short cervix are also identified and treated, an additional absolute risk reduction of 0.02 percent would be achieved, assuming efficacy [5].

This topic will review issues related to use of progesterone supplementation for prevention of spontaneous preterm birth. 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 "Preterm birth: Risk factors, interventions for risk reduction, and maternal prognosis".)

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, which are likely mediated via progesterone receptors [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 inflammatory pathways, both systemic and intrinsic to the uterus, leading to 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, the circulating levels of endogenous progesterone in the third trimester are already very high and likely saturate progesterone receptors, so it is unclear why exogenous supplementation might have biologic effects.

CANDIDATES FOR PROGESTERONE SUPPLEMENTATION

Background — The efficacy of progesterone supplementation for preventing preterm birth depends primarily on appropriate patient selection, which remains controversial (table 1). 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].

Patients with singleton pregnancy and a short cervix or previous spontaneous preterm birth — In patients with a singleton pregnancy, progesterone supplementation appears to reduce the rate of spontaneous preterm birth in those with a past history of spontaneous preterm birth and those with cervical shortening (usually defined as ≤25 mm at 16 to 24 weeks) in the current pregnancy. (See "Preterm birth: Risk factors, interventions for risk reduction, and maternal prognosis", section on 'Reproductive 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 randomized trials evaluating progestins for preventing preterm birth (30 trials, >11,600 participants), in singleton pregnancies with either a previous spontaneous preterm birth or cervical shortening in the current pregnancy (≤25 mm at 16 to 24 weeks in most of the studies) [26]:

●Preterm birth <34 weeks was reduced by approximately 20 percent in patients who received vaginal progesterone (relative risk [RR] 0.78, 95% CI 0.68-0.90; nine trials, 3769 pregnant people) or hydroxyprogesterone caproate (17-OHPC; RR 0.83, 95% CI 0.68-1.01; five trials, 3053 women), but the confidence interval (CI) for 17-OHPC was wider and crossed 1.0. Confidence in reductions in preterm birth <37 and <28 weeks were unclear as the CIs for both preparations included/crossed 1.0. Data were insufficient to reliably determine whether the preterm births were spontaneous for all participants in all trials.

●The risks for neonatal morbidity (neonatal intensive care unit admission, respiratory distress syndrome, respiratory support, necrotizing enterocolitis, severe intraventricular hemorrhage, retinopathy of prematurity) and neonatal death were reduced, but the confidence intervals for most of the individual outcomes crossed the line of no effect. For the composite of serious neonatal complications, the risk reduction for vaginal progesterone was RR 0.82 (95% CI 0.65-1.04) and for 17-OHPC RR 0.81 (95% CI 0.60-1.09).

●There was no clear difference in effect between vaginal progesterone and 17-OHPC by short cervical length or by history of a previous preterm birth; however, only two small trials directly compared the two drugs. Network meta-analysis showed an uncertain trend favoring vaginal progesterone in patients with a short cervix and favoring 17-OHPC for patients with a prior preterm birth.

Absolute risk reductions were not provided. A network meta-analysis of the same trials but not using individual participant data calculated the following absolute rates for preterm birth <34 weeks with intervention versus no intervention: vaginal progesterone (9.6 versus 19.1 percent) and 17-OHPC (13.0 versus 19.1 percent) [27]. Limitations of these analyses include lack of stratification of data by short cervix versus previous spontaneous preterm birth and inclusion of older trials, which had unusually high preterm birth rates in the control group. More recent trials had lower preterm birth rates in controls and did not show a benefit.

Based on these and previous data, the American College of Obstetricians and Gynecologists endorsed offering progesterone supplementation (either vaginal progesterone or intramuscular 17-OHPC) to patients with a singleton pregnancy and a prior spontaneous preterm birth and offering vaginal progesterone to asymptomatic patients with a singleton pregnancy with a short cervix and no history of preterm birth [28]. The Society for Maternal-Fetal Medicine reaffirmed their guidance to offer vaginal progesterone to patients with a singleton pregnancy and a short cervix, and 17-OHPC to those with a singleton gestation and a history of prior spontaneous preterm birth between 20 and 36+6 weeks of gestation [29]. Both emphasized shared decision-making after discussion of the benefits, potential risks, patient values, cost, limitations of the data, and choice of progestogen.

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

Twin pregnancy

●Unselected twin pregnancies – Progesterone is not effective in reducing spontaneous preterm birth in unselected multiple gestations. One reason may be that the pathogenesis of preterm labor and delivery in multiple gestations may be different from that in singleton gestations (eg, increased uterine distention is more common in twins than singletons) and their endogenous progesterone levels are even higher than in singletons; thus, twin pregnancies may be less impacted by changes in progesterone levels.

In a meta-analysis of individual participant data from 13 randomized trials evaluating progestins for preventing preterm birth in multifetal pregnancies (mostly twins) in which most had no recorded risk factor for preterm birth other than the multifetal gestation, major findings were [26]:

•Progesterone supplementation did not reduce preterm birth <34 weeks (vaginal progesterone: relative risk [RR] 1.01, 95% CI 0.84-1.20; hydroxyprogesterone caproate [17-OHPC]: RR 1.04, 95% CI 0.92-1.18).

•Progesterone supplementation did not reduce serious neonatal morbidity (vaginal progesterone: RR 0.94, 95% CI 0.74-1.20; 17-OHPC: RR 1.12, 95% CI 0.76-1.65).

•Multiple gestations receiving 17-OHPC appeared to have an increased risk of preterm prelabor rupture of membranes (PPROM) compared with untreated controls (eg, PPROM <34 weeks RR 1.59, 95% CI 1.15-2.22), but there was no increase with vaginal progesterone (RR 0.92, 95% CI 0.62-1.35).

The analysis did not include multiple gestations with additional risk factors for preterm birth, such as short cervix or previous preterm birth, and thus a benefit of progesterone supplementation in these higher-risk populations cannot be excluded.

●Twin pregnancies with short cervix – In a 2017 meta-analysis of individual patient data from six randomized trials including 303 patients with twin gestations and midtrimester cervical length ≤25 mm [30]:

•Vaginal progesterone reduced preterm birth <33 weeks compared with no treatment/placebo (RR 0.69, 95% CI 0.51-0.93; 50 of 159 [31 percent] versus 62 of 144 [43 percent]).

•The relative risks of neonatal death, respiratory distress syndrome, and birth weight <1500 g were also reduced significantly, on average by 30 to 50 percent.

Based on these data, which should be confirmed in larger trials, the author treats patients with twin pregnancies and a short cervix with vaginal progesterone. This is controversial as available trials have involved a relatively small number of preterm births and participants, with a wide confidence interval in the meta-analysis. Not providing progesterone supplementation in this setting is also reasonable.

Data regarding 17-OHPC are even more limited but do not appear to show benefit for managing twin pregnancies with a short cervix. In a randomized trial, twice-weekly injections of 17-OHPC 500 mg did not result in a reduction in preterm birth (<37, <34, or <32 weeks) or neonatal morbidity/mortality in patients with twin pregnancy and a short cervix [31]. In fact, intramuscular 17-OHPC may increase adverse perinatal outcome in twin pregnancy [32-34].

●Current twin pregnancy and prior singleton preterm birth – A prior spontaneous preterm birth of a singleton pregnancy is an independent and additive risk factor for preterm birth of twins [35]. In the absence of data clearly showing harm or lack of efficacy in this specific setting, the author prescribes 17-OHPC to patients with twin pregnancies who have had a prior spontaneous singleton preterm birth, unless it could be attributed to a nonrecurring etiology (eg, an invasive procedure). However, this approach is controversial [36].

Not providing progesterone supplementation in this setting is also reasonable. A subgroup analysis of a 2015 meta-analysis using individual patient data from randomized trials found that vaginal progesterone was not effective for reducing spontaneous preterm birth in patients with twins who had a prior singleton spontaneous preterm birth, although data were limited [32]. A small retrospective study also found that weekly 17-OHPC was not effective in this setting [37].

Singleton pregnancy with prior spontaneous twin preterm birth — Patients with a past spontaneous twin preterm birth are at increased risk of spontaneous preterm birth in a subsequent singleton pregnancy [38-40]. Some trials of progesterone supplementation for prevention of recurrent preterm birth in singleton pregnancies were limited to patients with prior singleton preterm births, while others included both patients with prior singleton and those with prior twin preterm births, but no trial has specifically evaluated the efficacy of progesterone supplementation in patients with a singleton pregnancy and a prior spontaneous twin preterm birth.

The author offers 17-OHPC supplementation to pregnant people with a singleton pregnancy who have had a prior spontaneous twin preterm birth. Not providing progesterone supplementation in this setting is also reasonable, given the lack of data for this specific clinical scenario and, as discussed above, differences between singletons and twins in pathogenesis of preterm labor and delivery. (See 'Twin pregnancy' above.)

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 [41]. Progesterone supplementation did not improve obstetric, neonatal, or childhood outcomes in this trial.

After cerclage placement — In pregnant people with a prior spontaneous preterm birth, continuing 17-OHPC supplementation after placement of an ultrasound-indicated cerclage has not been proven to be useful in reducing preterm birth compared with discontinuing supplementation postoperatively, but available data are limited to secondary analysis of one underpowered trial. Some UpToDate authors, including this author, continue 17-OHPC in the absence of high-quality data showing lack of benefit after cerclage placement. (See "Cervical insufficiency", section on 'Cerclage placement and use of progesterone supplementation'.)

After preterm prelabor rupture of membranes — Beginning progesterone supplementation is not beneficial in pregnant people who develop PPROM in the current pregnancy. In a meta-analysis of randomized trials (five trials, 545 participants), initiating progesterone supplementation (primarily 17-OHPC) after PPROM did not prolong the latency period or increase the mean gestational age at birth [42].

By contrast, pregnant people with a history of preterm birth due to PPROM appear to benefit from progesterone supplementation in subsequent pregnancies; these patients were included in the prior randomized trials of the efficacy of progesterone supplementation for prevention of spontaneous preterm birth [26]. As discussed above, progesterone appears to prevent apoptosis in fetal membranes in vitro under both basal and proinflammatory conditions [18], thereby providing a mechanism by which progesterone supplementation may prevent recurrent PPROM and preterm birth. (See 'Rationale for progesterone supplementation' above.)

Threatened or established preterm labor — A meta-analysis 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 grams (RR 1.08, 95% CI 0.59-1.97; one trial, 105 participants), but a possible reduction in preterm birth <37 weeks (RR 0.62, 95% CI 0.39-0.98; three trials, 283 participants); however, the small number of events and participants precludes meaningful conclusions from these data [43].

Maintenance therapy after threatened preterm labor — The use of progesterone in patients who remain undelivered after an episode of threatened preterm labor is investigational, and most providers (including the author) do not prescribe progesterone supplementation for maintenance tocolysis. Randomized trials evaluating various types of progesterone supplementation in this setting have reported disparate results, likely related to factors such as differences in size, type of progestin, route of administration, and inclusion of a placebo versus a no treatment arm. When only high-quality trials were evaluated by meta-analysis, maintenance progesterone was not more effective than placebo [44]:

●Delivery <37 weeks – RR 0.91 (95% CI 0.67-1.25)

●Delivery <34 weeks – RR 1.21 (95% CI 0.85-1.70)

●Latency to delivery – RR 0.60 (95% CI -3.73 to 4.94)

A randomized trial that evaluated use of progesterone (17-OHPC or vaginal progesterone) after an episode of threatened preterm labor specifically in patients with a short cervix also reported no reduction in preterm birth with either drug compared with untreated patients [45].

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. The effectiveness of progesterone therapy for prevention of spontaneous preterm birth in these patients is unknown [46]. (See "Assisted reproductive technology: Pregnancy and maternal outcomes" and "Congenital uterine anomalies: Clinical manifestations and diagnosis".)

Patients with obesity — In patients with a history of prior spontaneous preterm birth and prepregnancy body mass index (BMI) >30 kg/m², a secondary analysis of data from the Maternal-Fetal Medicine Units Network Trial [4] suggested that 17-OHPC did not prevent recurrent preterm birth <37 weeks (RR of preterm birth 1.55, 95% CI 0.83-2.89) [47]. The threshold for efficacy appeared to be <165 pounds (74.8 kg). While secondary analysis has several weaknesses (eg, it was an unplanned post hoc analysis, prepregnancy weights were self-reported, no data were available on weight gain during pregnancy or 17-OHPC serum levels), it raises an important clinical question that needs to be addressed further.

Until additional confirmatory studies are available, this author suggests not limiting 17-OHPC supplementation by any BMI or weight criteria.

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 [26]. 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 [41].

●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) [48]. 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 – A possible increase in risk of hypospadias in male offspring exposed to exogenous progestins before 11 weeks of gestation has been described [49,50]. Even if confirmed, the concern is not relevant to patients with prior preterm delivery since they will receive the drug after 16 weeks of gestation.

●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 [51]. 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) [52]. 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.

CHOICE OF PROGESTERONE PREPARATION AND DOSE — The body of evidence does not clearly favor one progesterone preparation over the other. As discussed above, an individual participant data meta-analysis found no clear difference in effect between vaginal progesterone and 17-OHPC by history of a previous preterm birth or by short cervical length [26]. A network meta-analysis showed very weak trends favoring 17-OHPC in patients with a previous preterm birth and vaginal progesterone in patients with a short cervix, but only two small trials directly compared the two drugs. (See 'Patients with singleton pregnancy and a short cervix or previous spontaneous preterm birth' above.)

●For patients with a history of spontaneous preterm birth, the author's preference is:

•Hydroxyprogesterone caproate (17-OHPC) 250 mg intramuscularly (IM) weekly beginning at 16 to 20 weeks of gestation and continued until 36+6 weeks. Ideally, progesterone is started earlier rather than later within the 16 to 20 week range for maximum effect [53].

This preference is largely based on results of the Maternal-Fetal Medicine Units Network trial of 17-OHPC supplementation in this group of patients, which reported a 30 percent reduction in preterm birth <35 weeks (relative risk [RR] 0.67, 95% CI 0.48-0.93) [4]. For this patient population, the American College of Obstetricians and Gynecologists suggests offering progesterone supplementation (either vaginal or intramuscular) in the context of shared decision-making, incorporating the available evidence and the patient's preferences [28].

The author also follows cervical length with serial ultrasound examinations until 24 weeks of gestation and considers cerclage if cervical length is ≤25 mm or the cervical dilation occurs in the absence of labor (physical examination-indicated cerclage). (See "Cervical insufficiency", section on 'Ultrasound-based cervical insufficiency' and "Cervical insufficiency", section on 'Physical examination-based cervical insufficiency'.)

●For patients with a short cervix before 24 weeks, the author's preference is:

•Natural progesterone 100 mg vaginally daily beginning upon diagnosis and continued until 36+6 weeks of gestation.

This preference is largely based on the results of a meta-analysis of individual patient data from randomized trials of patients with short cervical length treated with vaginal progesterone, which reported a 30 percent reduction in preterm birth <34 weeks (RR 0.72, 95% CI 0.55-0.95) [54].

The reproductive effects of 17-OHPC and natural progesterone are not identical [55]. They may have different clinical effectiveness because synthetic 17-OHPC and natural progesterone have different biological activities in the myometrium and uterine cervix: Progesterone decreases myometrial contractility and prevents cervical ripening, but 17-OHPC does not [56], possibly because natural progesterone has greater binding affinity for nuclear progesterone receptors than 17-OHPC [57]. There also appear to be differential effects on prevention of membrane weakening and, in turn, preterm prelabor rupture of membranes. Large comparative trials are needed to determine whether one drug is superior to the other for all pregnancies at high risk for spontaneous preterm birth, whether the choice of drug should depend on the specific risk factor for spontaneous preterm birth (past history or short cervix), and whether differences in outcomes among trials were due to differences in dosing, formulation, or route of delivery [23,25,58].

PROGESTERONE PREPARATIONS

Hydroxyprogesterone caproate — Hydroxyprogesterone caproate (17-OHPC) is a synthetic progestogen with minimal to no androgenic activity. Doses have ranged from 25 mg every five days to 1000 mg weekly, beginning as early as 16 weeks of gestation. We use a 250 mg dose, administered intramuscularly (IM). Standard contraindications to progesterone administration include hormone-sensitive cancer, liver disease, and uncontrolled hypertension.

Makena (United States brand name) is a 17-OHPC preparation approved in 2011 by the US Food and Drug Administration (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 [59]. Two methods for delivery are available: an autoinjector for subcutaneous administration of 275 mg and single- and multidose vials for IM injection of 250 mg. No clinical trials using the autoinjected subcutaneous dose have been performed in pregnant people; both clinical efficacy and bioequivalence to the IM dose are unproven [60]. However, in October 2019 and 2020, FDA advisory committees recommended withdrawing Makena from the market based in part on findings of the PROLONG trial [61,62]. At this time, most major obstetric organizations have not revised their recommendations regarding use of IM progesterone to reduce the risk of preterm birth. The Society for Maternal-Fetal Medicine concluded that providers may continue to use 17-OHPC in women with a risk profile similar to the very high-risk population reported in the Maternal-Fetal Medicine Units network trial of 17-OHPC supplementation [4,63]. Discussions with patients should include the uncertainty regarding the benefit, the lack of short-term safety concerns [64], the possibility of injection site pain, extra patient visits, and substantial costs.

Alternatively, 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 [65-69].

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. The 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 [70]. 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.

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 0.60, 95% CI 0.41-0.90), but data were limited to two trials with a total of 181 patients [26]. A daily dose of 400 mg is common [71,72], although doses have varied widely. Reported side effects, which are less than with synthetic progesterone, include sleepiness and fatigue [73,74].

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

●For pregnant people with a singleton pregnancy who have had a previous spontaneous singleton preterm birth and pregnant people with a short cervix on ultrasound examination, we suggest progesterone supplementation (Grade 2C). Progesterone supplementation may reduce the risk of preterm birth by 20 percent; however, 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.)

●If the decision is made to proceed with progesterone supplementation:

•For pregnant people with a singleton pregnancy who had a previous spontaneous singleton preterm birth, we suggest intramuscular (IM) injections of hydroxyprogesterone caproate (17-OHPC) rather than vaginal progesterone (Grade 2C). We prescribe 250 mg IM weekly, beginning in the second trimester (16 to 20 weeks) and continuing through 36+6 weeks of gestation. Daily administration of natural progesterone vaginally is a reasonable alternative. (See 'Patients with singleton pregnancy and a short cervix or previous spontaneous preterm birth' above and 'Choice of progesterone preparation and dose' above.)

We also follow the cervical length with serial ultrasound examinations until 24 weeks of gestation and consider cerclage if cervical length is ≤25 mm. (See "Cervical insufficiency", section on 'Ultrasound-based cervical insufficiency'.)

We manage pregnant people with a singleton pregnancy who have had a prior spontaneous preterm twin birth the same way. (See 'Singleton pregnancy with prior spontaneous twin preterm birth' above.)

•For pregnant people with midtrimester cervical shortening (defined as ≤25 mm before 24 weeks) and no prior spontaneous singleton preterm birth, we suggest daily vaginal progesterone treatment (Grade 2C). Progesterone is administered from diagnosis of short cervix until 36+6 weeks of gestation. Reasonable options include a vaginal suppository (100 or 200 mg), gel (90 mg), or tablet (100 mg micronized progesterone). (See 'Patients with singleton pregnancy and a short cervix or previous spontaneous preterm birth' above and 'Choice of progesterone preparation and dose' above.)

●For multiple gestations, we recommend not administering progesterone supplementation routinely (Grade 1B) (see 'Twin pregnancy' above). However:

•For pregnant people with twin gestations and a previous spontaneous preterm birth, the author prescribes 17-OHPC. Not prescribing progesterone supplementation or prescribing natural progesterone vaginally is also reasonable. (See 'Twin pregnancy' above.)

•For pregnant people with twin gestations and a short cervix in the current pregnancy, the author prescribes vaginal progesterone. Not prescribing progesterone supplementation is also reasonable. (See 'Twin pregnancy' above.)

●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 'After cerclage placement' above and 'Threatened or established preterm labor' above.)