Combined vaginal progesterone and cervical Pessary effect on preterm birth in Singleton pregnancies with short cervix: a retrospective cohort study

A total of 322 pregnant women were included in the final analysis, with 161 participants assigned to the combination therapy group (vaginal progesterone + cervical pessary) and 161 to the progesterone-only group. Clinical characteristics and baseline demographics were similar between the groups. The mean maternal age was 27.14 years in the combination group and 27.23 years in the progesterone-only group ( p  = 0.695). Body mass index (BMI) at enrollment averaged 24.30 kg/m² and 24.82 kg/m², respectively ( p  = 0.217) (Table  1 ). No significant differences were observed in gestational age at enrollment (36.90 vs. 37.26 weeks, p  = 0.189), gravidity, parity, education level, marital status, or behavioral risk factors such as tobacco exposure or alcohol use. Table 1 Baseline demographic and clinical characteristics of study participants Characteristic Pessary + Progesterone ( n  = 161) Progesterone Only ( n  = 161) p -value Maternal Age (years), mean ± SD 27.14 ± 5.3 27.23 ± 5.6 0.695 BMI at enrollment (kg/m²), mean ± SD 24.30 ± 3.1 24.82 ± 3.4 0.217 Gestational Age at Enrollment (weeks), mean ± SD 36.90 ± 1.8 37.26 ± 2.0 0.189 Baseline demographic and clinical characteristics of study participants Rates of preterm birth were significantly lower in the combination therapy group compared to those who received progesterone alone. Specifically, 22.4% (36/161) of patients in the combination group delivered before 37 weeks, versus 37.3% (60/161) in the progesterone-only group ( p  = 0.003). Early preterm birth before 34 weeks occurred in just 5 participants (3.1%) in the combination group, compared to 20 (12.4%) in the progesterone-only group a statistically significant reduction ( p  = 0.002). These findings are summarized in Table  2 . To identify independent predictors of preterm birth, multivariable Cox proportional hazards regression was performed. As shown in Table  2 , combination therapy (pessary + progesterone) significantly reduced the risk of preterm birth both < 37 weeks (adjusted HR: 0.65, 95% CI: 0.42–0.98) and < 34 weeks (adjusted HR: 0.30, 95% CI: 0.12–0.75). History of preterm birth and shorter cervical length were also significant predictors of preterm birth, while maternal age, BMI, and parity were not associated with risk (Table  3 ). Table 2 Preterm birth outcomes by treatment group Outcome Combination Therapy ( n  = 161) Progesterone Only ( n  = 161) Adjusted HR (95% CI)¹ Preterm Birth < 37 weeks 36 (22.4%) 60 (37.3%) 0.65 (0.42–0.98) Preterm Birth < 34 weeks 5 (3.1%) 20 (12.4%) 0.30 (0.12–0.75) 1 Adjusted Hazard Ratio (HR) from Cox proportional hazards regression models for preterm birth outcomes, controlling for maternal age, body mass index, parity, history of spontaneous preterm birth, and cervical length at diagnosis Table 3 Adjusted hazard ratios (HR) for predictors of preterm birth Covariate Preterm Birth < 37 weeks Adjusted HR (95% CI) Preterm Birth < 34 weeks Adjusted HR (95% CI) p -value Treatment Group  ‣ Pessary + Progesterone (Ref: Progesterone Only) 0.65 (0.42–0.98) 0.30 (0.12–0.75) 0.003  Maternal Age (per year increase) 1.02 (0.95–1.10) 0.98 (0.88–1.09) 0.712  BMI (per kg/m² increase) 0.97 (0.91–1.03) 0.94 (0.86–1.03) 0.201 Parity (Ref: Nulliparous)  ‣ Multiparous 0.85 (0.52–1.38) 0.70 (0.32–1.52) 0.369  History of Preterm Birth (Yes vs. No) 2.10 (1.20–3.68) 3.25 (1.50–7.05) 0.001  Cervical Length at Diagnosis (per mm decrease) 1.12 (1.05–1.20) 1.18 (1.08–1.30) < 0.001 Preterm birth outcomes by treatment group 1 Adjusted Hazard Ratio (HR) from Cox proportional hazards regression models for preterm birth outcomes, controlling for maternal age, body mass index, parity, history of spontaneous preterm birth, and cervical length at diagnosis Adjusted hazard ratios (HR) for predictors of preterm birth Several neonatal outcomes favored the combination therapy group. Mean birth weight was higher in the combination group (2.99 ± 0.52 kg) compared to the progesterone-only group (2.87 ± 0.58 kg), approaching statistical significance ( p  = 0.062). NICU admission was significantly less frequent in the combination group, with 56 neonates (34.8%) requiring admission versus 87 (54.0%) in the progesterone-only group ( p  = 0.012). Furthermore, a greater proportion of neonates in the combination group were discharged from the NICU within 3 days compared to those in the progesterone-only group (66% vs. 34%, p  = 0.012). The need for neonatal resuscitation at birth was also significantly lower in the combination group (5.6%) compared to the progesterone-only group (12.4%) ( p  = 0.032). Apgar scores were generally reassuring across both groups, and no clinically significant differences were noted. Exact counts of low Apgar scores (< 7) at 1 and 5 min were not consistently recorded and could not be analyzed. Full neonatal outcomes are presented in Table  4 . Table 4 Neonatal outcomes by treatment group Outcome Combination Therapy Progesterone Only p -value Mean Birth Weight (kg) 2.99 ± 0.52 2.87 ± 0.58 0.062 NICU stay ≤ 3 days 56 (34.8%) 87 (54.0%) 0.012 Resuscitation Required 9 (5.6%) 20 (12.4%) 0.032 Neonatal outcomes by treatment group The incidence of maternal complications was significantly lower among women who received the combination therapy. Only 4 participants (2.5%) in the combination group experienced complications, compared to 17 (10.6%) in the progesterone-only group ( p  = 0.003). Among the progesterone-only group, maternal complications included approximately 9 cases of postpartum hemorrhage, 5 infections, and 3 preeclampsia. In the combination group, complications were fewer and included 2 hemorrhages and 2 infections. No maternal deaths occurred. There were no significant differences in maternal ICU admission rates (22.9% vs. 25.5%, p  = 0.603) or in the length of hospitalization ( p  = 0.262), although trends were in favor of the combination group. The mode of delivery was similar across groups. Cesarean section was performed in 36.0% of women in the combination group and 30.4% in the progesterone-only group ( p  = 0.287). The live birth rate exceeded 85% in both groups, with no statistically significant difference. A full summary of maternal outcomes is provided in Table  5 . Table 5 Maternal outcomes by treatment group Outcome Combination Therapy ( n  = 161) Progesterone Only ( n  = 161) p -value Maternal Complications 4 (2.5%) 17 (10.6%) 0.003 Hemorrhage 2 9 Infection 2 5 preeclampsia 0 3 ICU Admission (overall) 37 (22.9%) 41 (25.5%) 0.603 Cesarean Delivery 58 (36.0%) 49 (30.4%) 0.287 Live Births 157 (97.5%) 119 (73.9%) < 0.001 Length of Hospitalization  14 days 22 (13.7%) 15 (9.3%) Maternal outcomes by treatment group No statistically significant differences were observed between the groups for the following variables: pregnancy-induced hypertension ( p  = 0.176), gestational diabetes mellitus ( p  = 0.300), maternal anxiety ( p  = 0.220), depression ( p  = 1.000), GBS colonization ( p  = 0.384), or prior history of preterm premature rupture of membranes ( p  = 0.297).

This study was designed as a retrospective cohort analysis and was conducted at Akbarabadi Hospital, a major tertiary care referral center specializing in obstetrics and gynecology. The hospital serves a large urban population and includes a level III neonatal intensive care unit. The study aimed to assess whether the use of a cervical pessary in combination with vaginal progesterone would be more effective in reducing the incidence of preterm birth among individuals with singleton pregnancies and a short cervical length, compared to individuals treated with vaginal progesterone alone. This retrospective cohort study included patients who were managed at Akbarabadi Hospital between January 1, 2015, and December 31, 2019. Ethical approval for the study was obtained from the institutional review board prior to data collection. Women eligible for inclusion were those carrying singleton pregnancies and diagnosed with a short cervical length (≤ 25 mm) between 18 weeks and 22 weeks plus 6 days of gestation. The cervical length was measured using transvaginal ultrasound as part of routine second-trimester screening. Women were included if they were 18 years of age or older, had a normal cell-free fetal DNA screening result, and had no known fetal structural anomalies. Additionally, the pregnancy had to be uncomplicated at the time of diagnosis. Women with multiple gestations, a history of cervical cerclage placement, uterine anomalies, or signs of active labor or ruptured membranes at the time of diagnosis were excluded. Other exclusion criteria included significant maternal health conditions such as thromboembolic disease, hepatic dysfunction, and a history of malignancy. Women who smoked more than 10 cigarettes per day, or had a history of alcohol or illicit drug use, were also excluded. Based on clinical documentation and treatment protocols at the time, participants were categorized into two groups. The first group, referred to as the combination therapy group, received daily vaginal micronized progesterone at a dose of 200 mg and also had an Arabin cervical pessary inserted between 18 and 22 + 6 weeks of gestation. The second group, the progesterone-only group, received the same dosage of vaginal progesterone but did not receive a pessary. Both treatments continued up to 37 weeks of gestation unless delivery occurred sooner. All women received standard antenatal care, including routine ultrasounds, screenings, and follow-up visits according to the hospital’s protocol. Because this was a retrospective, non-randomized study, the assignment of patients to combined therapy versus progesterone alone was determined by real-world clinical practice rather than by protocolized randomization. In practice, the use of a cervical pessary (Arabin pessary) was introduced into our treatment protocol for short cervix in March 2017. From this date onward, all eligible patients were routinely offered the combined treatment (pessary + progesterone), while patients before this date received progesterone only. However, pessary use was still subject to physician discretion and patient consent, and in some cases a pessary was not placed due to physician decision, financial issues, patient refusal, or contraindications. This approach to treatment allocation may introduce selection bias; however, we compared baseline characteristics between groups to ensure they were similar, and we performed adjusted analyses to account for key differences in risk factors between the two groups. All patients in the combination group were treated with an Arabin cervical pessary, a flexible silicone ring device. Pessary size was selected by the obstetrician based on digital cervical examination and standard manufacturer guidelines, aiming for a snug yet comfortable fit around the cervix. The pessary was inserted transvaginally during a speculum examination (typically between 18 and 22 weeks of gestation) by an experienced clinician, and correct positioning was confirmed on examination. After insertion, patients were monitored during regular prenatal visits for pessary position and potential side effects. They were advised that increased vaginal discharge is common with pessary use and were instructed to report any signs of infection (e.g. foul discharge, fever) or significant discomfort. The pessary was planned to remain in place until 37 weeks of gestation, at which time it was removed if the patient had not delivered. Early removal was performed if indicated for example, in the event of preterm premature rupture of membranes (PPROM), onset of active preterm labor, significant vaginal bleeding, or signs of chorioamnionitis [ 11 ]. Key contraindications to pessary placement at the time of short cervix diagnosis included evidence of intrauterine infection, lethal fetal abnormality, or ruptured membranes; if any of these were present, only progesterone was used [ 12 ]. Clinical data were collected retrospectively from the hospital’s electronic medical records system. Information retrieved included maternal demographic details such as age, body mass index (BMI), parity, gravidity, marital status, educational level, and gestational age at the time of diagnosis. Behavioral and lifestyle factors such as alcohol consumption, tobacco exposure (both active and passive), level of physical activity, and any reported illicit drug use were recorded based on standardized antenatal intake forms and patient self-report. Patients who reported alcohol or illicit drug use were excluded regardless of quantity, while smoking exclusion was applied only for > 10 cigarettes/day. Relevant obstetric history, including prior second-trimester losses, spontaneous preterm births, and history of preterm premature rupture of membranes, was also documented. Clinical comorbidities such as gestational diabetes, hypertensive disorders of pregnancy, anxiety, and depression were noted, along with screening results for Group B Streptococcus colonization. The primary outcomes evaluated were spontaneous preterm birth before 34 weeks and before 37 weeks of gestation. Secondary outcomes included neonatal birth weight, 1- and 5-minute APGAR scores, need for neonatal resuscitation at birth, and NICU admission and duration of stay. A composite neonatal morbidity variable was also created, including one or more of the following: respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), sepsis, or death prior to hospital discharge. Maternal outcomes included mode of delivery, ICU admission, duration of hospital stay, and any reported complications such as hemorrhage, infection, or maternal mortality. Maternal complications were analyzed as a composite outcome, defined as any occurrence of postpartum hemorrhage, puerperal infection, ICU admission, or other severe obstetric adverse events. No maternal deaths occurred in the study. Pregnancy outcome (live birth vs. miscarriage) was also recorded. Data analysis was performed using IBM SPSS Statistics for Windows, Version 26.0 (IBM Corp., Armonk, N.Y., USA). Continuous variables were reported as means with standard deviations and were analyzed using independent samples t-tests or the Mann–Whitney U test, depending on data distribution. Categorical variables were presented as frequencies and percentages, and comparisons between groups were made using Pearson’s chi-square test or Fisher’s exact test where appropriate. The primary association between treatment allocation and preterm birth outcomes was further analyzed using Cox proportional hazards regression to calculate hazard ratios with 95% confidence intervals. The models adjusted for maternal age, body mass index (BMI), parity, history of spontaneous preterm birth, and cervical length at diagnosis. Results are reported as adjusted hazard ratios (HR) with 95% confidence intervals (CI). A p-value of less than 0.05 was considered statistically significant.

This study demonstrates that adding a cervical pessary to standard vaginal progesterone treatment significantly improves both maternal and neonatal outcomes in women with singleton pregnancies and a short cervix. This dual approach represents a promising, non-invasive, and well-tolerated strategy for lowering the burden of preterm birth. If confirmed by future trials, it may warrant broader implementation in obstetric care guidelines. These findings, while promising, should be interpreted with caution given the retrospective design and potential for selection bias, and confirmation in randomized trials is needed before widespread clinical adoption.

The findings from this retrospective cohort study support the conclusion that combined use of vaginal progesterone and cervical pessary significantly reduces the rate of spontaneous preterm birth in individuals carrying singleton pregnancies with a short cervical length. In Iran, the reported national preterm birth rate is estimated to be 10% ranged from (5.4% to 19.85%) in recent years [ 13 ]. The live birth rate was 97.5% in the combination therapy group, which aligns with the expected range in the general population. In contrast, the progesterone-only group had a notably lower live birth rate of 73.9%, highlighting the high-risk profile of this group and possibly reflecting the benefit of combined therapy. Both early (< 34 weeks) and late (< 37 weeks) preterm birth rates were significantly lower in the combination group. Importantly, improvements extended beyond prolongation of gestation to include key neonatal outcomes such as birth weight, NICU admission, and need for resuscitation. These results provide compelling support for the potential clinical benefit of dual therapy in this high-risk population. Our findings align with previous research demonstrating the efficacy of vaginal progesterone in reducing preterm birth among individuals with a short cervix. Fonseca et al. conducted a multicenter randomized trial showing that progesterone administration significantly lowered the rate of delivery before 34 weeks in this population [ 4 ]. Hassan et al. further confirmed these results, reporting a reduction in both early preterm birth and composite neonatal morbidity using vaginal progesterone. These studies helped establish progesterone as the standard pharmacologic intervention for cervical shortening [ 6 ]. The cervical pessary has also been investigated as a non-invasive mechanical approach to preterm birth prevention. The PECEP trial by Goya et al. showed a notable reduction in early preterm birth (< 34 weeks) in pregnant women with a short cervical length treated with a cervical pessary [ 7 ]. However, subsequent trials, including the large-scale randomized study by Nicolaides et al. failed to reproduce these benefits, prompting ongoing debate about the pessary’s efficacy [ 8 ]. These discrepancies may stem from differences in patient selection, cervical length thresholds, or timing of intervention. The present study offers a potential explanation for the variability seen in prior research by examining the synergistic effect of combining these two modalities. Progesterone, which exerts anti-inflammatory and uterine-quiescence effects, may complement the mechanical support provided by the pessary. This dual mechanism has been hypothesized but not adequately tested in large clinical datasets. Our results add to a small but growing body of evidence including work by Stricker et al., Tajima et al., and Rehal et al. suggesting that combination therapy may be more effective than either treatment alone, particularly in real-world, unselected populations [ 10 , 14 , 15 ]. The improved neonatal outcomes seen in this study are clinically relevant. Lower NICU admissions and reduced resuscitation rates translate to substantial cost savings and better early neurodevelopmental trajectories. These findings echo those of Rehal et al., who also reported improved neonatal survival and reduced morbidity with early use of vaginal progesterone in twin pregnancies, a population also at high risk of cervical insufficiency. While our cohort was limited to singleton pregnancies, the underlying pathophysiologic mechanisms may be similar. From a maternal health perspective, combination therapy was associated with significantly fewer obstetric complications. This finding is especially noteworthy given concerns that adding a pessary might increase local irritation or infection. Our results suggest that, at least in carefully selected cases, pessary use does not appear to increase maternal morbidity and may even be protective when paired with progesterone. Nonetheless, several limitations must be acknowledged. First, the retrospective design introduces the potential for selection bias, despite rigorous efforts to compare baseline characteristics. This non-randomized, retrospective design means that selection bias is unavoidable, as treatment allocation was based on real-world clinical judgment rather than standardized randomization. In addition, there is the possibility of confounding by indication clinicians may have been more likely to offer pessary to women perceived to be at higher risk (e.g., with a very short cervix or prior preterm birth), which could have influenced outcomes independently of the intervention. Second, treatment allocation was not randomized, and clinical decisions may have been influenced by factors not captured in the dataset. Third, while the sample size was sufficient to identify significant differences in primary outcomes, future prospective randomized controlled trials are necessary to validate these results and to establish the most appropriate timing, duration, and patient selection criteria for implementing combined therapy. Finally, this work was a single-center study conducted in Iran, and differences in population characteristics, standard antenatal care practices, and the availability or protocols for interventions may limit the direct applicability of our results to other healthcare settings. Therefore, caution is warranted when generalizing these findings beyond similar clinical environments.

Preterm birth (PTB), defined as delivery before 37 completed weeks of gestation, affects approximately 11% of pregnancies globally and remains a leading cause of neonatal mortality and long-term morbidity [ 1 ]. In addition to its contribution to immediate complications such as respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis, PTB is associated with increased risk of cerebral palsy, neurodevelopmental delay, and significant economic burden on healthcare systems [ 2 ]. One of the most consistently validated risk factors for spontaneous PTB is a short cervical length, typically defined as ≤ 25 mm on transvaginal ultrasound in the mid-trimester. Studies have shown that cervical shortening precedes many cases of PTB and can be used to identify at-risk patients, even in the absence of a prior history of preterm delivery [ 3 ]. In such cases, vaginal progesterone has been demonstrated to reduce the incidence of PTB and improve perinatal outcomes. Notably, a pivotal randomized controlled trial [ 4 ] and subsequent meta-analyses [ 5 ] have shown that progesterone significantly reduces PTB rates in women with a short cervix, and it has since become the standard pharmacologic intervention in this population [ 6 ]. Another non-pharmacologic strategy that has gained interest is the cervical pessary, a silicone ring device inserted around the cervix to reduce direct pressure and angulation from the growing uterus. The PECEP trial [ 7 ] showed that pessary use in asymptomatic women with singleton pregnancies and short cervix significantly reduced the rate of delivery before 34 weeks. However, subsequent large randomized trials, such as that by Nicolaides et al. [ 8 ], failed to replicate this benefit, leading to ongoing debate regarding its effectiveness. Some studies suggest that the pessary may be more effective in certain subgroups, such as women with cervical length < 20 mm or specific anatomical factors [ 9 ]. Given the complementary mechanisms of action progesterone modulating uterine contractility and inflammation, and pessary providing mechanical support combined therapy has emerged as a promising yet understudied approach. Limited observational studies suggest that using vaginal progesterone alongside a cervical pessary may reduce PTB rates more than either intervention alone, but robust comparative data are lacking, particularly from large-scale real-world cohorts [ 10 ]. To address this evidence gap, we conducted a retrospective cohort study of singleton pregnancies with a short cervix to evaluate whether the combined use of vaginal progesterone and cervical pessary, initiated in the second trimester, reduces the incidence of preterm birth and improves neonatal outcomes compared to progesterone monotherapy. We hypothesized that this combined intervention would be associated with lower rates of PTB before 34 weeks, higher mean gestational age at delivery, and reduced neonatal morbidity.