Low-dose prednisone and pregnancy prolongation in threatened preterm birth a randomized pilot study
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Nikolina Penava
,
Ana Ćuk
,
Dejan Tirić
,
Oliver Vasilj
,
Vajdana Tomić
and
Vedran Stefanovic
Abstract
Objectives
To compare pregnancy prolongation and neonatal outcomes in women with signs of threatened preterm birth (PTB) and intact membranes by administration of low-doses of prednisone for 3 weeks compared to women who received standard protocols of tocolysis and respiratory distress syndrome (RDS) prophylaxis in a pilot randomized controlled trial.
Methods
We randomized 26 women with signs of threatened PTB and intact membranes between 24 and 34 weeks of gestation to either continued prednisone administration for 3 weeks following the initiation of the standard protocol (intervention group) or standard therapy for threatened PTB (control group). The primary outcome was the gestational length in women with and without using low-doses of prednisone. The secondary outcome included incidence of RDS, intraventricular hemorrhage, necrotizing enterocolitis, the need for mechanical ventilation, and perinatal mortality in newborns from both study groups.
Results
Participants in the intervention group had significantly longer pregnancy prolongation than the control group (65.38 vs. 40.54 days, p=0.001). Although the difference was not statistically significant (p=0.153), the gestational age at delivery in the intervention group (38.35 weeks) was 10 days longer than in the control group (36.89 weeks). There were no significant differences between the groups in neonatal outcomes.
Conclusions
The first pilot randomized controlled study on low-dose prednisone in threatened PTB and intact membranes suggests it may prolong pregnancy without adverse neonatal outcomes. Due to the small sample size and single-centre design, these preliminary findings should be interpreted with caution and confirmed in larger, adequately powered trials.
Introduction
According to the World Health Organization, PTB is defined as birth before 37 weeks of gestation, affects approximately 11 % of pregnancies worldwide and is a leading cause of infant mortality and morbidity [1]. Tocolysis can delay labour for up to 7 days but does not prevent PTB or improve neonatal outcomes [2]. Its main goal is to extend pregnancy by at least 48 h to enable antenatal corticosteroid (CS) therapy, reducing neonatal mortality, RDS, intraventricular hemorrhage, and necrotizing enterocolitis [3]. So far, the most useful intervention for improving neonatal outcomes is antenatal CS administration either until the 34th week of pregnancy or even up to 36+6 weeks [4]. Despite advances in prenatal medicine, global PTB rates remain unchanged, likely due to its multifactorial and often unknown aetiology, which complicates the development of effective preventive therapies [5]. Inflammation plays multiple roles in pregnancy, being essential for implantation, fetal tolerance, and labour initiation. It also represents a critical pathophysiological mechanism in PTB. It contributes to membrane weakening, cervical remodelling, and stimulation of uterine contractility [6]. Previously, infection was considered the main driver of PTB, promoting the use of prophylactic antibiotics. However, such interventions did not show a benefit and may alter vaginal flora, increase resistance, and worsen neonatal outcomes [7], 8]. Although infection is an important factor, particularly in cases of preterm premature rupture of membranes (PPROM), recent research emphasizes that most spontaneous PTBs with intact membranes are mediated by sterile inflammation and immune dysregulation at the maternal-fetal interface [9], [10], [11]. Inflammation may be triggered by microorganisms (infection-associated) or occur in the absence of detectable pathogens, referred to as sterile intra-amniotic inflammation. While intrauterine infection, especially bacterial, is a major contributor to PTB, sterile inflammation is a pathogen-free immune response likely driven by tissue damage, necrosis, or cellular stress [10]. Such inflammation may precede labour even without infection, particularly in pregnancies characterized by maternal immune dysregulation, including a reduced proportion of regulatory T cells [9], 11]. Although initial triggers differ, both infectious and sterile pathways converge through common inflammatory mechanisms involving various cytokines and immune mediators, ultimately leading to PTB. While nonsteroidal anti-inflammatory drugs may serve as tocolytics, their use is restricted to pregnancies below 32 weeks and limited to 2–3 days due to risks such as fetal renal impairment and premature ductus arteriosus closure [12].
CSs have anti-inflammatory and immunosuppressive effects and can be either natural or synthetic. Natural ones are essential for regulating metabolism, immunity, and inflammation, while synthetic forms treat various diseases. Oral CSs are one of the leading therapies for autoimmune diseases, commonly affecting women of childbearing age. During pregnancy, they are used to treat maternal diseases like adrenal insufficiency, thrombocytopenia, organ transplant recovery, inflammatory bowel diseases, lupus, scleroderma, and hyperemesis [13]. Long-acting CSs (betamethasone, dexamethasone) cross the placental barrier and are used to treat fetal diseases such as fetal lupus and congenital adrenal hyperplasia and to prevent RDS. In contrast, intermediate-acting CSs (prednisone, methylprednisolone) have limited placental transfer and are primarily used to treat maternal diseases [14]. Under stress-free conditions, the adrenal gland produces about 20 mg of hydrocortisone (cortisol) daily, equivalent to 5–7 mg of prednisone [15]. Higher doses are supraphysiological and may cause long-term effects like hypothalamic–pituitary–adrenal axis suppression and iatrogenic Cushing’s syndrome. However, no suppression occurs with use under three weeks, regardless of dosage [16].
Idiopathic PTB often results from an immune imbalance between the mother and fetus, involving T cell activation, macrophages, and the fetal immune system [9], 11], 17]. Although inflammation is a key factor, current therapies primarily target contractions rather than addressing its underlying cause. Prednisone, a well-established and safe drug during pregnancy, has never been used for this purpose. This is the first pilot randomized, placebo-controlled trial designed to evaluate its efficacy as an anti-inflammatory therapy for prolonging pregnancy and reducing neonatal morbidity in singleton pregnancies with threatened PTB and intact membranes.
Materials, methodology, and study plan
This randomized experimental clinical pilot study was conducted from 8th November 2023 to 2nd December 2024 at the Department of Gynecology and Obstetrics, University Clinical Hospital Mostar, Bosnia and Herzegovina. The study was approved by the Ethics Committee of the University Clinical Hospital Mostar (Approval No. 1236/23) and is registered on ClinicalTrials.gov under the identifier NCT06103227.
Participants
Pregnant women included in the study met the following criteria: primiparity, singleton pregnancy between 24 + 0 and 34 + 0 weeks, and signs of threatened PTB at admission. Gestational age was determined by using fetal crown-rump-length at ultrasound examination performed between 10 + 0 and 13 + 6 gestational weeks according to the last menstrual period. Threatened PTB was defined as regular uterine contractions (>4 in 20 min or>8 in 60 min), with or without bleeding, along with cervical dilation greater than 2 cm or cervical length less than 20 mm, confirmed by transvaginal ultrasound or clinical progression.
Exclusion criteria included contraindications to tocolysis or systemic CSs therapy, such as intrauterine fetal death, lethal fetal anomaly, abnormal cardiotocography recording, severe preeclampsia or eclampsia, hemodynamically significant bleeding, laboratory or microbiological signs of infection, uncontrolled diabetes, ongoing CS therapy for underlying conditions, severe liver impairment or PPROM.
Each participant was assigned a number using a random number generator (https://www.randomizer.org/), which employs JavaScript’s “Math.random” method. All participants gave informed consent before enrolment and were randomly assigned to either the control group (threatened PTB without prednisone) or the intervention group (threatened PTB with prednisone).
Intervention
At admission, cervical swabs were collected from all participants to test for Ureaplasma species, Mycoplasma hominis, and Chlamydia trachomatis, along with urine analysis for culture and venous blood samples for analysis of complete blood count, differential blood count, C-reactive protein (CRP), liver function tests and urine sediment analysis.
If inclusion/exclusion criteria were met, a standardized two-day therapy was initiated, including tocolysis, RDS prophylaxis (dexamethasone 6 mg twice daily), and magnesium sulfate for neuroprotection. Indomethacin was used for tocolysis up to 32 weeks, and nifedipine from 32–34 weeks. Magnesium sulphate was given as a 4 g bolus followed by a 1 g/h infusion. After two days, if the cervical swab and urine culture results were sterile, participants were randomized. Cases with cervical or urinary infections were excluded to minimize confounding, as most infections occur through the ascending route [18]. The control group completed standard therapy, while the intervention group received a low-dose oral prednisone regimen for three weeks, including the day of RDS prophylaxis. If tocolysis was completed at 34 + 0 weeks, prednisone continued, given that almost 80 % of PTBs are late preterm [19]. Dosing was 5 mg every other morning for participants<90 kg and daily for those≥90 kg, with the alternate-day dose providing an immunomodulatory effect with fewer adverse effects [20]. Blood glucose was measured before RDS prophylaxis to prevent misattribution of corticosteroid-induced effects. Blood pressure was monitored twice daily with maternal and fetal monitoring adjusted based on medical conditions. Participants were discharged two days after tocolysis cessation if they had not given birth.
Sample preparation and determination methods
Biochemical analyses were conducted in the Laboratory Diagnostics Department of SKB Mostar. Blood counts were measured using the Sysmex XN 1,000 analyzer, while CRP and liver function tests were performed on the Beckman Coulter DxC analyzer. Urine cultures and cervical swabs were analyzed in the Microbiology and Molecular Diagnostics Department. Ureaplasma and Mycoplasma were identified with Mycoplasma IST two tests, and Chlamydia detection used Enzyme Immunoassay antigen tests.
Statistical analysis
The sample size for this pilot study was determined using a priori power analysis for a two-tailed t-test comparing two independent means. With α=0.05, 95 % power, an effect size of 1.5, and an equal allocation ratio (1:1), the required sample was 26 participants (13 per group) to ensure sufficient statistical power.
Data were entered into Microsoft Excel and analyzed using SPSS version 21 (SPSS Inc., Chicago, IL). Descriptive, parametric, and nonparametric methods were applied based on data distribution and assessed using the Kolmogorov–Smirnov test. Categorical variables were reported as frequencies and percentages, while continuous variables were presented as mean ± standard deviation or median (interquartile range). Differences between categorical variables were analyzed using the Chi-square or Fisher’s exact test, while continuous variables were compared using the Student’s t-test, Mann–Whitney U test, one-way ANOVA, or Kruskal–Wallis test, with post-hoc analysis via Scheffe’s test or Kruskal–Wallis Z test. Paired t-tests or Wilcoxon signed-rank tests assessed paired variables, while Pearson’s or Spearman’s coefficients evaluated correlations. Logistic regression identified risk factors for preterm birth and other outcomes, with statistical significance set at p<0.05.
Results
Characteristics of the study population
Demographic, clinical and laboratory characteristics of the study population are displayed in Table 1. All participants were Caucasian, and there were no significant differences in laboratory variables between the groups. Women in the intervention group were significantly younger than those in the control group (p=0.036); however, this difference is not clinically relevant.
Demographic, biochemical, perinatal characteristics and pregnancy prolongation of the study population.
| Groups | t | p-Value | ||||
|---|---|---|---|---|---|---|
| Experimental | Control | |||||
| X‾ | SD | X‾ | SD | |||
| Maternal age, years | 27.62 | 3.906 | 31.46 | 4.858 | 2.225 | 0.036 |
| Leukocytes, × 109/L | 9.838 | 3.4316 | 11.700 | 1.8285 | 1.726 | 0.097 |
| Hemoglobin g/dL | 115.54 | 8.569 | 115.31 | 7.398 | 0.073 | 0.942 |
| Gestational age at delivery, weeks | 38.3531 | 1.98213 | 36.8992 | 2.94259 | 1.477 | 0.153 |
| Birthweight, g | 3,435.38 | 435.443 | 2,997.69 | 642.186 | 2.034 | 0.053 |
| Birth length, cm | 54.00 | 2.799 | 50.85 | 4.259 | 2.231 | 0.035 |
| Pregnancy prolongation in days | 65.38 | 18.182 | 40.54 | 16.133 | 3.685 | 0.001 |
Perinatal outcomes
Table 1 shows that pregnancy prolongation was notably longer in the intervention group, with a mean of 65.38 days compared to 40.54 days in the control group (p=0.001). Gestational age at delivery and birth weight showed no statistically significant differences. However, the intervention group had a slightly higher gestational age at delivery (38.35 weeks) than the control group (36.89 weeks). Newborns in the experimental group were significantly taller (p=0.035), and their higher birth weight was not statistically significant (p=0.053).
Additional observations
There were no statistically significant differences in BMI between groups at the beginning or end of pregnancy (Figures 1 and 2).
Box plot of BMI at the beginning of pregnancy in the experimental and control groups.
Box plot of BMI at birth in the experimental and control groups.
Categorical variables
The groups had no significant differences in smoking status and maternal comorbidities (Table 2). None of the participants had hypertension or glucose metabolism disorders, and two were overweight exceeding 90 kg, one in each group. In the control group, four participants had thyroid disorders: two had hypothyroidism, one had undergone a thyroidectomy due to papillary carcinoma, and one had Hashimoto’s disease. In the intervention group there were four patients: two participants had Hashimoto’s disease, one had depression and was taking antidepressants, and one was obese with a BMI>35 kg/m2.
Differences in the prevalence of comorbidities, smoking, intraventricular hemorrhage, incidence of RDS, and mechanical ventilation between groups.
| Groups | χ2 | p-Valuea | ||||
|---|---|---|---|---|---|---|
| Experimental | Control | |||||
| n | % | n | % | |||
| Maternal comorbidities | 4 | 30.77 | 4 | 30.77 | 0 | 1 |
| Smoking (5 cigarettes/day) | 1 | 7.7 | 0 | 0.0 | 0 | 1a |
| Intraventricular hemorrhage | 0 | 0.0 | 2 | 15.4 | 0.542 | 0.480a |
| RDS | 0 | 0.0 | 1 | 7.7 | 0 | 1a |
| Mechanical ventilation | 0 | 0.0 | 1 | 7.7 | 0 | 1a |
-
aFisher’s exact test.
No neonatal complications were observed in the intervention group. In contrast, in the control group, there were two cases of intraventricular haemorrhage, one case of RDS, and one newborn requiring mechanical ventilation. Although the intervention group had better neonatal outcomes, the differences were not statistically significant (Table 2). Despite the lack of statistical significance, the complete absence of complications in the intervention group is clinically important. Confidence intervals have been included to convey the degree of uncertainty, and the possibility of a Type II error should be considered given the limited sample size (Table 3).
Distribution of neonatal complications by group with statistical significance and uncertainty estimates.
| Groups | χ2 | p-Valuea | Uncertainty coefficient | 95 % CI | |||||
|---|---|---|---|---|---|---|---|---|---|
| Experimental | Control | ||||||||
| n | % | n | % | Lower | Upper | ||||
| Intraventricular hemorrhage | 0 | 0.0 | 2 | 15.4 | 0.542 | 0.480a | 0.117 | 0.044 | 0.238 |
| RDS | 0 | 0.0 | 1 | 7.7 | 0 | 1a | 0.064 | 0.034 | 0.177 |
| Mechanical ventilation | 0 | 0.0 | 1 | 7.7 | 0 | 1a | 0.064 | 0.034 | 0.177 |
-
aFisher’s exact test.
Figure 3 shows that mean gestational age at randomization was 29 weeks in the intervention group and 31 weeks in the control group, with no statistically significant difference. However, the median gestational age at the start of treatment was lower in the intervention group.
Box plot of gestational age at randomization.
Discussion
We conducted the first pilot randomized controlled trial suggesting that low-dose prednisone (≤10 mg/day) significantly prolongs pregnancy in threatened PTB with intact membranes, highlighting its potential benefits beyond conventional use.
However, due to the small sample size (n=26) and the absence of blinding, the strength of these conclusions is limited and findings should be interpreted with caution.
Previous data on oral CSs use in pregnancy remain inconclusive, particularly regarding their effects on PTB, low birth weight, preeclampsia, and gestational diabetes. Observational studies on prednisone for the treatment of autoimmune diseases suggest that higher doses (>10 mg) are often required in severe cases and are linked to shorter gestation. However, disease severity was likely the main driver of adverse obstetric outcomes [21], 22].
As inflammation plays a crucial role in PTB, ongoing research investigates anti-inflammatory treatments for its prevention, including repurposed drugs like simvastatin, melatonin, and naltrexone, which show promise but lack pregnancy-specific safety data [23]. Other potential therapies, including interleukin (IL) inhibitors, prostaglandin, and Toll-like receptor antagonists, remain in early research stages [24], 25]. Due to potential long-term effects, these medications require further safety evaluation before clinical use.
Animal studies suggest that long-acting CSs prolong pregnancy with a tocolytic effect. Galaz et al. found that betamethasone treated sterile intra-amniotic inflammation and extended pregnancy in murine models without increasing neonatal mortality associated with high mobility group box 1 [26]. Similarly, dexamethasone in rhesus models reduced uterine contractility in cases of amniotic inflammation or infection by suppressing IL-1β-induced activity and lowering prostaglandin levels. Its tocolytic effect is believed to stem from reduced estrogen biosynthesis and inhibition of tumor necrosis factor-alpha (TNF-α) and leukocyte migration [27]. These results highlight the potential effectiveness of CSs in managing PTB associated with inflammation or infection. In animal models, long-acting CSs were used for up to 3 days, as prolonged administration would pose a risk to the fetus. Therefore, we opted for an intermediate-acting CS, prednisone, due to its common use in pregnancy and minimal placental transfer. The fetus is protected from maternal and certain synthetic CSs through two mechanisms. First, protein-bound steroids cannot cross the placental barrier. Second, the placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts cortisol and prednisolone into their inactive forms, cortisone and prednisone. These mechanisms maintain a maternal-to-fetal prednisolone concentration ratio of approximately 10:1, as maternal liver activation of prednisone to prednisolone is reversed by placental metabolism before reaching the fetus [28]. Fluorinated (dexamethasone, betamethasone) and methylated CSs (methylprednisolone) resist oxidation by 11β-HSD2, whereas prednisone and prednisolone are efficiently inactivated.
The weight-based dosing regimen implemented in our study represents a physiology-guided approach, accounting for increased CS binding globulin, plasma volume expansion, and hepatic clearance during pregnancy, especially in women with higher BMI, to optimize immunomodulatory efficacy while minimizing cumulative glucocorticoid exposure [29].
Safety profile of intermediate acting CSs in pregnancy
Systemic side effects depend exclusively on dose and treatment duration, with short-term use (<30 days) posing risks only at high doses [15]. Low-dose CSs used for up to three weeks are safe for mother and fetus, with no increased infection risk or contraindications for women with glucose metabolism disorders, as hyperglycemia risk rises only above 30 mg of prednisone daily [21], 22], 30]. This dose effectively reduces inflammation without increasing infection risk, even in the presence of endotoxemia [31]. In our study, initiation after 24 weeks, well beyond organogenesis, aligns with increased 11β-HSD2 activity, enhancing fetal protection [32]. Also, intermediate-acting CSs effectively manage severe COVID-19 in pregnancy by controlling cytokine storms, similar to PTB. They suppress inflammation, reducing TNF-α, IL-1, and IL-6, thereby mitigating disease severity [33]. Based on the RECOVERY study, leading gynecological societies recommend intermediate-acting CSs for their limited placental transfer, ensuring fetal protection [34].
CSs and inflammation
CSs have strong anti-inflammatory and immunosuppressive effects through glucocorticoid receptors, activating genomic and non-genomic pathways depending on dose and duration [35]. Immunity regulation is achieved by suppressing pro-inflammatory gene expression, inhibiting cytokine secretion, destabilizing mRNA coding for IL-1, IL-2, IL-6, IL-8, and TNF, and suppressing prostaglandin synthesis by inhibiting cyclooxygenase-2 [36], 37]. Genomic effects depend on receptor binding, while non-genomic actions occur at high drug concentrations via biological membranes. Although anti-inflammatory and immunosuppressive effects share molecular pathways, clinically relevant immunosuppression typically occurs only at high cumulative doses and with prolonged exposure, mostly when CSs are administered intravenously, but also with high-dose oral regimens. Low-dose prednisone mainly provides anti-inflammatory and immunomodulatory effects without causing clinically significant systemic immunosuppression. At low doses of prednisone, approximately 50 % of receptors are saturated, limiting genomic effects while exerting immunomodulatory activity sufficient for the control of autoimmune diseases without inducing systemic immunosuppression [38], 39]. Although prednisone is primarily indicated for autoimmune conditions, it has occasionally been used in obstetric settings involving immune-mediated disorders such as repeated implantation failure and antiphospholipid syndrome despite its limited and off-label application. In such contexts, low-dose prednisone has shown the potential to improve pregnancy outcomes, particularly by enhancing success rates following prior implantation failure [40]. Its benefits come from modulating maternal T-cell subsets, enhancing immune tolerance, reducing inflammation, and supporting maternal-fetal homeostasis [41]. Recent meta-analyses suggest that adding low-dose prednisone to aspirin and low molecular weight heparin reduces pregnancy loss in women with antiphospholipid syndrome and poor obstetric history [42], 43]. Given its well-established safety profile, low-dose prednisone is considered the preferred oral CS for the management of maternal rheumatologic and musculoskeletal conditions during pregnancy, as recommended by the American College of Obstetricians and Gynecologists and the American College of Rheumatology [44], 45].
Strengths and limitations
This is the first randomized, experimental pilot study to evaluate the efficacy of low-dose prednisone in prolonging pregnancy and to explore its potential repurposing beyond conventional indications in cases of threatened PTB with intact membranes. For decades, prednisone has been used during pregnancy primarily in the management of autoimmune diseases, often associated with adverse obstetric outcomes. However, these outcomes are more likely attributable to underlying disease activity and high CS doses than to the drug itself. Results of our pilot study showed a significant prolongation of pregnancy in the intervention group, suggesting a potential benefit that warrants further investigation. The study population was clinically homogeneous, with all participants admitted at a similar gestational age. There were no statistically significant differences in gestational age at delivery between the groups, though the intervention group reached full term (38.35 weeks), whereas the control group did not (36.89 weeks). Even a modest prolongation of pregnancy may positively influence long-term outcomes. Although differences in neonatal outcomes did not reach statistical significance, the absence of adverse events in the intervention group may be clinically meaningful, particularly as all participants reached term. Moreover, low-dose prednisone has not been associated with adverse neonatal effects, especially when administered short-term. These preliminary findings suggest a promising strategy for reducing the incidence of late preterm birth and its associated risks of neurodevelopmental delays, including cognitive, speech, and behavioural impairments later in life [46]. Importantly, a substantial proportion of preterm neonates develop RDS and poor outcomes despite timely antenatal CSs prophylaxis, often due to therapeutic nonresponsiveness [47]. Delaying delivery with low-dose prednisone may mitigate such outcomes by suppressing inflammation, which is recognized as a central driver of neonatal morbidity and CS. Given that the majority of PTBs occur in the late preterm period and are driven by multifactorial or idiopathic mechanisms rather than overt infection, continuation of prednisone beyond 34 weeks was pragmatically justified [48]. By modulating inflammation at the maternal-fetal interface, low-dose prednisone may complement conventional therapy in this critical gestational window, potentially improving neonatal outcomes, though these findings remain preliminary and require validation in larger randomized controlled trials.
The study has several limitations, including a small sample size, the absence of blinding, and the inability to determine the precise aetiology of PTB. Without amniocentesis, it was not possible to distinguish between sterile inflammation, maternal-fetal immune dysregulation, and potential subclinical microbial infection [49]. Despite growing interest in biomarker-guided approaches, currently available non-invasive tools, such as fetal fibronectin and maternal serum cytokines, lack sufficient predictive accuracy and are not routinely available in all clinical settings [50], 51]. Amniocentesis remains the gold standard for distinguishing between microbial and sterile intra-amniotic inflammation and may enhance diagnostic precision in selected high-risk cases [49]. However, due to its invasive nature, dependence on specialized personnel, and limited feasibility in general obstetric care, there is a pressing need to develop safe, accessible, non-invasive biomarkers capable of identifying immune-mediated mechanisms and guiding individualized treatment strategies. Furthermore, variability in diagnostic criteria for PTB across gynecological societies and the unavailability of fetal fibronectin testing at our institution may have affected diagnostic accuracy. Although the statistical power calculated for our primary outcome was high (95.6 %), the limited sample size substantially increases the possibility of a Type II error regarding secondary neonatal outcomes, and thus caution in interpretation remains warranted. While the absence of neonatal complications in the intervention group is clinically intriguing, the study appears underpowered for secondary outcomes. Despite these limitations, the study provides valuable preliminary insights into the potential role of low-dose prednisone in prolonging pregnancy, achieving term delivery, and potentially improving long-term neonatal outcomes, all of which warrant further investigation in well-powered, double-blinded randomized controlled trials.
Conclusions
An optimal therapy for prolonging pregnancy in cases of PTB has not yet been established. Although prednisone has been used in obstetric care for decades, it has not previously been evaluated for this specific indication. This pilot randomized controlled trial provides preliminary evidence that low-dose prednisone may be effective in prolonging pregnancy in women with threatened PTB and intact membranes without adverse neonatal outcomes. However, the study’s limited sample size (n=26), single-centre setting, and lack of blinding substantially constrain the strength and generalizability of the conclusions. These limitations are inherent to pilot studies but must be addressed in larger, rigorously designed double-blinded randomized trials to validate these findings and reduce potential bias.
Although current biomarkers such as fetal fibronectin and inflammatory cytokines lack sufficient predictive accuracy for routine clinical use, the development of novel, validated stratification tools is essential to improve diagnostic precision and identify patients most likely to benefit from immunomodulatory strategies. Such advancements could pave the way for personalized therapeutic interventions in cases of PTB driven by maternal-fetal immune dysregulation and sterile inflammation.
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Research ethics: The data from this study are unavailable due to ethical restrictions but can be requested from the corresponding author in line with institutional guidelines and regulations. The study was approved by the Ethics Committee of the University Clinical Hospital Mostar (ID 1236/23), conducted in accordance with the Declaration of Helsinki (2013), and registered at ClinicalTrials.gov (ID NCT06103227).
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Informed consent: Informed consent was obtained from all participants included in this study.
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Author contributions: V.S. and N.P. designed the study. N.P., A.C. and D.T. collected the data, V.S., V.T., and O.V. analysed the data. N.P. wrote the first draft of the manuscript. All authors contributed to the final version of the manuscript and approved it for submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors state no conflict of interest.
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Research funding: None declared.
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Data availability: Not applicable.
References
1. Blencowe, H, Cousens, S, Chou, D, Oestergaard, M, Say, L, Moller, AB, et al.. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health 2013;10:S2. https://doi.org/10.1186/1742-4755-10-s1-s2.Search in Google Scholar
2. Lamont, RF, Jørgensen, JS. Safety and efficacy of tocolytics for the treatment of spontaneous preterm labour. Curr Pharm Des 2019;25:577–92. https://doi.org/10.2174/1381612825666190329124214.Search in Google Scholar PubMed
3. McGoldrick, E, Stewart, F, Parker, R, Dalziel, SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2020;12:CD004454. https://doi.org/10.1002/14651858.CD004454.pub4.Search in Google Scholar PubMed PubMed Central
4. Stock, S, Thomson, A, Papworth, S, The Royal College of Obstetricians and Gynaecologists. Antenatal corticosteroids to reduce neonatal morbidity and mortality. BJOG Int J Obstet Gynaecol 2022;129:e35–60. https://doi.org/10.1111/1471-0528.17027.Search in Google Scholar PubMed
5. Ohuma, EO, Moller, AB, Bradley, E, Chakwera, S, Hussain-Alkhateeb, L, Lewin, A, et al.. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet 2023;402:1261–71.10.1016/S0140-6736(23)00878-4Search in Google Scholar PubMed
6. Romero, R, Espinoza, J, Gonçalves, LF, Kusanovic, JP, Friel, LA, Nien, JK. Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med 2006;11:317–26. https://doi.org/10.1016/j.siny.2006.05.001.Search in Google Scholar PubMed PubMed Central
7. Thinkhamrop, J, Hofmeyr, GJ, Adetoro, O, Lumbiganon, P, Ota, E. Antibiotic prophylaxis during the second and third trimester to reduce adverse pregnancy outcomes and morbidity. Cochrane Database Syst Rev 2015;1:CD002250. https://doi.org/10.1002/14651858.CD002250.pub3.Search in Google Scholar PubMed PubMed Central
8. Care, A, Nevitt, SJ, Medley, N, Donegan, S, Good, L, Hampson, L, et al.. Interventions to prevent spontaneous preterm birth in women with singleton pregnancy who are at high risk: systematic review and network meta-analysis. Br Med J 2022:e064547. https://doi.org/10.1136/bmj-2021-064547.Search in Google Scholar PubMed PubMed Central
9. Gomez-Lopez, N, Galaz, J, Miller, D, Farias-Jofre, M, Liu, Z, Arenas-Hernandez, M, et al.. The immunobiology of preterm labor and birth: intra-amniotic inflammation or breakdown of maternal-fetal homeostasis. Reproduire 2022;164:R11–45. https://doi.org/10.1530/rep-22-0046.Search in Google Scholar PubMed PubMed Central
10. Romero, R, Miranda, J, Chaiworapongsa, T, Korzeniewski, SJ, Chaemsaithong, P, Gotsch, F, et al.. Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol 2014;72:458–74. https://doi.org/10.1111/aji.12296.Search in Google Scholar PubMed PubMed Central
11. Koucky, M, Lastuvka, Z, Koprivova, H, Cindrova-Davies, T, Hrdy, J, Cerna, K, et al.. Reduced number of regulatory T cells in maternal circulation precede idiopathic spontaneous preterm labor in a subset of patients. Am J Obstet Gynecol 2025;232:222.e1–222.e11. https://doi.org/10.1016/j.ajog.2024.11.001.Search in Google Scholar PubMed
12. Xiong, Z, Pei, S, Zhu, Z. Four kinds of tocolytic therapy for preterm delivery: systematic review and network meta-analysis. J Clin Pharm Therapeut 2022;47:1036–48. https://doi.org/10.1111/jcpt.13641.Search in Google Scholar PubMed
13. McGee, DC. Steroid use during pregnancy. J Perinat Neonatal Nurs 2002;16:26–39. https://doi.org/10.1097/00005237-200209000-00004.Search in Google Scholar PubMed
14. Homar, V, Grosek, S, Battelino, T. High-dose methylprednisolone in a pregnant woman with Crohn’s disease and adrenal suppression in her newborn. Neonatology 2008;94:306–9. https://doi.org/10.1159/000151652.Search in Google Scholar PubMed
15. Waljee, AK, Rogers, MAM, Lin, P, Singal, AG, Stein, JD, Marks, RM, et al.. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. Br Med J 2017;357:j1415. https://doi.org/10.1136/bmj.j1415.Search in Google Scholar PubMed PubMed Central
16. Axelrod, L. Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin N Am 2003;32:367–83.10.1016/S0889-8529(03)00008-2Search in Google Scholar PubMed
17. Gomez-Lopez, N, Arenas-Hernandez, M, Romero, R, Miller, D, Garcia-Flores, V, Leng, Y, et al.. Regulatory T cells play a role in a subset of idiopathic preterm labor/birth and adverse neonatal outcomes. Cell Rep 2020;32:108041. https://doi.org/10.1016/j.celrep.2020.107874.Search in Google Scholar PubMed PubMed Central
18. Romero, R, Gomez-Lopez, N, Winters, AD, Jung, E, Shaman, M, Bieda, J, et al.. Evidence that intra-amniotic infections are often the result of an ascending invasion – a molecular microbiological study. J Perinat Med 2019;47:915–31. https://doi.org/10.1515/jpm-2019-0297.Search in Google Scholar PubMed PubMed Central
19. Martin, JA, Hamilton, BE, Osterman, MJK, Driscoll, AK. Births: final data for 2019. Natl Vital Stat Rep 2021;70:1–51.Search in Google Scholar
20. Fukui, S, Nakai, T, Kawaai, S, Ikeda, Y, Suda, M, Nomura, A, et al.. Advantages of an alternate-day glucocorticoid treatment strategy for the treatment of IgG4-related disease: a preliminary retrospective cohort study. Medicine 2022;101:e30932. https://doi.org/10.1097/md.0000000000030932.Search in Google Scholar PubMed PubMed Central
21. Palmsten, K, Rolland, M, Hebert, MF, Clowse, ME, Schatz, M, Xu, R, et al.. Patterns of prednisone use during pregnancy in women with rheumatoid arthritis: daily and cumulative dose. Pharmacoepidemiol Drug Saf 2018;27:430–8. https://doi.org/10.1002/pds.4410.Search in Google Scholar PubMed PubMed Central
22. Palmsten, K, Bandoli, G, Vazquez-Benitez, G, Xi, M, Johnson, DL, Xu, R, et al.. Oral corticosteroid use during pregnancy and risk of preterm birth. Rheumatology 2020;59:1262–71. https://doi.org/10.1093/rheumatology/kez405.Search in Google Scholar PubMed PubMed Central
23. Zierden, HC, Shapiro, RL, DeLong, K, Carter, DM, Ensign, LM. Next generation strategies for preventing preterm birth. Adv Drug Deliv Rev 2021;174:190–209. https://doi.org/10.1016/j.addr.2021.04.021.Search in Google Scholar PubMed PubMed Central
24. Habelrih, T, Ferri, B, Côté, F, Sévigny, J, Augustin, TL, Sawaya, K, et al.. Preventing preterm birth: exploring innovative solutions. Clin Perinatol 2024;51:497–510. https://doi.org/10.1016/j.clp.2024.02.006.Search in Google Scholar PubMed
25. Pavlidis, I, Stock, SJ. Preterm birth therapies to target inflammation. J Clin Pharmacol 2022;62:S79–93. https://doi.org/10.1002/jcph.2107.Search in Google Scholar PubMed PubMed Central
26. Galaz, J, Romero, R, Arenas-Hernandez, M, Panaitescu, B, Para, R, Gomez-Lopez, N. Betamethasone as a potential treatment for preterm birth associated with sterile intra-amniotic inflammation: a murine study. J Perinat Med 2021;49:897–906. https://doi.org/10.1515/jpm-2021-0049.Search in Google Scholar PubMed PubMed Central
27. Sadowsky, DW, Novy, MJ, Witkin, SS, Gravett, MG. Dexamethasone or interleukin-10 blocks interleukin-1β-induced uterine contractions in pregnant rhesus monkeys. Am J Obstet Gynecol 2003;188:252–63. https://doi.org/10.1067/mob.2003.70.Search in Google Scholar PubMed
28. Murphy, VE, Fittock, RJ, Zarzycki, PK, Delahunty, MM, Smith, R, Clifton, VL. Metabolism of synthetic steroids by the human placenta. Placenta 2007;28:39–46. https://doi.org/10.1016/j.placenta.2005.12.010.Search in Google Scholar PubMed
29. Zhao, W. Pregnancy alters the disposition of prednisone and prednisolone. Pharm Res 2018;35:111. https://doi.org/10.1007/s11095-018-2396-0.Search in Google Scholar
30. den Uyl, D, van Raalte, DH, Nurmohamed, MT, Lems, WF, Bijlsma, JWJ, Hoes, JN, et al.. Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: balance between diabetogenic effects and inflammation reduction. Arthritis Rheum 2012;64:639–46. https://doi.org/10.1002/art.33378.Search in Google Scholar PubMed
31. de Kruif, MD, Lemaire, LC, Giebelen, IA, van Zoelen, MAD, Pater, JM, van den Pangaart, PS, et al.. Prednisolone dose-dependently influences inflammation and coagulation during human endotoxemia. J Immunol 2007;178:1845–51. https://doi.org/10.4049/jimmunol.178.3.1845.Search in Google Scholar PubMed
32. Murphy, VE, Clifton, VL. Alterations in human placental 11beta-hydroxysteroid dehydrogenase type 1 and 2 with gestational age and labour. Placenta 2003;24:739–44.10.1016/S0143-4004(03)00103-6Search in Google Scholar PubMed
33. Lamontagne, F, Brower, R, Meade, M. Corticosteroid therapy in acute respiratory distress syndrome. CMAJ (Can Med Assoc J) 2013;185:216–21. https://doi.org/10.1503/cmaj.120582.Search in Google Scholar PubMed PubMed Central
34. Ssekandi, AM, Sserwanja, Q, Olal, E, Kawuki, J, Adam, MB. Corticosteroids use in pregnant women with COVID-19: recommendations from available evidence. J Multidiscip Healthc 2021;14:659–63. https://doi.org/10.2147/JMDH.S301255.Search in Google Scholar PubMed PubMed Central
35. Buttgereit, F, Da Silva, JAP, Boers, M, Burmester, G, Cutolo, M, Jacobs, J, et al.. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 2002;61:718–22. https://doi.org/10.1136/ard.61.8.718.Search in Google Scholar PubMed PubMed Central
36. Cain, DW, Cidlowski, JA. Immune regulation by glucocorticoids. Nat Rev Immunol 2017;17:233–47. https://doi.org/10.1038/nri.2017.1.Search in Google Scholar PubMed PubMed Central
37. Busillo, JM, Cidlowski, JA. The five Rs of glucocorticoid action during inflammation: ready, reinforce, repress, resolve, and restore. Trends Endocrinol Metab 2013;24:109–19. https://doi.org/10.1016/j.tem.2012.11.005.Search in Google Scholar PubMed PubMed Central
38. Silva JAP, D, Jacobs, JWG, Kirwan, JR, Boers, M, Saag, KG, Inês, LBS, et al.. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis 2006;65:285–93. https://doi.org/10.1136/ard.2005.038638.Search in Google Scholar PubMed PubMed Central
39. Da Silva, JA, Bijlsma, JW. Optimizing glucocorticoid therapy in rheumatoid arthritis. Rheum Dis Clin N Am 2000;26:859–80.10.1016/S0889-857X(05)70173-3Search in Google Scholar PubMed
40. Huang, Q, Wu, H, Li, M, Yang, Y, Fu, X. Prednisone improves pregnancy outcome in repeated implantation failure by enhancing regulatory T cells bias. J Reprod Immunol 2021;143:103245. https://doi.org/10.1016/j.jri.2020.103245.Search in Google Scholar PubMed
41. Fu, XQ, Cai, JY, Li, MJ. Prednisone may rebuild the immunologic homeostasis: alteration of Th17 and treg cells in the lymphocytes from rats’ spleens after treated with prednisone‐containing serum. Mol Genet Genomic Med 2019;7:e00800. https://doi.org/10.1002/mgg3.800.Search in Google Scholar PubMed PubMed Central
42. Yang, Z, Shen, X, Zhou, C, Wang, M, Liu, Y, Zhou, L. Prevention of recurrent miscarriage in women with antiphospholipid syndrome: a systematic review and network meta-analysis. Lupus 2021;30:70–9. https://doi.org/10.1177/0961203320967097.Search in Google Scholar PubMed
43. Riancho-Zarrabeitia, L, Lopez-Marin, L, Cacho, PM, López-Hoyos, M, Barrio, RD, Haya, A, et al.. Treatment with low-dose prednisone in refractory obstetric antiphospholipid syndrome: a retrospective cohort study and meta-analysis. Lupus 2022;31:808–19. https://doi.org/10.1177/09612033221091401.Search in Google Scholar PubMed
44. ACOG Practice Bulletin No. 207. Thrombocytopenia in pregnancy. Obstet Gynecol 2019;133:e181–93.10.1097/AOG.0000000000003100Search in Google Scholar PubMed
45. Sammaritano, LR, Bermas, BL, Chakravarty, EE, Chambers, C, Clowse, MEB, Lockshin, MD, et al.. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol 2020;72:529–56, https://doi.org/10.1002/art.41191.Search in Google Scholar PubMed
46. Woythaler, M. Neurodevelopmental outcomes of the late preterm infant. Semin Fetal Neonatal Med 2019;24:54–9. https://doi.org/10.1016/j.siny.2018.10.002.Search in Google Scholar PubMed
47. Takahashi, T, Jobe, AH, Fee, EL, Newnham, JP, Schmidt, AF, Usuda, H, et al.. The complex challenge of antenatal steroid therapy nonresponsiveness. Am J Obstet Gynecol 2022;227:696–704. https://doi.org/10.1016/j.ajog.2022.07.030.Search in Google Scholar PubMed
48. Shapiro-Mendoza, CK, Lackritz, EM. Epidemiology of late and moderate preterm birth. Semin Fetal Neonatal Med 2012;17:120–5. https://doi.org/10.1016/j.siny.2012.01.007.Search in Google Scholar PubMed PubMed Central
49. Short, HL, Wloch, C, Atkinson, S, Thomson, AJ, Stock, SJ. The safety, acceptability, and success rates of amniocentesis in the context of preterm prelabor rupture of membranes and threatened preterm labor: a systematic review and meta-analysis. Acta Obstet Gynecol Scand 2024;103:112–22. https://doi.org/10.1111/aogs.14613.Search in Google Scholar PubMed PubMed Central
50. Hornaday, KK, Stephenson, NL, Canning, MT, Tough, SC, Slater, DM. Maternal cytokine profiles in second and early third trimester are not predictive of preterm birth. PLoS One 2024;19:e0311721. https://doi.org/10.1371/journal.pone.0311721.Search in Google Scholar PubMed PubMed Central
51. American College of Obstetricians and Gynecologists. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin. Obstet Gynecol 2021;138:e65–90.10.1097/AOG.0000000000004479Search in Google Scholar PubMed
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