Tailored-prom: tailored therapeutic regime in patients with preterm premature rupture of membranes to prolong pregnancy, improve maternal and neonatal outcomes, and reduce antibiotic burden: a randomized controlled trial protocol

Abstract

Background

Preterm premature rupture of membranes is a major cause of preterm birth and is associated with substantial maternal and neonatal morbidity. Current management is largely uniform and includes routine administration of antibiotics and antenatal corticosteroids, although a considerable proportion of women do not have infection or inflammation at the time of membrane rupture. This approach may lead to unnecessary exposure to medication and suboptimal timing of treatment. Measurement of interleukin-6 in amniotic fluid is a promising marker of intra-amniotic inflammation and may allow a more individualized management strategy. The aim of this study is to evaluate whether tailored antibiotic and corticosteroid therapy based on interleukin-6 levels in amniotic fluid can prolong pregnancy compared with standard care.

Methods

This is a prospective, randomised controlled trial conducted at two tertiary perinatal centres. Pregnant women aged 18 years or older with singleton pregnancies complicated by confirmed preterm premature rupture of membranes between 22 + 0 and 33 + 6 weeks of gestation will be eligible. After providing signed informed consent, participants will be randomised in a 1:1 ratio to tailored management or standard care. In the tailored arm, transabdominal amniocentesis will be performed within 24 h of admission, and subsequent antibiotic and corticosteroid therapy will be guided by the interleukin-6 concentration in amniotic fluid. In the standard care arm, antibiotics and antenatal corticosteroids will be administered at admission according to current guidelines. The primary outcome is pregnancy latency longer than 7 days from membrane rupture to delivery. Secondary outcomes include overall latency to birth, maternal infectious and non-infectious morbidity, and short-term neonatal outcomes. A total of 138 women will be randomised to account for the expected drop-out and non-feasible amniocentesis.

Discussion

This trial addresses an important clinical question by testing a personalised approach to the management of preterm premature rupture of membranes. If effective, tailored treatment based on interleukin-6 measurement may prolong pregnancy, reduce unnecessary exposure to antibiotics and corticosteroids, and improve maternal and neonatal outcomes. The results may support a change toward more individualised care in this high-risk obstetric population.

Trial registration

EU Clinical Trials Register: 2024-520237-77-00. Registered on 30th March 2025.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12978-026-02353-6.

Plain language summary

Some pregnant women experience their waters breaking too early, which can lead to early birth and health problems for both the mother and the baby. Currently, most women receive the same treatment, even though not all of them have an infection. This study tests a more individual approach to care. It compares standard treatment with a tailored approach that uses a small sample of fluid from around the baby to help doctors decide when antibiotics and steroids are really needed. The main goal is to find out whether this personalised care can help women stay pregnant longer and improve outcomes for mothers and babies, while reducing unnecessary medication.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12978-026-02353-6.

Background

Preterm premature rupture of membranes (pPROM), defined as rupture of the foetal membranes before the onset of labour prior to 37 weeks of gestation [1], affects approximately 3–4% of pregnancies and accounts for 40–50% of all preterm births worldwide [2, 3]. Despite advances in prenatal care, its incidence has remained largely unchanged [4]. The aetiology of pPROM is multifactorial, involving genetic, environmental, and microbial factors, with infection and inflammation playing a central role through microbial invasion of the amniotic cavity (MIAC) and ascending intrauterine infection [5, 6]. These underlying pathogenic mechanisms not only contribute to membrane rupture but also directly influence subsequent maternal and neonatal outcomes.

Consequently, pPROM is associated with substantial maternal and neonatal morbidity and mortality, including neonatal sepsis, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage, and long-term neurodevelopmental impairment [7, 8]. Maternal complications include chorioamnionitis, placental abruption, sepsis, and, in severe cases, the need for hysterectomy [9]. Clinical management therefore aims to balance prolongation of pregnancy to improve foetal maturity against the risks of infection and inflammation.

Current management strategies focus on pregnancy prolongation through the use of latency antibiotics and antenatal corticosteroids, as gestational age at birth is a key determinant of neonatal outcome [10]. However, treatment is largely uniform, despite the absence of intra-amniotic infection or inflammation in a substantial proportion of patients at presentation [11]. This approach may result in unnecessary exposure to antibiotics and corticosteroids, while suboptimal timing of treatment may limit potential benefits.

Therefore, individualized management strategies have been proposed to improve maternal and neonatal outcomes [12]. Such individualized management requires reliable tools for objective and timely assessment of the intra-amniotic environment. In this context, amniocentesis is feasible in nearly 90% of pPROM cases [13, 14] and enables direct assessment of the intra-amniotic environment. Interleukin-6 (IL-6) is the most extensively studied biomarker in amniotic fluid and serves as a reliable indicator of intra-amniotic inflammation, with elevated levels (≥ 2600 pg/mL) associated with adverse neonatal outcomes, including sepsis and respiratory morbidity [15–18]. Recent evidence confirms the safety of transabdominal amniocentesis in this context, with a very low complication rate and no reported long-term maternal or foetal harm [14, 19].

Despite its prognostic value, IL-6–guided management has not been integrated into routine clinical practice due to variability in assays, lack of standardized cut-offs, and limited interventional evidence demonstrating clear clinical benefit [14, 20, 21]. In light of these limitations, further research is needed to determine whether biomarker-guided, individualized treatment strategies can improve outcomes in pregnancies complicated by pPROM.

This study aims to evaluate whether an interleukin-6–guided, individualized management strategy in pregnancies complicated by pPROM can prolong pregnancy latency and improve maternal and neonatal outcomes compared with standard uniform care. By integrating biomarker-based risk stratification into clinical decision-making, the trial seeks to provide evidence for a more precise and targeted approach to the management of this high-risk obstetric condition.

Methods

Objectives of the trial

We aim to evaluate whether tailored antibiotic and antenatal corticosteroid therapy guided by IL-6 levels in amniotic fluid, obtained by amniocentesis, is associated with prolongation of pregnancy compared with standard uniform management treatment in patients with premature rupture of membranes (pPROM).

Primary endpoint

The primary endpoint is pregnancy latency > 7 days from pPROM to delivery [Latency ˃ 7d is an outcome traditionally used in trials studying pPROM and PTB [12, 22].

Other endpoints

1. Overall latency to birth [days from pPROM to birth].

2. incidence of chorioamnionitis and funisitis [diagnosed during pregnancy or postpartum based on histological examination of placenta and umbilical cord].

3. short-term adverse maternal outcomes [23].

4. short-term neonatal outcomes [24, 25].

5. microbiome in mother and newborn – exploratory endpoint.

Study design

Inclusion criteria

1. ≥ 18 years

2. pPROM confirmed by Amnisure test [placental alpha-microglobulin-1 (PAMG-1) in cervicovaginal fluid] and/or clinical signs of pPROM on examination.

3. Weeks of pregnancy 22+0 – 33+6 [20, 26–28].

4. Singleton pregnancy.

5. Signed informed consent form (ICF).

6. Completely uncomplicated pregnancy until the occurrence of pPROM.

Exclusion criteria

1. Active labour or an immediate obstetric indication for delivery

2. Multiple pregnancy

3. Major foetal chromosomal or structural abnormalities

4. Clinical or laboratory signs of chorioamnionitis at admission [29]

5. Severe immunodeficiency, active malignancy, or immunosuppression

6. Patients with an active drug abuse⁴

7. Non-compliant patients

8. Contraindications to study medications according to the SmPC

Study description

Selection of patients and randomization

For trial scheme, see Fig. 1. Women presenting with suspected pPROM will undergo clinical assessment and diagnostic testing of presence of placental alpha microglobulin-1 protein (PAMG-1; Amnisure test). At enrolment, participants will undergo standardized clinical evaluation, maternal vital sign monitoring, ultrasound examination, cardiotocography, laboratory testing for inflammatory markers, and microbiological assessment using vaginal swabs and blood samples. Patients meeting exclusion criteria after initial assessment will be withdrawn prior to randomization.

Fig. 1.

Trial Scheme: IL-6 – interleukin 6, y – years, IM – intramuscular, IV intravenous, ICF – informed consent form, ABX – antibiotics, GBS prophylaxis + macrolides: Penicillin G (benzylpenicillin) 5mil IU IV initially and then 2–3 IU (dose adjusted to body weight) IV every 4 h twice, then every 6 h + Clarithromycin 500 mg po every 12 h for 7–10 days or till delivery. Initial broad-spectrum ABX: Ampicillin/sulbactam 3 g IV every 6 h + Gentamicin 5 mg/kg IV (< 60 kg 240 mg, 61–80 kg 320 mg, > 80 kg 400 mg) every 24 h for 5–7 days according to the clinical state. Details in Sect.  3.3.3.1. ANS - antenatal steroids: 2 doses of betamethasone acetate/phosphate 12 mg IM 24 h apart, or 2 doses of dexamethasone phosphate 12 mg IM 24 h apart, details in Sect.  3.3.3.2. pPROM – preterm premature rupture of membranes, AMC – amniocentesis. Neuroprotection: imminent labour prior 32 + 0 week, MgSO4 in an intravenous loading dose of 4 g (administered slowly over 20–30 min), followed by a 1 g per hour maintenance dose. This regimen should continue until birth but should be stopped after 24 h if undelivered. ¹if not already administered, or as a single course prior to 34 + 0 if at least 7 days have passed after the previous course, ² prior to 32 + 0 if not yet administered, ³depending on the week of pregnancy and clinical status

Eligible patients who provide written informed consent will be randomized in a 1:1 ratio to either tailored management or standard care. Randomization will be performed using a secure electronic data capture system REDCap, and all study data will be recorded in a centralized database.

Study interventions

Initial Interventions

All participants receive standardized initial antibiotic prophylaxis consisting of GBS prophylaxis combined with macrolide therapy at hospital admission, in accordance with Czech national guidelines [27, 30].

Arm A: tailored management

Participants randomized to the tailored management arm undergo amniocentesis within 24 h of admission. Follow-up amniocentesis is repeated at weekly intervals until delivery. No antenatal corticosteroids are administered at admission.

Subsequent management is guided by amniotic fluid interleukin-6 (IL-6) levels:

• IL-6 < 2600 pg/mL: discontinuation of antibiotic prophylaxis and no administration of antenatal corticosteroids.

• IL-6 ≥ 2600 pg/mL: administration of antenatal corticosteroids and initiation of broad-spectrum antibiotic therapy, with subsequent adjustment based on microbiological results.

Arm B: standard care

Participants randomized to standard care receive antenatal corticosteroids at admission. Antibiotic prophylaxis is continued for 7–10 days and subsequently discontinued.

Concomitant treatments

In cases of imminent preterm birth before 32 + 0 weeks of gestation, fetal neuroprotection with magnesium sulfate is administered according to national guidelines [27, 30].

Detailed intervention protocols are provided in Supplementary Appendix 1.

Biological material assessment

Biological samples will be collected in both study arms according to a predefined schedule (Table 1). At enrolment, blood, urine, and vaginal swabs will be obtained from all participants. Blood sampling will be performed daily during the first three days, then three times per week and once weekly thereafter. Vaginal swabs will be repeated weekly. In the tailored management arm, amniotic fluid will be analysed weekly. Placental tissue and umbilical cord samples will be collected after delivery. Optional maternal buccal swabs and neonatal rectal swabs will be obtained after birth for microbiome analyses by sequencing 16 S rDNA (or WGS).

Table 1.

Biological samples and analyses

Sample type	Timing	Analyses
Amniotic fluid (Arm A)	Weekly	IL-6; aerobic/anaerobic cultures; PCR (N. gonorrhoeae, Mycoplasma spp., Ureaplasma spp., Chlamydia spp.); optional microbiome
Blood	Enrolment; daily ×3 days; 3×/week; weekly	Biochemistry; CBC with differential, ICIS; CRP, PCT, IL-6, presepsin; sFlt-1/PlGF
Vaginal swabs	Enrolment; weekly	Aerobic/anaerobic cultures; PCR (N. gonorrhoeae, Mycoplasma spp., Ureaplasma spp., Chlamydia spp.)
Urine	Enrolment	Aerobic/anaerobic culture; chemical analysis and sediment
Placenta & umbilical cord	After delivery	Histopathological assessment for inflammation and infection
Buccal swabs (mother)	After delivery (optional)	Microbiome sequencing
Rectal swabs (newborn)	After delivery (optional)	Microbiome sequencing

Pregnancy and delivery

All participants will remain under inpatient observation until delivery, with daily standardized maternal and foetal monitoring. Clinical or laboratory signs of chorioamnionitis will result in an intervention consisting of the course of antenatal steroids (if not already administered, or as a single course prior 34 + 0 if at least 7 days have passed after the previous course), initial broad-spectrum antibiotics, or delivery, according to gestational age and clinical status.

In uncomplicated cases, delivery will be planned after 36 + 0 weeks of gestation. Earlier delivery will be undertaken in cases of maternal or foetal compromise, based on clinical judgment.

All patients and their children will be followed up 6 months after delivery and data on secondary outcomes will be collected.

Adverse events

Adverse events and serious adverse events will be recorded and reported in accordance with Good Clinical Practice and regulatory requirements. Safety monitoring will follow standardized classification systems, and all serious adverse events will be reported to relevant regulatory and ethics authorities.

Data management, monitoring, and participant follow-up

Study data will be collected and managed using a secure REDCap-based electronic data capture system compliant with applicable data protection and regulatory standards. Data will be recorded in pseudonymised form and monitored for completeness and accuracy by the study investigators and an independent data monitor.

Participants will be followed from enrolment until 6 months after delivery. Written informed consent may be withdrawn at any time without affecting standard clinical care. Every effort will be made to minimise loss to follow-up and to obtain outcome data for all randomized participants.

The study design accounts for an anticipated dropout rate, and recruitment may be adjusted during the trial to preserve statistical power.

Power analysis

The power calculation was based on a previous pilot study [12], in which patients receiving individualized management had a higher latency of pregnancy > 7 days (76.0% vs. 41.6%; P<.001) compared to patients with standard care. The power analysis was computed on the following settings: binary endpoint latency of pregnancy > 7 days, power 90%, level of statistical significance α = 0.05, difference in occurrence of endpoint in reference and experimental group of 30%. Based on this, 53 subjects will be needed in each arm. This makes a total of 106 for the study. According to the literature, in approximately 10% cases amniocentesis is not feasible [13, 14] and the IL-6 results will therefore not be obtained, together with expected drop-out of 20% and rounded-up to even numbers, at least 138 patients are needed to be randomised, 69 in each arm. Analysis was computed using PASS 16 Power Analysis and Sample Size Software (2018). NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass.

Study timeline

A total of 138 participants will be enrolled over a 24-month recruitment period, accounting for anticipated drop-out and non-feasible amniocentesis. Maternal and neonatal follow-up will continue until 6 months after delivery of the last enrolled participant. Final analyses will be performed in the final year, with a total planned study duration of 3 years.

The study is coordinated by a central trial office at the leading institution and conducted by a multidisciplinary team across participating tertiary perinatal centres. All participants are insured in accordance with applicable institutional and national regulations.

Discussion

This trial addresses a major unmet need in the management of preterm premature rupture of membranes (pPROM): the lack of individualized treatment strategies despite substantial heterogeneity in intra-amniotic inflammation at presentation [6, 31–33]. Current standard care applies antibiotics and antenatal corticosteroids uniformly [20, 34]., although a large proportion of patients show no evidence of infection or inflammation at the time of membrane rupture [11, 31]. By integrating interleukin-6 (IL-6) assessment into clinical decision-making, this study evaluates whether a tailored approach can more effectively prolong pregnancy while reducing unnecessary treatment exposure.

The central hypothesis of the trial is that IL-6–guided management will allow earlier identification of patients who benefit most from immediate intervention, while safely deferring antibiotics and corticosteroids in those without intra-amniotic inflammation [12]. Even modest prolongation of gestation in pPROM may translate into clinically meaningful reductions in neonatal morbidity, particularly respiratory complications and early-onset sepsis [35, 36]. In parallel, optimized timing of antenatal corticosteroids is expected to increase the proportion of neonates delivered within the window of maximal steroid efficacy [37].

Maternal outcomes may also improve through early detection and treatment of subclinical intra-amniotic infection, potentially preventing progression to severe infectious morbidity [6, 38]. Importantly, reducing unnecessary antibiotic exposure may lower the risk of adverse maternal effects and antimicrobial resistance [39]. Together, these mechanisms support the potential of a biomarker-guided strategy to improve both maternal and neonatal outcomes without increasing procedural risk.

The use of transabdominal amniocentesis is a key enabling component of the study. Existing evidence demonstrates that the procedure is safe and feasible in pPROM, with a very low complication rate [13, 14]. While amniocentesis may not be technically feasible in all cases, this limitation has been anticipated in the study design and sample size calculation. Operational challenges related to laboratory turnaround times and protocol adherence are addressed through standardized procedures, investigator training, and centralized monitoring.

A major strength of this trial is its randomized controlled design, which allows robust evaluation of a biomarker-guided management strategy in a high-risk obstetric population. The use of IL-6, a well-validated marker of intra-amniotic inflammation [15–18], strengthens the biological rationale of the intervention. The study is conducted in tertiary perinatal centres with experienced operators, ensuring procedural safety and high-quality clinical monitoring. Standardized treatment algorithms, centralized data monitoring, and predefined criteria for protocol deviations further support internal validity and reproducibility.

Several limitations should be acknowledged. Amniocentesis may not be feasible in all patients, potentially limiting availability of IL-6 results in a subset of participants. In the tailored arm, corticosteroid administration may be delayed until biomarker results are available, which could reduce steroid efficacy in cases of rapid disease progression, although mitigation strategies are incorporated into the protocol. Repeated amniocentesis may affect patient acceptability and quality of life, despite careful counselling and monitoring. Finally, while the study is powered for pregnancy latency, it may not detect differences in less frequent but clinically important neonatal outcomes.

Overall, this trial is designed to generate high-quality evidence on whether biomarker-guided, precision-based management can meaningfully improve outcomes in pregnancies complicated by pPROM. By integrating interleukin-6–based risk stratification into routine clinical decision-making, the study has the potential to support a shift from uniform treatment strategies toward more individualized care, optimize timing of interventions, reduce unnecessary treatment exposure, and ultimately inform future clinical guidelines for the management of this high-risk obstetric population.

Abbreviations

ABX

Antibiotics

AMC

Amniocentesis

ANS

Antenatal steroids

CBC

Complete blood count

CRP

C–reactive protein

CTIS

Clinical Trials Information System

GBS

Group B Streptococcus

ICF

Informed consent form

ICIS

Intensive Care Infection Score

IL

6–interleukin–6

IM

Intramuscular

IV

Intravenous

MIAC

Microbial invasion of the amniotic cavity

NCSS

National Council for Statistical Software

PAMG

1–placental alpha–microglobulin–1

PCT

Procalcitonin

PCR

Polymerase chain reaction

PlGF

Placental growth factor

pPROM

Preterm premature rupture of membranes

REDCap

Research Electronic Data Capture

sFlt

1–soluble fms–like tyrosine kinase–1

SmPC

Summary of Product Characteristics

WGS

Whole genome sequencing

Authors' contributions

KMk and KM conceived and designed the study. KM, DC, MK, JV, PH, JT and ZL contributed to the development of the study protocol and overall study coordination. AJ, AS and LH contributed to protocol development and study implementation at the Brno study site. VA, HB, and JH contributed to microbiological, biochemical, and immunological aspects of the study and to the interpretation of laboratory data. LP contributed to pathological assessment and interpretation of placental and tissue findings. KJ, TL, MB, and JV contributed to patient recruitment, data collection, and clinical management of study participants. NTA, JT and RP contributed to neonatal data collection, outcome assessment, and interpretation of neonatal outcomes. MK and KM were major contributors to drafting the manuscript. All authors critically reviewed the manuscript for important intellectual content, read, and approved the final manuscript.

Funding

This study is partially supported by institutional funding of the Ministry of Health of the Czech Republic (MH CZ – DRO – VFN00064165). No other specific external funding has been secured at the time of protocol submission. An application for additional institutional support has been submitted. Open access publishing facilitated by General University Hospital in Prague, Open Access Fund.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

The study protocol was reviewed and approved through the Clinical Trials Information System (CTIS) in accordance with Regulation (EU) No 536/2014. The trial was authorised under EU CT number 2024-520237-77-00, with approval granted on 17 April 2025. The study will be conducted in compliance with the Declaration of Helsinki and the principles of Good Clinical Practice. Written informed consent will be obtained from all participants prior to enrolment.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.