European Journal of Cardiovascular Medicine

The fetal membranes' proper development, structural integrity, and function are crucial for the normal progression of pregnancy, the labor process, and overall pregnancy outcomes. One of their key roles is to remain intact until the onset of labor at term. Preterm Premature Rupture of Membranes (PPROM) [1] Under normal circumstances, spontaneous rupture occurs near the end of the first stage of labor. [2] However, in approximately 10% of pregnancies, the fetal membranes fail to maintain their integrity, leading to rupture either before term or at term but before the onset of labor.

Preterm Premature Rupture of Membranes (PPROM) is defined as the spontaneous rupture of the amniotic membranes before the onset of uterine contractions or the initiation of labor, occurring after the gestational age of viability up to 36 weeks and 6 days.[3] This condition poses significant risks to both the mother and fetus, necessitating careful monitoring and appropriate medical intervention to optimize pregnancy outcomes.

The incidence of Preterm Premature Rupture of Membranes (PPROM) varies between 2% and 4.5% of all deliveries. [4] It is a significant contributor to preterm births, accounting for approximately 30% of all preterm deliveries. Additionally, PPROM is associated with around 10% of perinatal mortality, highlighting its critical impact on neonatal outcomes and the need for timely medical management.[5]

Microbial invasion of the amniotic cavity (MIAC) occurs in 30–40% of PPROM cases, especially at earlier gestational ages, triggering an inflammatory response that leads to earlier delivery and a shorter latency period. [6] The latency period, defined as the time from membrane rupture to the onset of contractions, varies, with the term PROM occurring after 37 weeks and preterm PROM (PPROM) before 37 weeks. Histological chorioamnionitis (HCA) is seen in up to 60% of preterm births and is linked to neonatal complications like chronic lung disease and neurodevelopmental issues.[7] PPROM increases maternal risks, including chorioamnionitis, dysfunctional labor, higher cesarean rates, postpartum hemorrhage, and endometritis, while fetal risks include hyaline membrane disease, intraventricular hemorrhage, sepsis, cord prolapse, and fetal distress. [8] A prolonged latency period raises the risk of ascending infections, particularly in cesarean deliveries, making early gestational PPROM more prone to complications.

Early detection of infection can help expedite preterm birth and reduce complications. Laboratory markers like CRP, WBC count, ESR, and bacterial analysis aid in identifying at-risk pregnancies. [9] CRP, an acute-phase protein produced by the liver, binds to phosphocholine on microbes, aiding complement binding to damaged or foreign cells and enhancing macrophage phagocytosis as an early defense against infection. [10] Stimulated by cytokines like IL-1, IL-6, and INF-α, CRP remains stable in serum and is elevated in both blood and amniotic fluid in intrauterine infections, making it a valuable early predictor of chorioamnionitis. [11] This study aims to assess CRP’s role in predicting clinical outcomes in PPROM patients.

However, the most effective, non-invasive technique for diagnosing PPROM and providing prompt results remains controversial. Therefore, our study aims to evaluate the association between elevated CRP levels in PPROM and maternal and neonatal outcomes, assessing CRP as a potential predictive biomarker.

A prospective observational study was conducted over 12 months at a tertiary care hospital to evaluate the association between elevated CRP levels in PPROM and maternal and neonatal outcomes. The study included pregnant women with confirmed PPROM before 37 weeks of gestation in singleton pregnancies who provided informed consent. Women in active labor at admission, those with congenital fetal anomalies, maternal inflammatory or autoimmune diseases, recent antibiotic or steroid use, and multiple pregnancies were excluded.

A total of 78 participants were enrolled and categorized based on CRP levels: those with elevated CRP (≥0.5 mg/L) and those with normal CRP (<0.5 mg/L). Data collection involved recording demographic, obstetric, and medical history. PPROM was confirmed through clinical examination, and serum CRP levels were measured using ELISA with a cutoff value of 0.5 mg/L. CRP testing was conducted in the central laboratory of KIMS Bangalore, following standardized protocols. To ensure accuracy, inter-observer variability was minimized through structured training sessions and regular audits.

Table-1: Gravida Status, Age Group, and Time to Delivery Based on CRP Levels

The above table showed that Group-B (Positive CRP) had more Primi Gravida and individuals aged 20-30 years, while Group-A (Negative CRP) had more individuals aged 31-40 years and quicker deliveries (<24 hours).

Table-2: Preterm Classification and CRP Levels

The above table showed that both the Negative CRP and Positive CRP groups had similar distributions, with the majority being late preterm (34wks-<37wks).

Table-3: Induction of Labour and Mode of Delivery Based on CRP Levels

The above table showed that Group-A (Negative CRP,) had more spontaneous inductions (45.7%) and vaginal deliveries (60%), while Group-B (Positive CRP) had a higher rate of induced labor (69.76%) and C-sections (69.76%).

Table-4: Maternal Complications and Comorbidities Based on CRP Levels

The above table showed that Group-B (Positive CRP) had higher rates of sepsis, UTI, wound infections, and atonic PPH compared to Group-A (Negative CRP). Both groups had no cases of chorioamnionitis or subinvolution.

Table-5: Neonatal Complications and NICU Stay Duration Based on CRP Levels

The above table showed that the Group-A (Negative CRP) had higher rates of TTNB and lower probable sepsis, while Group-B (Positive CRP) had more cases of perinatal depression, birth asphyxia, and longer NICU stays.

Table-6: Apgar score Distribution Based on CRP Levels

The above table showed that the Group-A (Negative CRP) had more infants with higher APGAR scores (8/10 to 9/10), while Group-B (Positive CRP) had a wider range of scores, including some below 7/10.

PPROM and subsequent preterm birth contribute significantly to perinatal complications, accounting for approximately one-third of perinatal mortality. Additionally, PPROM is a major risk factor for maternal morbidity, predisposing affected individuals to chorioamnionitis, placental abruption, and an increased likelihood of preterm cesarean delivery. [12] CRP has been widely recognized as a reliable acute-phase reactant in various pathological conditions, demonstrating significant predictive value in disease processes. Its utility extends to obstetric complications, where it has been employed as an important biomarker for detecting infections in cases of PPROM. Given its role in the systemic inflammatory response, CRP serves as a valuable indicator for early identification and risk stratification of infections in pregnant individuals affected by PPROM, facilitating timely medical intervention to improve maternal and neonatal outcomes.[13]

Several studies have highlighted the demographic and socioeconomic characteristics of PPROM patients. Sudha et al. [5]  reported 42% of cases in the 21–25-year age group, while Noor et al. [14]  (2006, Ayub Medical College) found 58.8% in the same category. In our study, 67% of the 141 patients were from a lower socioeconomic background, aligning with Sheela et al. [15] (68.2%). Gravidity analysis showed 63.12% were primigravida, similar to Gandhi et al.[16] (60.7%) and Okeke et al. [17] (29.1%). Comparatively, Group B (CRP-positive) had more primigravida women and individuals aged 20–30 years, whereas Group A (CRP-negative) had more 31–40-year-olds and faster deliveries (<24 hours).

In the present analysis, the classification of neonates based on gestational age revealed a similar distribution between the Negative CRP and Positive CRP groups, with the majority classified as late preterm (34 weeks to <37 weeks). However, a review of the existing literature indicates that this specific parameter has not been extensively discussed, highlighting a gap in research on the relationship between CRP status and neonatal classification in PPROM cases.

The analysis showed higher rates of sepsis, UTI, wound infections, and atonic PPH in Group B (Positive CRP), while Group A (Negative CRP) had more TTNB and lower probable sepsis. Both groups had no cases of chorioamnionitis or subinvolution, but Group B had more perinatal depression, birth asphyxia, and longer NICU stays. Comparatively, Sudha R et al., [5] reported 18% chorioamnionitis and 8% abruption in early PPROM with prolonged latency. Studies by Emechebe et al. [18] and Singhal et al. [19] found RDS rates of 61% and 92%, while Emechebe et al. also reported 22% RDS, 17.8% hyperbilirubinemia, and 16% sepsis in PPROM cases. Furthermore, 

The present analysis found that Group A (Negative CRP) had a higher proportion of infants with APGAR scores between 8/10 and 9/10, while Group B (Positive CRP) exhibited a wider range of scores, including some below 7/10, indicating greater neonatal distress. Similarly, the study by Martin Stepan on PPROM pregnancies from 24+4 to 36+6 weeks reported 5-minute APGAR scores <7 in 10% and 6% of cases, and 10-minute APGAR scores <7 in 6% and 2%, demonstrating a comparable trend of lower APGAR scores in certain subgroups. These findings reinforce the association between elevated CRP levels and compromised neonatal outcomes in PPROM cases.[20]

A retrospective study by Smith EJ et al. [21] found that CRP was not an effective independent predictor of clinical or histological chorioamnionitis, and sequential testing lacked statistical significance in detecting infection in preterm PROM. Similarly, a meta-analysis by RD Trochez-Martinez et al.,[22]  of eight studies found that only three supported CRP as a reliable predictor, all of which utilized serial CRP monitoring, suggesting its potential usefulness in longitudinal assessment.

Serial CRP monitoring may be impractical in clinical practice, adding unnecessary strain on healthcare systems without significant patient benefit, as prophylactic antibiotics are routinely administered after 18 hours of membrane rupture. This study aims to evaluate the association of elevated CRP levels in PPROM with maternal and neonatal outcomes, assessing its role as a predictive biomarker.

Elevated CRP levels in PPROM were associated with increased maternal complications, including sepsis, UTI, and atonic PPH, as well as adverse neonatal outcomes such as lower APGAR scores, perinatal depression, and prolonged NICU stays. While CRP serves as a useful inflammatory marker, its predictive value for chorioamnionitis remains inconclusive, as demonstrated by previous studies. Given the routine use of prophylactic antibiotics after membrane rupture, serial CRP monitoring may not offer significant clinical benefits. Further research is needed to establish standardized protocols for utilizing CRP in the management of PPROM to optimize maternal and neonatal outcomes.

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