Relationships Between Preterm Premature Rupture of Membrane at Gestational Age 20 - 36⁺⁶ Weeks and Perinatal Outcomes; A Cross-Sectional Study from Tehran, Iran

Premature rupture of membranes (PROM) refers to the tearing of the fetal membranes before the onset of uterine contractions (1). Preterm premature rupture of membranes (PPROM) occurs before 37 weeks of gestation (2). Approximately 150,000 pregnancies are affected by PPROM annually in the United States (3). The reported frequency of PPROM is 5.3% in Egypt (4), 19.2% in China (5), 9.6% in Pakistan (6), and 2.41% in Iran (7). The PPROM occurs in approximately 3% of all pregnancies and is associated with one-third of all preterm births (25% - 30%) and 18% - 20% of all neonatal deaths (8-10).

Studies have identified several maternal risk factors associated with PPROM. These include abnormal Body Mass Index (BMI) (< 18.5 kg/m² or > 23 kg/m²), a positive history of preterm delivery or PPROM, cervical bacterial colonization and genital tract infections, chorioamnionitis, antepartum bleeding, cigarette smoking, ethnicity, gynecological surgeries, and socioeconomic status (1, 8, 11, 12).

Premature rupture of membranes adversely affects perinatal outcomes by leading to preterm delivery, oligohydramnios, intrauterine infection, placental abruption, umbilical cord compression, neonatal sepsis, intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, and neurological or neuromuscular dysfunction (13-15). Although the duration of PPROM (> 12 hours) or its latency period (> 24 hours) has been identified as significant factors influencing unfavorable outcomes (16), these findings have not been confirmed by other studies (5, 17).

In the present study, we assessed maternal and neonatal outcomes following PPROM at a gestational age of 20 - 36⁺⁶ weeks. The study also highlighted the prevalence of fetal and maternal deaths, fetal condition at the time of pregnancy termination, duration of neonatal and maternal hospital admission, and PPROM-related comorbidities in a tertiary maternity care hospital.

An observational, retrospective, cross-sectional study was conducted at Imam Khomeini Hospital, a tertiary center affiliated with Tehran University of Medical Sciences in Tehran, Iran, from March 2020 to March 2023. The study included all hospitalized pregnant women with PPROM at a gestational age of 20 to 36⁺⁶ weeks. The diagnosis of PPROM was considered the rupture of membranes before 37 weeks of gestation and was confirmed by clinical and biological diagnostic procedures (18). Patient triage involved history taking by a midwife. PPROM was diagnosed based on sonographic evidence of reduced amniotic fluid volume (19), observed vaginal watery leakage, or a positive AmniSure/fern test. To eliminate bias, suspicious cases were reviewed and consulted with the present perinatologist. Additionally, cases with false-positive tests or uncertain diagnoses were admitted and monitored for 12 to 24 hours to confirm the diagnosis.

Inclusion criteria were a definitive PPROM diagnosis between the 20th week and 36⁺⁶ weeks of gestation. Patients with a gestational age under 20 weeks or beyond 36⁺⁶ weeks were excluded. Fetal demise cases were excluded due to maternal discharge before delivery. The study also excluded patients whose medical records were inaccessible. A combination of demographic, obstetrical, and clinical data was extracted from medical records and recorded in a checklist. Data included patient admission codes, maternal age, underlying diseases, gestational age at admission, cervical length, duration of neonatal and maternal hospital admission, anthropometric values, and neonatal complications. Laboratory and radiology databases were reviewed to complete data collection. Evaluating clinical data, a body temperature above 38°C was considered as fever (20). According to laboratory findings, white blood cell (WBC) counts between 4000 and 10,000 were considered normal, below 4000 as leukopenia, and above 10,000 as leukocytosis (21). Regarding the assessment of the Amniotic Fluid Index (AFI), values above 24 cm and below 5 cm were considered polyhydramnios and oligohydramnios, respectively (22). Data related to neonatal outcomes were also gathered and recorded. The relationships between variables were analyzed to assess the impact of PPROM on neonatal and maternal outcomes. Neonatal outcomes included prematurity, respiratory distress syndrome (RDS), low Apgar score, low birth weight, surfactant administration requirement, hospital admission, and mortality. Considered maternal morbidities were fever, abnormal WBC values, or AF-related complications.

Through the present study, we aimed to understand the common outcomes, potential corresponding risk factors, and consequences of PPROM in our tertiary maternity center. Although few studies from Iran (23-25) have reported the prevalence, causes, and consequences of PPROM, our study provides more informative and comparative data.

A total of 396 patients with a gestational age of 20 - 36⁺⁶ weeks and 153 neonatal files were screened in this study to assess maternal and neonatal outcomes following PPROM. Consistent with evidence showing significant associations between prenatal complications and PPROM (11), the results of the present study identified prevalent complications such as diabetes (gestational and chronic) in 21% of cases and hypertensive disorders (gestational hypertension, preeclampsia, and chronic hypertension) in 12.6% of cases.

Diabetes can promote the production of advanced glycation end products (AGEs) and their receptors (RAGEs) (26). A recent study showed that first-trimester AGEs blood levels were significantly higher in cases complicated by PPROM (27). It was also reported that gestational diabetes mellitus could increase the risk of PPROM by 1.87-fold (11). Confirming our findings regarding the association between PPROM and hypertensive disorders, Wenas and Al-Massawi (28) reported a statistically significant relationship between gestational hypertension and PPROM. A systematic review from Iran also revealed that diabetes and maternal hypertensive disorders were among the most important risk factors for PPROM (25).

Regarding PPROM comorbidities, the results of the present study showed that vaginal bleeding was the most common event, followed by labor pain, chorioamnionitis, fetal distress, placenta previa, or cord prolapse. This finding suggests that PPROM may put the preterm fetus at risk of several complications, including vaginal bleeding, labor pain, placental abruption, ascending infection, intrapartum fetal distress, and cord prolapse.

Moreover, in contrast to existing evidence that identifies chorioamnionitis as the most significant PPROM-associated complication (29-31), our results demonstrated that this complication was not as frequent among our participants. The COVID-19 pandemic was also at its peak during the study period and significantly affected PPROM cases, with an influence rate of 5.3%.

In accordance with our findings, Gafner et al. (32) reported that vaginal bleeding, occurring in 19.7% of cases, was the most frequently observed event following PPROM among 61 included cases. The authors found chorioamnionitis and sepsis in only 8% of patients. Similarly, Addisu et al. (2) investigated obstetrical complications associated with PPROM in 424 pregnant women and reported common events such as abnormal vaginal discharge, urinary tract infections, a positive history of PPROM, and vaginal bleeding. Consistent with our results, a study by Smith et al. (8) showed a high rate of chorioamnionitis (53%) in PPROM cases with placental histopathology examination.

Regarding neonatal outcomes, the results indicated a mortality rate of 11%, Apgar scores < 6 in 28.3%, RDS in 66.7%, meconium aspiration in 1.3%, and surfactant administration in 66.7% of the 153 included neonates. Neonatal complications such as surfactant administration, RDS, and mortality were predominantly observed in neonates with lower gestational age. Moreover, surfactant use was significantly associated with low birth weight.

Consistent with our findings, an investigation from Iran demonstrated a significant relationship between PPROM and the 5th-minute Apgar score, corticosteroid administration, RDS, and other adverse neonatal outcomes (23). Kim et al. (33) reported a significant association between early-onset PPROM and neonatal mortality and morbidity. Additionally, the authors highlighted a significant relationship between PPROM and low Apgar scores in neonates with younger gestational age. Pinto et al. (34) pointed to correlations between PPROM and increased risks of RDS [odds ratio 3.05 (95% CI 1.31; 7.12)] as well as the requirement for exogenous surfactant administration [odds ratio 3.87 (95% CI 1.60; 9.35)] in 266 neonates with a gestational age of < 34 weeks. Another study by Madan et al. (35) demonstrated a significant decrease in the frequency of RDS and low Apgar scores (< 7) with advancing gestational age among 134,502 PPROM patients at 32 - 36⁺⁶ weeks of gestation. The authors also concluded that gestational age at delivery could significantly predict the risk of neonatal mortality.

Antenatal corticosteroid administration is a critical intervention to prevent neonatal morbidity and mortality. The intramuscular injection of betamethasone or dexamethasone before preterm birth reduces the risks of RDS, intraventricular hemorrhage, necrotizing enterocolitis, and death. These benefits have been observed in women with PPROM without any proven increased risk of neonatal or maternal infection (36-38).

Based on our results, the frequency of corticosteroid administration among the included participants was 46%. The highest corticosteroid administration rate was observed in the gestational age group of 26 - 34 weeks, while the lowest rate was in the 20 - 26 week group. Pauluschke‐Frohlich et al. (39) reported a lower corticosteroid administration rate of 35% in PPROM patients.

Correlations between gestational age at the time of corticosteroid administration and maternal and neonatal outcomes were also assessed. Regarding AFI groups, the results showed that oligohydramnios was more frequent among pregnant women who received corticosteroids at 20-26 weeks of gestation. Another study reported higher chances of optimal corticosteroid administration in cases diagnosed with early PPROM and oligohydramnios (39).

According to our findings, the majority of our subjects (70.2%) underwent cesarean section (CS), while 11.1% had NVD. The results also showed a relationship between corticosteroid administration at lower gestational ages and an increased frequency of NVD. Consistent with our findings, a cohort study by Bouvier et al. (11) demonstrated a potential association between PPROM and maternal outcomes in 6,968 PPROM patients, indicating a significant increase in CS as a complication of PPROM.

Contrary to our results, Jiang et al. (40) conducted a three-year investigation of 1,178 PPROM cases and found that the majority of patients underwent NVD. Similarly, a study by Sajitha et al. (41) reported that among PPROM patients with a gestational age between 28 and 38⁺⁶ weeks, 66.7% had NVD, while 31.7% underwent CS. Differences in findings across studies may be attributed to factors such as sample size and included gestational ages.

Additionally, the present study demonstrated a relationship between NVD and neonatal mortality. This finding may be related to the practice of performing vaginal deliveries in cases with a gestational age below 26 weeks to avoid the risks associated with CS. However, extremely preterm birth is inherently associated with an increased neonatal mortality rate.

Maternal leukocytosis was another variable more frequently observed among patients who received corticosteroid administration at lower gestational ages. This finding may be associated with the severity of PPROM-related complications, which necessitate early antenatal corticosteroid administration. Furthermore, the high prevalence of low Apgar scores among neonates who received corticosteroids at 20 - 26 weeks of gestation might be related to early PPROM and inevitable preterm birth.

In line with other studies (42-44), our results also demonstrated significant relationships between Apgar scores < 6 and the occurrence of RDS, meconium aspiration, and surfactant administration.

Through this study, we identified the risk factors and perinatal outcomes associated with PPROM pregnancies. Our findings highlight that this maternal complication places the fetus and neonate at risk of adverse outcomes. The gestational age at the time of PPROM emerged as the most crucial prognostic indicator for neonatal complications.

However, our study had several limitations. The primary limitation was missing data, which resulted in a relatively small sample size. Additionally, some medical records lacked precise documentation. Another constraint was the limited timeframe for conducting the study. A prospective study design, rather than a retrospective approach, might be more beneficial. Recruiting expectant mothers at high risk of developing PPROM at least a month before delivery could facilitate earlier identification of the causes of PPROM.

Several maternal and neonatal variables — such as maternal socioeconomic factors, gestational age at pregnancy termination, the cause of pregnancy termination, PPROM duration, and latency period — were not considered in this study. Finally, we recommend that before participant recruitment begins, specific criteria be established by the research faculty through an evaluation of existing guidelines. This is particularly important due to the absence of a universally recognized criterion proposed by obstetric medical communities worldwide.