Perinatal outcomes following immediate delivery or expectant management of preterm premature rupture of membranes during the late preterm period

The aim of this study is to evaluate maternal and neonatal outcomes following immediate delivery or expectant management of preterm premature rupture of membranes (PPROM) during the late preterm period at 34 + 0 –36 + 6 weeks of pregnancy. We conducted a retrospective study on singleton pregnancies with PPROM during the late preterm period using medical records at twelve tertiary medical centres in Korea from January 2007 to December 2016. Data on demographic characteristics and outcome measures were collected. The primary outcomes were maternal sepsis for maternal outcome and neonatal sepsis and neonatal death for neonatal outcomes. Of the 1,072 women, 782 cases (72.9%) were assigned to the immediate delivery group, and 290 cases (27.1%) were categorized into the expectant management group. There was a signicant difference in the rate of clinical neonatal sepsis (immediate delivery, 3.8% vs expectant management, 15.8%; p < 0.0001), however, no differences in maternal sepsis (p = 0.5424), culture-proven neonatal sepsis (p = 0.2108), or neonatal death (p = 0.3899) were observed. In conclusion, expectant management in women with PPROM during the late preterm period does not increase the risk of severe maternal and neonatal morbidities and mortality; however, careful monitoring for chorioamnionitis or fetal compromise should be considered during expectant management.


Introduction
Preterm premature rupture of membranes (PPROM) is the rupture of amniotic membranes prior to the onset of labor before 37 weeks of gestation. PPROM occurs in 2-3% of all pregnancies and one-third of preterm births 1,2 . The mother exposed to PPROM might be at higher risk for preterm labor resulting in preterm delivery, potential intra-amniotic infection, placental abruption, and cord prolapse during the latent period. Neonates exposed to PPROM show an increased risk of sepsis, pulmonary hypoplasia, respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and neonatal death due to prematurity and decreased amniotic uid [3][4][5] . Some clinical guidelines recommend that immediate delivery should be considered for women with PPROM on the basis of the following conclusions: "delivery should be considered at 32 gestational weeks if fetal lung maturity can be documented or at 34 weeks of gestation because prolonged latent period exposes the fetus to intra-amniotic infection, retroplacental hematoma or fetal distress." 3,6,7 . However, prolonged latent period in women with PPROM without overt signs of infection or fetal compromise can lower neonatal morbidities due to prematurity and lessen the economic burden of premature infants in neonatal intensive care units (NICU). Recent randomised controlled trials demonstrated that expectant management of PPROM during the late preterm period provided good neonatal outcomes without signi cant risk to neonates 8- 10 . Therefore, optimal timing for delivery in women with PPROM during the late preterm period remains controversial because both reducing fetal prematurity at birth and avoiding complications including intra-amniotic infection during the latent period should be regarded. In addition, it is now clear that neonates born at 34-37 weeks of gestation are physiologically immature and are associated with a substantial short-and long-term health burden such as RDS, sepsis work-ups, phototherapy for hyperbilirubinemia, signi cantly increased use of intensive care, longer hospitalization, and concomitant increased hospital charges. 8,11 .
Hence, we aimed to evaluate maternal and neonatal outcomes following immediate delivery or expectant management of PPROM during the late preterm period at 34 + 0 -36 + 6 weeks of gestation to establish the optimal management and time for delivery. This investigation of current management status can help clinicians in counselling affected women and assist decision making process for optimal timing of delivery.

Study design
We conducted a retrospective study of singleton pregnancies complicated by PPROM during the late preterm period using medical records at twelve tertiary medical centers in Korea from January 2007 to December 2016. Late preterm period was de ned as gestational age from 34 + 0 weeks to 36 + 6 weeks. All hospitals were referral institutions equipped with NICUs that were capable of providing comprehensive care for preterm infants. At least one obstetric specialist con rmed all medical records.
Inclusion criteria were a singleton pregnancy and clinically diagnosed ruptured membranes at 34 + 0 − 36 + 6 weeks of gestation. The exclusion criteria were multiple pregnancies, active labor at admission time, suspected clinical chorioamnionitis, placenta previa, placental abruption, preeclampsia, or any other contraindication to continue the pregnancy (Fig. 1).

Pregnancy management
Diagnosis of PPROM was based on maternal history (including the exact time of amniotic uid leakage by history taking) and sterile speculum examination con rming amniotic uid draining from the cervical os that changed the color of nitrazine paper, or biochemical tests when in doubt 3 . Eligible women in this study were divided into two groups according to management: immediate delivery and expectant management. Immediate delivery was de ned as active management, such as decision of labor induction or caesarean delivery within 24 hours after rupture of membranes. Expectant management was de ned as a decision of close observation with careful monitoring of maternal and fetal complications, and performing conservative management until 37 gestational weeks or any other indications for delivery during latent period, such as non-reassuring fetal heart rate (FHR) pattern, initiation of labor, or suspected intrauterine infections. Whether administration of antenatal corticosteroids and antibiotics during latent period was con rmed on medical records. All women were hospitalised and managed until delivery. Careful evaluation of labor and fetal well-being was assessed via continuous cardiotocography (CTG) and fetal ultrasonography. Indications for delivery during latent period included progress of labor, suspected clinical chorioamnionitis, or suspected fetal compromise.

Maternal, Obstetrics and Neonatal Outcomes
Clinical data including maternal demographics, obstetric outcomes, and neonatal outcomes were obtained from the electronic medical records. Maternal demographics included age, gestational age at the time of PPROM diagnosis, underlying medico-surgical illness, and cervical or vaginal culture. Data on obstetric outcomes including gestational age at delivery, latent period, mode of delivery, and incidences of complications such as maternal sepsis, endometritis, postpartum hemorrhage, and wound infection were collected. Neonatal outcomes included admission to the NICU, Apgar score, surfactant administration, and neonatal complications during the hospital stay. Progress of labor was de ned as cervical change with regular labor. Clinical chorioamnionitis was de ned as the presence of two or more of the following symptoms: maternal pyrexia, leukocytosis, uterine tenderness, maternal or fetal tachycardia, and malodorous vaginal discharge 12 . Suspected fetal compromise was de ned as a non-reassuring FHR pattern or abnormal Doppler ndings on ultrasonography. Non-reassuring FHR was de ned as suspicious pattern of FHR in CTG such as loss of variability, recurrent late or variable deceleration, and persistent bradycardia.
The primary outcome was the rate of maternal sepsis as a maternal outcome, and the incidence of either clinical or culture-proven neonatal sepsis and neonatal death as neonatal outcomes. Maternal sepsis was de ned as the presence of clinical infectious signs such as fever above 38°C, heart rate higher than 90 beats per minute (bpm), breathing rate higher than 20 bpm, oliguria, and probable or con rmed infection by culture in blood. Clinical neonatal sepsis was de ned as the presence of clinical infectious signs such as abnormal C-reactive protein (CRP), temperature instability, diminished spontaneous activity, less vigorous sucking, apnea, bradycardia, respiratory distress, vomiting, diarrhea, abdominal distention, jitteriness, seizures, and jaundice 13 . Culture-proven neonatal sepsis was de ned as a positive culture of a known pathogen from blood or cerebrospinal uid, and the presence of one or more clinical signs of infection. Clinical signs of infection were respiratory distress, apnoea, lethargy, abnormal level of consciousness, circulatory compromise including hypotension, poor perfusion, need for inotropic support, volume expansion, temperature instability (temperature < 36°C or ≥ 38°C), or a combination thereof 14,15 .
Antibiotic therapy was continued for 7-10 days in these neonates.
Secondary neonatal outcomes included other neonatal morbidities such as mechanical ventilation, RDS, BPD, surfactant administration, grade 3-4 IVH, periventricular leukomalacia (PVL), convulsion, NEC, retinopathy of prematurity (ROP), admission to the NICU, and duration of stay in the NICU. Mechanical ventilation included intermittent positive pressure ventilation, continuous positive airway pressure, or high-frequency ventilation. RDS was de ned as respiratory distress, which was con rmed by chest radiography and the need for ventilator support in clinical examination. IVH and PVL were diagnosed via skull ultrasonographic examination. NEC was diagnosed by clinical symptoms including poor oral feeding, blood in the stool, frequent vomiting of bile-coloured uid, abdominal distention, and radiographic ndings 16 . ROP was diagnosed and graded according to the International Classi cation of Retinopathy of Prematurity revisited 17 .
Secondary maternal outcomes were divided into antepartum and postpartum complications, respectively. Antepartum complications included antepartum fever, CRP elevation, antepartum hemorrhage, cord prolapse, and intrauterine fetal death. Postpartum complications included the primary cesarean section rate, postpartum fever, endometritis, postpartum hemorrhage, wound infection, deep vein thrombosis, and chorioamnionitis. A primary cesarean section was de ned as the total percentage of caesarean deliveries for women without a history of previous caesarean delivery 18 . Chorioamnionitis was a trial entry of exclusion criteria, but the result of maternal outcomes was de ned as a positive culture in amniotic uid or in ammatory changes in visual/microscopic evaluation of the placenta in both groups after delivery.

Ethics
This study was conducted retrospectively. This study was carried out in accordance with the principles outlined in the Declaration of Helsinki, and the privacy of all subjects was protected. Only investigators had the permission to review personal medical records, and data anonymity was applied during data management. Because this is a retrospective study and authors planned to investigate the medical records, requirement for informed consent was approved exemption and the study protocol had been

Statistical analysis
Continuous variables are expressed as means and standard deviations, while categorical variables are expressed as numbers and percentages. To evaluate the differences in outcomes according to management, we compared continuous variables using the two-sample t-test or Wilcoxon rank-sum test and categorical variables using the Chi-square test or Fisher's exact test between immediate delivery and expectant management. The association between delivery timing for women with PPROM and neonatal outcomes was evaluated through the calculation of adjusted odds ratio (OR) in a logistic regression analysis. The reference group was the immediate delivery and OR adjusted for maternal age, and gestational age at the diagnosed PPROM. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA). P-values < 0.05 were considered statistically signi cant.

Results
Demographic and obstetric outcomes in the study population A total of 2,429 eligible women were screened, and 1,072 women were enrolled. Of those, 782 women were assigned to the immediate delivery group, and 290 were assigned to the expectant management group (Fig. 1).
The mean maternal age was 33.4 ± 4.7 years and the mean gestational age at the time of PPROM was 35.5 ± 0.9 weeks of gestation. A total of 686 (64.0%) women were nulliparous and 164 (15.3%) had a previous cesarean section. The mean gestational age at delivery was 35.6 ± 0.8 weeks of gestation and 465 (43.4%) women underwent cesarean delivery. The mean neonatal birthweight was 2565.1 ± 342.8 g. Clinical or culture-proven neonatal sepsis occurred in 78 (7.3%) of the 1,072 neonates, and two neonatal deaths occurred in the immediate delivery group.
Demographic and obstetric outcomes of the study groups are presented in Table 1. There were signi cant differences in maternal age, gestational age at the time of PPROM, and parity between the two groups. The mean gestational age at the time of PPROM was 35 gestational weeks in both groups; however, the distribution of earlier gestational age was greater in the expectant management group than that in the immediate delivery group. In the expectant management group, 54.1% of women were diagnosed with PPROM at 34 + 0 -34 + 6 weeks of gestation, compared to 22.6% of those in the immediate delivery group (p < 0.0001). Women in the immediate delivery group were more likely to have a history of previous cesarean delivery than those in the expectant management group (19.3% vs 4.5%, p < 0.0001). Women in the expectant management group were more likely to receive antenatal corticosteroids (14.5% vs 3.3%, p < 0.0001), antibiotics (98.6% vs 85.8%, p < 0.0001), and tocolytic agents (24.1% vs 3.7%, p < 0.0001).
Women in the expectant management group were delivered at earlier gestational age (35.4 ± 0.7 weeks vs 35.7 ± 0.8 weeks, p < 0.0001) and had a longer latent period compared to those in the immediate delivery group (2.8 ± 2.9 days vs 0.5 ± 0.9 days, p < 0.0001). There was a signi cantly higher incidence of cesarean delivery in the immediate delivery group than in the expectant management group (50.8% vs 23.4%, p < 0.0001). More neonates born in the expectant management group showed smaller birthweights (p < 0.0001). All other maternal demographics and obstetric outcomes were similar between the two groups.

Primary maternal and neonatal outcomes
Results of maternal and neonatal outcomes are presented in Table 2. All neonatal sepsis and clinical neonatal sepsis were more frequently observed in the expectant management group (all, p < 0.0001); however, there was no signi cant difference in culture-proven neonatal sepsis in both groups (p = 0.2108). Two neonatal deaths occurred in the immediate delivery group. One neonate was complicated by cultureproven neonatal sepsis, and the other was due to unknown origin. However, there was no signi cant difference in neonatal death between the immediate delivery group and the expectant management group (p = 0.3899). Maternal sepsis occurred in the immediate delivery group, but there was no signi cant difference between the two groups.

Secondary neonatal outcomes
Neonates born in the immediate delivery had a signi cant need for surfactant compared to those delivered after expectant management (6.1% vs 2.9%, p = 0.0102). The incidence of ROP, hyperbilirubinemia, admission to the NICU, and administration of antibiotics were signi cantly higher in neonates born in the expectant management group (all, p < 0.0001) than those born in the immediate delivery group. The period of NICU stay showed signi cantly longer in the expectant management group (p = 0.0052). Other neonatal outcomes including RDS, BPD, PVL, convulsion, NEC, and hypoglycemia were not signi cantly different between the two groups. Grade 3-4 IVH was not occurred in both groups ( Table 2).

Secondary maternal outcomes
In secondary maternal outcomes, the proportion of primary cesarean section was signi cantly higher in the immediate delivery group than in the expectant management group (31.5% vs 19.0%, p < 0.0001). Women in the expectant management group had a higher frequency of CRP elevation during the latent period (21.4% vs 9.0%, p < 0.0001); however, other antenatal and postpartum complications did not differ between the two groups. Antepartum haemorrhage and IUFD was not occurred in both group (Table 2).
Similar to the entire cohort, women in the expectant management group showed more frequent neonatal complications (e.g., clinical neonatal sepsis, neonatal hyperbilirubinemia, antibiotic administration for neonates, and maternal CRP elevation in the latent period), and had a lower frequency of surfactant administration in neonates and primary cesarean section. However, unlike in the entire cohort, expectant management for women who were diagnosed with PPROM at 34 + 0 -34 + 6 weeks of gestation was signi cantly associated with decreased risk of mechanical ventilation for premature neonates (OR 0.49, 95% CI 0.26-0.96) and neonatal RDS (OR 0.33, 95% CI 0.15-0.73) ( Table 4).

Discussion
In this retrospective study, we evaluated neonatal and maternal outcomes following different delivery timing for the management of PPROM during the late preterm period. Neonates in the expectant management group required less surfactant use; however, they were associated with an increased risk of clinical neonatal sepsis, admission to the NICU, hyperbilirubinemia, and antibiotic administration. Women managed expectantly were associated with a lower risk of primary cesarean section; however, they had a higher risk of antepartum fever and CRP elevation. There were no signi cant differences in maternal sepsis and neonatal death between the two groups.
Neonatal sepsis is one of the main causes of neonatal mortality and long-term complications of development, especially in preterm infants. Rupture of the membrane may result in loss of a barrier to ascending infection from the lower genital tract, and it is possible that the prolonged latent period in PPROM can increase the risk for neonatal sepsis. To reduce the risks of late-onset sepsis, NEC, and mortality, broad-spectrum antimicrobial agents should be administered. In our study, the incidence of clinical neonatal sepsis was higher in the expectant management group. This may lead to more NICU admissions and antibiotics use. However, infectious complications, including severe IVH, PVL, NEC, and neonatal death, were not signi cantly increase in the expectant management group.
Several studies have attempted to demonstrate the signi cant bene ts or risks of neonatal sepsis in immediate delivery and expectant management for women with PPROM; however, optimal management remains controversial. Similar to our ndings, Ocviyanti D 19 et al. and Gyam -Bannerman et al. 20 reported that the long interval between membrane rupture and delivery was associated with an increased risk for neonatal sepsis after adjusting for gestational age. In contrast, other studies demonstrated that the prolonged latent period was not associated with the risk of neonatal sepsis [21][22][23] . In randomised controlled trials, the PPROMT trial and PPROMEXIL studies suggest that expectant management for women with PPROM has bene ts without a signi cant increase in the risk of neonatal sepsis 8,9,24 . This Clinical neonatal sepsis is diagnosed more often in the expectant management group probably because neonates in that group are more likely to be exposed to infection during the latent period. However, there was no signi cant difference in culture-proven neonatal sepsis.
Neonates in the expectant management group required less surfactant use after controlling for gestational age. This may be associated with gestational age at delivery and antenatal corticosteroid administration. In our study, although gestational age at delivery was higher in the immediate delivery group, 41.6% of women in the immediate delivery group were diagnosed with PPROM and delivered after 36 weeks of gestation; however, a high proportion of women (54.1%) with expectant management were diagnosed with PPROM at 34 + 0 -34 + 6 weeks and delivered at 35 + 0 -35 + 6 weeks of gestation (44.5%). In the subgroup analysis of women with PPROM at 34 weeks of gestation, expectant management was associated with a reduced risk of surfactant administration as well as the need for mechanical ventilation and neonatal RDS. Women managed expectantly could be prolonged gestational age and may be injected a complete course of antenatal corticosteroids therapy during the latent period. This nding was consistent with those of previous studies. Earlier gestational age is associated with more frequent neonatal respiratory complications than a longer latent period 22,27 . The results of our study and other studies are rational because gestational age and antenatal corticosteroid therapy at ≥ 34 weeks of gestation can improve fetal lung maturation and reduce neonatal respiratory complications 28,29 .
Women delivered immediately after PPROM showed a signi cantly higher frequency of cesarean section. The number of women who previously underwent a cesarean section was higher in the immediate delivery group, and the primary cesarean section rate was also higher in the immediate delivery group than that in the expectant management group. This may be related to the unfavourable cervix and the concerning about fetal distress with oligohydramnios during labor. However, primary cesarean section is associated with higher morbidity and mortality, such as placenta accrete, cesarean section scar pregnancy, postpartum hemorrhage, hysterectomy, and subsequent uterine rupture 18,30 . To reduce maternal complications related to cesarean section, expectant management of PPROM during the late preterm period may be helpful.
Women managed expectantly show a higher incidence of non-reassuring FHR pattern, CRP elevation, and fever during the latent period. These ndings could be applied to predict chorioamnionitis, which is necessary for prompt delivery 31,32 . However, low sensitivity limits clinical utility 33 .
For the time of delivery on PPROM, several guidelines recommend that delivery should be considered at 32 weeks 6 or 34 weeks of gestation 3,34 . After 34 weeks of gestation, the risk for developing intrauterine infection-related adverse perinatal outcomes exceeds the advantages of continuing the pregnancy. As per these guidelines, in Korea, immediate delivery is usually performed for the management of PPROM at 34-37 weeks. However, the management of pregnancies complicated with PPROM during the late preterm period is challenging. In contrast to several national guidelines, some studies have demonstrated that expectant management does not increase the risk of adverse perinatal outcomes, compared to immediate delivery. In the Cochrane review, the rate of neonatal sepsis was not signi cantly different between the immediate delivery and expectant management for PPROM 11 . Expectant management was associated with decreased neonatal RDS and need for ventilation; however, it was associated with an increased incidence of chorioamnionitis. For preferable maternal and neonatal outcomes, the authors suggest that expectant management with careful monitoring should be considered in women with PPROM before 37 weeks of gestation with no contraindications to continuing the pregnancy. However, this meta-analysis included a wide range of gestational ages between 25 and 37 weeks of gestation; thus, the results could not be applied in women with late PPROM. Several multi-centre randomised controlled trials, which only included women with a late preterm period, were similar to the Cochrane review 8- 10,35 . These studies demonstrated that the rate of neonatal sepsis did not increase in expectant management, and immediate delivery did not improve perinatal outcomes in women with PPROM in the late preterm period. Guidelines for clinical practice from the French College of Gynaecologists and Obstetricians reported that expectant management is recommended for uncomplicated PROM before 37 weeks despite positive results for Streptococcus B and antibiotic prophylaxis administration at admission 36 . Based on these studies and our study, expectant management for PPROM in the late preterm period is a reasonable option.
For optimal expectant management of PPROM during the late preterm period, there are several recommendations. It is important to distinguish patients who have clear indications for delivery. Women with strongly suspected chorioamnionitis, signi cant placental abruption, and non-reassuring fetal status should be delivered immediately. To reduce the risk of intra-amniotic infection, antibiotics for group B streptococcus prophylaxis should be administered. Periodic assessment for infection, fetal well-being, umbilical cord prolapse, and regular uterine contraction should be performed. Evidence of tocolysis was insu cient.
Our study had several limitations. The retrospective data review was limited by the accuracy of previously recorded information, and not all data elds were available for each patient. In addition, most hospitals were referral centres; thus, this study was subject to preadmission selection bias. Data on composite neonatal morbidity may not appropriately represent future childhood developmental outcomes. However, to the best of our knowledge, this is the rst study to evaluate immediate delivery and expectant management in women with PPROM during the late preterm period in multi-tertiary centers in Korea. Our results may be useful for patient counselling and for further research on the optimal timing of delivery in women with PPROM in the late preterm period. In addition, we evaluated various neonatal complications and short-term neonatal morbidities.
In conclusion, we evaluated the bene ts and risks of immediate delivery and expectant management in women with late preterm PPROM. These ndings may provide a foundation for future clinical research to investigate the optimal timing of delivery for PPROM during the late preterm period, considering both short-and long-term pregnancy outcomes.

Declarations Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.  IVH, intra-ventricle hemorrhage; NICU, neonatal intensive care unit; CRP, C-reactive protein; DVT, deep vein thrombosis * Primary cesarean section was defined as cesarean delivery in women who had not undergone a previous cesarean section. §Mechanical ventilation included intermittent positive pressure ventilation, continuous positive airway pressure, or high frequency ventilation. †Chorioamnionitis was diagnosed by positive culture in amniotic fluid or histologic inflammatory changes in the gross/microscopic evaluation of the placenta. ¥Low Apgar score defined as an Apgar score below 7 at 5 minutes. †Chorioamnionitis was defined as a positive culture in amniotic fluid or inflammatory changes in the visual/microscopic evaluation of placenta postpartum.
Odds ratio adjusted for maternal age, pre-pregnancy body mass index, and gestational age at preterm premature rupture of membranes (PPROM) ¥Low Apgar score defined as an Apgar score below 7 at 5 minutes. †Chorioamnionitis was defined as a positive culture in amniotic fluid or inflammatory changes in the visual/microscopic evaluation of placenta postpartum.
Odds ratio adjusted for maternal age and pre-pregnancy body mass index. Figure 1 Study population