Analysis of Maternal and Neonatal Outcome of Patients with Preterm Prelabor Rupture of Membranes

Background Preterm prelabor rupture of membranes (PPROM) increases risk of maternal and neonatal diseases. Expectant treatment is one major treatment for PPROM patients, but it raises concerns on infection. Currently, the optimal delivery time for PPROM patients is still unclear, and there are various outcomes for the patients with PPROM. Previous studies conducted to analyze the pregnancy outcome showed inconsistent results. The purpose of this study is to retrospectively analyze the maternal and neonatal outcomes for comparison among different latency periods of patients with PPROM at a university hospital in China. Method This was a retrospective study. We divided all patients with PPROM into four groups according to gestational weeks, namely, group A (GA 24–27+6), group B (GA 28–31+6), group C (GA 32–33+6), and group D (GA34-36+6). The maternal and neonatal outcomes of each group were observed, respectively. Groups B and C were separately divided into two subgroups according to the median latency period of each group, namely, B1, B2, C1, and C2. Then, the differences of pregnancy outcomes between B1 and B2, C1 and C2, were compared, respectively. A p value < 0.05 was considered statistically significant. Result Group A: the common maternal and neonatal complications were the increased infection index before labour, neonatal hyperbilirubinemia and neonatal respiratory distress syndrome. Groups B, C, and D: the common maternal and neonatal complications were the increased infection index before labour, fetal distress, neonatal pneumonia, neonatal hyperbilirubinemia, and patent foramen ovale. Comparison of pregnancy outcome between group B1 and group B2 showed higher incidence rate of increased infection index before labour, lower incidence rate of respiratory distress syndrome, electrolyte disturbance, and premature brain in group B2 than those in group B1. Comparison of pregnancy outcome between group C1 and group C2 showed the higher incidence of increased infection index before labour, bigger birth weight, and shorter hospital stay in group C2 than those in group C1. Conclusion Increased infection index before labour was common maternal complication in four groups. Neonatal hyperbilirubinemia and neonatal pneumonia were top neonatal complications in four groups. The prolongation of latency period was beneficial to newborns of patients with gestational week at 28–31+6 weeks, while it did not benefit those with gestational week beyond 32 weeks.


Introduction
Preterm prelabor rupture of membranes (PPROM) is defined as the membrane rupture before the onset of labor that occurs before 37 weeks of gestation [1]. PPROM accompanies in approximately 3% of pregnancies and increases the risk of maternal and neonatal diseases [2][3][4][5].
Various epidemiological and clinical factors are considered to be related to PPROM, such as maternal with PPROM remain controversial, and the optimal delivery time is unclear [1], which depends on an evaluation of the risks and benefits of attempted pregnancy prolongation compared with expeditious delivery [11]. Due to the different variety of expectant treatment and different quality of medical care, the pregnancy outcomes of patients with PPROM are different [12][13][14][15]. In previous studies, there is a lack of comprehensive observations on maternal and neonatal complications as well as the consideration of grouping patients.
is study aimed to retrospectively analyze the pregnancy outcome of patients with PPROM at a university hospital located in northern China. Patients with PPROM in this study were grouped based on the gestational age, and their all maternal and neonatal complications were observed, screened, and analysed.

Study Design. Permission by the Ethics Committee of the Second Hospital of Shandong University was obtained.
is was a retrospective study. We divided all patients with PPROM into four groups based on gestational weeks, namely, group A (GA 24-27 +6 ), group B (GA 28-31 +6 ), group C (GA 32-33 +6 ), and group D (GA34-36 +6 ). e maternal and neonatal outcomes of each group were observed, respectively. e median latency period of group B was 4 days. Based on the median latency period, group B was divided into two groups B1 (latency period ≤4 days) and B2 (latency period >4 days). Similarly, group C was also divided into two groups according to its median latency period C1 (latency period ≤3 days) and C2 (latency period >3 days). en, the difference of pregnancy outcome between B1 and B2, C1 and C2, was compared, respectively. Maternal outcome indicators included cesarean section rate, increased infection index before labour, uterine atony, and postpartum hemorrhage. Neonatal outcome indicators included birth weight, neonatal asphyxia, and admission to neonatal care unit (NICU).
Inclusion criteria: all patients with prelabor rupture of membranes between 24 and 36 +6 gestational weeks were included who were admitted to the obstetrical department in the Second Hospital of Shandong University, between January 1, 2016, and December 31, 2019. e diagnosis of PROM (rupture of membranes) included (1) watery discharge or leakage of amniotic fluid from the cervical os and (2) the pH of the cervicovaginal or vaginal discharge ≥6.5. Gestational age was determined by the last menstruation and ultrasound performed during the first trimester.

Data Collection.
e study was approved by the Second Hospital of Shandong University Research Ethics Board (KYLL-2018 (KJ) P-0027). Clinical data were obtained from the electronic medical record of patients with PPROM and their newborns. First, all patients diagnosed with premature rupture of membranes on the first page of medical records from January 1, 2016, to December 31, 2019, were retrieved. en, patients with rupture of membranes at gestational weeks of 24 to 36 +6 were retained, and the corresponding neonatal data were retrieved through their mother's name.

Statistical
Analysis. e statistical differences of measurement data and enumeration data were tested by sample t test and independent chi-square test using SPSS, respectively. A p value < 0.05 was considered statistically significant.

Management of PPROM.
Patients were counselled by obstetricians about the condition, alternative treatment scheme, and the prognosis of the maternal and newborn at admission. Patients who selected experiment management were given the following treatments. Dexamethasone was given to promote fetal lung maturation (5 mg im bid within a 48 h interval). Antibiotics were applicated prophylactically for seven days at admission. Antibiotics were given again or upgraded when the infection index increased. Magnesium sulfate was applied to protect neonatal nervous system. Ritodrine, nifedipine, or atosiban were used as tocolysis before 35 gestational weeks depending on the patient's status. In addition, the maternal and fetal condition was closely monitored until delivery. Maternal vital signs were monitored every 8 hours. Continuous fetal heart rate monitoring was applicated until delivery. Serum C-reactive protein (CRP), procalcitonin (PCT), and the white blood cell count were checked every other day. Ultrasound was performed once a week to evaluate the status of the fetus. Any abnormal fetal monitoring (fetal movement, amniotic fluid volume, and continuous fetal heart monitoring), maternal complications (clinical chorioamnionitis, continuously rising of infection indicators, and placental abruption), and gestation weeks reached to 35 weeks were indicators for delivery. e mode of delivery depends on the situation of maternal and fetal condition. Pediatricians were informed to participate in the rescue of newborns in advance. Newborns were admitted to neonatal intensive care unit (NICU) according to individual conditions.

Maternal Characteristics and Maternal and Neonatal
Outcomes in Group A. A total of 35 patients were included in this group, including four nulliparous women and six twinpregnant women. e most common maternal complication was the increased infection index before labour (34.3%), followed by residual fetal membrane (22.9%) and the curettage (17.1%). A total of 41 newborns were born, and more than half of them were abandoned or died (63.41%), nearly a quarter survived (24.39%), and 6 newborns without endotracheal intubation all survived. e most common neonatal complication was neonatal hyperbilirubinemia (27%), followed by neonatal respiratory distress syndrome (24%), neonatal anemia (24%), and neonatal pneumonia (21%) ( Table 1).

Maternal Characteristics and Maternal and Neonatal
Outcomes in Group B. A total of 88 patients were enrolled in this group, including 12 nulliparous women and 12 twin-pregnant women. Nearly half of the patients delivered by cesarean section (48%), and the highest incidence of maternal complication was increased infection index before labour (36%), followed by pathological placental inflammation (17%), precipitate labor (15%), and fetal distress (15%). ere were a total of 94 newborns in this group, of which 82 survived. About four-fifths of the newborns suffered from neonatal pneumonia (81%) and neonatal hyperbilirubinemia (79%), and about half of the newborns were with complicated patent foramen ovale (50%) or electrolyte disorder (48%) ( Table 2).

Maternal Characteristics and Maternal and Neonatal
Outcomes in Group D. In group D, 567 patients were reviewed. Among them, 241 were nulliparous, and 33 were twin pregnancy. More than 10% pregnant women were complicated by precipitate labor, and nearly 10% of pregnant women were complicated by fetal distress and increased infection index before labour. e most common complications included neonatal hyperbilirubinemia (44%), neonatal pneumonia (29%), and patent foramen ovale (24%) ( Table 4).

Comparison of Maternal and Neonatal Outcomes between B1 Group and B2
Group. According to the median latency period of group B (4 days), the group B was divided into two groups B1 (the latency period ≤4 days, n � 48) and B2 (the latency period>4 days, n � 46).
In order to compare the maternal outcome, 14 indexes, including cesarean section rate, increased infection index before labour, and fever were observed. It was found that the increased infection index before labour in group B2 was twice as that in group B1 (p < 0.05).
To observe neonatal outcomes, we counted all neonatal complications and compared the high incidence rate index between group B1 and group B2. e results showed that the majority of neonatal index in group B2 were better than those in group B1, but only respiratory distress syndrome, electrolyte disturbance, and premature brain were statistically different between two groups. e incidence of respiratory distress syndrome in group B2 was about 1/3 of that in group B1 (B2 VS B1: 13.0% VS 33.3%, p � 0.028), and the incidence of electrolyte disorder in group B2 was about half of that in group B1 (B2 VS B1: 34.8% VS 60.4%, p � 0.015). e birth weight and Apgar scores (1 min, 5 min) of group B2 (9.09 ± 1.77, 9.80 ± 0.52) were significantly higher than those of group B1 (7.98 ± 2.58, 9.25 ± 1.51), and the difference was statistically significant. e average length of neonatal stay in group B2 (21.70 ± 12.11) was shorter than  that in group B1 (25.33 ± 17.18), but the difference was not statistically significant (Table 5).

Comparison of Maternal and Neonatal Outcomes between
Group C1 and Group C2. e group C were divided into two groups based on the median latency period (3 days) C1 (the latency period ≤3 days, n � 88) and C2 (the latency period >3 days, n � 72).
To compare the pregnancy outcome between group C1 and group C2, we reviewed all maternal and neonatal complications and compared indexes with high incidence rate. e maternal results showed the increased infection index before labour in group C2 was more than 4 times as that in group C1 (C2 VS C1: 45.83% VS 10.23%, p < 0.05). Neonatal outcome showed that the average birth weight in group C2 was about 200 g higher than that in group C1 (C2 VS C1: 2304.11 ± 369.13 VS 2140.59 ± 355.27, p � 0.003), and the average length of neonatal stay in group C2 was about 2 days shorter than that in group C1 (C2 VS C1: 2304.11 ± 369.13 VS 2140.59 ± 355.27, p � 0.003). Except that mycotic infection rate of group C2 was 4 times as that of group C1, all the other neonatal complications in group C2 were significantly lower than those in group C1, but there was no statistical difference (Table 6).

Discussion
PPROM is a serious pregnancy complication responsible for 28% of neonatal morbidities worldwide, which causes onethird of preterm birth [16]. PPROM can be caused by a variety of pathologic mechanisms that act individually or in concert [17,18]. According to ACOG, antibiotics, singlecourse of corticosteroids, and vaginal-rectal swab for GBS culture (GBS prophylaxis was administered when necessary) are recommended to patients with PPROM before 34 gestational weeks. In addition, magnesium sulfate was given for neuroprotection before anticipated delivery for pregnancies before 32 gestational weeks [1]. e optimal time for delivery depends on a continuous evaluation of gestational age, maternal and fetal complications, and even the medical service quality level. Previous studies have shown mixed results on the expected treatment results [19,20]. A metaanalysis of 23 randomized controlled trials (8,615 women) showed that shorter latency period was beneficial to both the mother and newborn [19]. However, short latency period in patients with PPROM between 28 and 34 weeks carries some maternal and neonatal risks with no additional benefits [20].
Current research showed the incidence of all serious neonatal complications was high among patients with gestation age between 28 and 31 +6 weeks. Prolonged gestational weeks (>4 days) significantly reduced the incidences of neonatal respiratory distress syndrome, premature brain, and electrolyte disorder and meanwhile increased neonatal weight and improved neonatal Apgar score. At the same

Characteristics
Result Neonatal gastrointestinal bleeding, n (%) 4,(2%) Neonatal respiratory failure, n (%) 4,(2%) Neonatal meningitis, n (%) 3,(2%) Septic shock, n (%) 1,(1%) time, it did not increase the risk of serious maternal complications. ese findings were consistent with the previous research results [19,21]. Reviewing the pregnancy outcomes of patients with gestational weeks at 32-33 +6 weeks, prolonging gestational weeks not only improved the neonatal birth weight and decreased average length of stay but also significantly increased the risk of maternal infection. is result is inconsistent with previous studies [22]. Accordingly, it is recommended to extend the gestational week for patients with gestational weeks between 28 and 31 +6 weeks. e analysis of the pregnancy outcome of patients with gestational week between 28 and 31 +6 weeks showed the incidence rate of all serious neonatal complications was high. Prolonged gestational week of patients with gestation week between 32 and 33 +6 weeks increased birth weight and shortened neonatal stay, but did not statistically reduce the incidence rate of neonatal complications. e possible reasons are as follows: first, under the current neonatal treatment conditions, while the extension of gestational weeks is of great significance for fetal maturity with gestational week between 28 and 31 +6 , it did not benefit newborns with gestation week greater than 32 weeks. Second is closely monitoring the infection index. Taking persistent increased infection index before labour, rather than chorioamnionitis as the indicator of pregnancy termination, greatly reduces the infection risk of mothers and newborns. e neonatal mortality rate in 24-27 +6 weeks was higher than that previously reported [22,23]. e reason is that more than half of newborns were abandoned before or at birth, as those families gave them up considering the prognosis and treatment cost of newborns. In this group, 10 of the 15 children admitted to NICU (neonatal intensive care unit) finally survived (66.7%), and the six newborns without endotracheal intubation at birth all survived. Perhaps the independence of endotracheal intubation is an indicator of good prognosis of newborns, which requires further studies to confirm. According to the detailed analysis results, obstetricians and pediatrician should give more optimistic suggestion to their parents, especially for newborns who do not need endotracheal intubation at birth. e contribution of this study lies in patient grouping according to gestational week, which reduced the bias caused by gestational age and the observation of all pregnancy index. e limitation of this study is that the number of patients in some groups is relatively small, and more patients should be recruited for further research.
In conclusion, this study revealed that pregnancy outcome of patients with PPROM were significantly associated with gestational week or the latency period. When the gestational age is 24-27 +6 , the mortality rate of newborns was high because they were abandoned, but the survival rate of newborns who received active treatment reached to 66.7%. e independence of endotracheal intubation was a good indicator of newborn prognosis. Increased infection index before labour was common maternal complication in four groups. Neonatal hyperbilirubinemia and neonatal pneumonia were common neonatal complications in four groups. e prolongation of latency period was beneficial to newborns with gestational week at 28-31 +6 weeks, while it did not benefit patients with gestation week beyond 32 weeks. ese results can guide the clinical treatment to improve the pregnancy outcome of patients with PPROM.

Data Availability
No datasets were generated or analysed during the current study.

Conflicts of Interest
e authors declare that they have no conflicts of interest.