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Introduction
Preterm birth before 37 weeks has been an obstetrical challenge for a long time. Among preterm births, late preterm babies who were born after 34 weeks have been thought to present with relatively better outcomes than those delivered earlier because sufficient maturation of the fetal lung is known to be accomplished around 34 weeks of gestation.1234 However, physicians experience neonatal morbidities, especially from respiratory complications, more commonly than expected in clinical practice.
A current systemic meta-analysis reviewed the morbidities of late preterm births and showed that there was a higher risk for respiratory morbidities such as respiratory distress syndrome (RDS), congenital pneumonia, pneumothorax, persistent pulmonary hypertension, transient tachypnea of the newborn, and apnea when using mechanical ventilation.5 Wang et al.6 reported that the incidence of hypoglycemia, jaundice, feeding difficulties and temperature instability was increased in late preterm infants compared to term infants. Several studies reported that infants born in the late preterm period are more likely to develop long-term complications including neuropsychiatric developmental delay and poor fetal growth.7891011
Therefore, the prolongation of pregnancy should be the definite goal for patients with a risk of preterm birth in the late preterm period. For certain fetal or maternal indications, the indicated delivery is considered, and many guidelines recommend the optimal timing of delivery in several circumstances. In especially late preterm period, patients and their family members expect their babies would have less problems than early preterm babies, however in clinical circumstances, late preterm babies frequently experience respiratory difficulties. The rates of specific respiratory complications or ventilator supports are not sufficient to explain or counsel to patients.
Premature rupture of membranes (PROM) is one of the major threats of preterm birth.12 It complicates 1–5% of all pregnancies131415 and is highly associated with both perinatal and maternal morbidity and mortality.161718 Traditionally intended delivery beyond 34 weeks of gestation has been considered for patients presented with PROM.119 It is evident from the recommendation of guidelines that being exposed to the condition of ruptured membranes has been known to be highly associated with the risk of intra-amniotic infection, chorioamnionitis, umbilical cord compression and adverse neonatal morbidities such as early onset sepsis.202122
However, a recent review by Cochrane revealed that planned delivery in PROM patients prior to 37 weeks was not associated with improved neonatal morbidity or reduced perinatal mortality.23 In addition, van der Ham et al.2425 reported on randomized trials showing that immediate intended delivery did not reduce the risk of neonatal sepsis (relative risk, 0.66; 95% confidence interval [CI], 0.30–1.5), and other neonatal outcomes were not different compared to those who underwent expectant management. The above study suggested that expectant management could be advocated in late preterm PROM if signs of infection did not develop.25
The aim of this study was to determine the incidence of neonatal respiratory morbidities and the use of assisted ventilation utilities according to the gestational age at delivery and the latency from rupture to delivery in late preterm births after PROM.
Methods
1. Study design
A retrospective study was performed on consecutive women who had delivered between 34+0 weeks and 36+6 weeks at Seoul National University Bundang Hospital from August 2008 to July 2018. Among them, the pregnancies who were administered for a diagnosis of preterm PROM were identified. Multifetal pregnancies and intrauterine fetal demise were excluded. The study protocol was approved by the Institutional Review Board (IRB) of Seoul National University Bundang Hospital (IRB No. E-1705-396-103).
2. The outcomes of the pregnancies and neonates
Data including maternal and neonatal outcomes were collected. Maternal characteristics included age, parity, use of any tocolytics, use of progesterone for prevention of preterm birth before PROM, antenatal steroid administration, use of intravenous oxytocin, the mode of delivery, and gestational age at the diagnosis of ruptured membranes and at delivery. Placental pathologic reports were collected to evaluate the presence of histologic chorioamnionitis and funisitis.
Basic information on the newborns such as birthweight, sex, Apgar scores, the presence of meconium, and major anomalies were collected. The outcome variables were the rate of neonatal intensive care unit (NICU) admission, the use of assisted ventilation, and respiratory morbidities including RDS, bronchopulmonary dysplasia (BPD), frequent apnea, transient tachypnea, and pneumothorax. Composite respiratory morbidity was defined as the presence of treatment for at least one of above respiratory presentations or diseases.
The definition of RDS was the presence of all of the following: clinical signs of respiratory distress, supplemental oxygen requirement (FiO2 >0.2), NICU admission for further respiratory support, diagnostic radiographic findings of reticular patterns and air bronchograms. Transient tachypnea was diagnosed when tachypnea had resolved in less than 72 hours with a normal radiography or showed increased perihilar interstitial markings in the infantogram.
The use of positive pressure ventilation through a facial mask and the application of an intubation procedure immediately after delivery were identified. The assisted ventilation utilities were divided into three modalities: nasal continuous positive airway pressure (CPAP), high-flow therapy, and mechanical ventilator through intubation. The management on ventilatory support was decided by neonatologists.
3. Statistical analysis
Continuous variables were compared using the Mann-Whitney U test; proportions were compared using the Fisher's exact test. The Jonckheere-Terpstra test for continuous variables and a linear-by-linear association for categorical variables were used when the data were analyzed according to trend as the gestational age at delivery changed. Multivariate logistic regression was used to determine factors associated with neonatal respiratory complications and with the use of assisted ventilation utilities adjusting for confounding variables that could affect the outcomes. A P value <0.05 was considered statistically significant. The analysis was done with SPSS, version 22 (IBM SPSS Inc., Armonk, NY, USA).
Results
A total of 584 women met the inclusion criteria. Table 1 shows the baseline characteristics of the patients according to the gestational age at delivery. As the gestational age of delivery was earlier, the use of tocolytics to prolong pregnancy was higher. Tocolytics are not recommended to be used after 34 weeks of gestation. There were statistically significant trends in the differences of the rate of antenatal steroid administration and the interval from the rupture of membranes to the delivery (P-trend <0.05). Because the study population included patients from 2008 and steroid administration had not been routinely performed before the change of recommendation which currently suggests the administration of steroids to stimulate fetal lung maturation even to late preterm births, the proportions of steroid administration were not as high as the current data. The pathologic findings such as acute histologic chorioamnionitis and funisitis tended to be found in decreased incidence as the gestational age of delivery advanced (both P-trend <0.05).
Table 2 reveals the neonatal outcomes according to the gestational age at delivery. As the gestational age at delivery advanced, the rates of low Apgar scores in 1 and 5 minutes decreased significantly. Assisted ventilation with positive pressure ventilation was performed in 23.6% (52/220) of the neonates born between 34+0 and 34+6 weeks while the rates remarkably decreased in neonates born after the 35 and 36 weeks (7.8% [17/217] and 3.4% [5/145], respectively, P-trend <0.001). The intubation procedure was done in 8 neonates: six in the 34-week-group and one in the 35- and 36-week-group each.
The rate of administration was over 90% in the 34-week-group, and it decreased below 10% when the gestational age at delivery reached over 36 weeks (P-trend <0.001). Assisted ventilation including nasal CPAP, high-flow therapy, and mechanical ventilator after admission to NICU was all significantly decreased as the gestational age at delivery advanced (P-trend < 0.05 for all). The incidences of RDS were 13.6% (30/220), 6.5% (14/217), and 3.4% (5/145) for 34-, 35-, and 36-week-group, respectively (P-trend <0.001). The rates of apnea decreased to 3.2% (7/220), 0.5% (1/217), and none for the 34-, 35-, and 36-week-group, respectively (P-trend =0.007). There were no significant trends or differences in BPD, transient tachypnea, and pneumothorax among the groups.
Since the recommendation of various guidelines suggest delivery when PROM is diagnosed after 34 weeks of gestation, a subgroup analysis was done only in patients who had been administered after 34 weeks. To determine the association between the interval from the rupture of membranes to the delivery and the clinical outcomes, a comparison was done between the patients who had delivered on the day of PROM and those who had delivered within 48 hours for discrete reasons such as completion of steroid administration or individual planning of expectancy decided by physicians (Table 3). The median values of gestational age at PROM were all 35 weeks; however, the difference between the two groups were statistically significant (P=0.002). The use of intravenous oxytocin increased (37.4% [138/369] vs. 77.5% [62/80], P<0.001), and the rate of cesarean section decreased (35.2% [130/369] vs. 10.0% [8/80], P<0.001) in the group who had delivered within 24 hours compared to the group who delivered within 48 hours from PROM.
In the neonatal outcomes, the group who delivered later had higher rates of a low Apgar score in 1 minute (25.0% [20/80] vs. 15.4% [57/369], P=0.049) and NICU admission (53.8% [43/80] vs. 37.2% [137/368], P=0.008) than the group who delivered in 1 day. Other variables including assisted ventilation and respiratory morbidities were comparable between the two groups.
Multivariate logistic regression analysis was done to evaluate the association of risk factors for each adverse neonatal outcome (Table 4). Advanced gestational age at delivery was independently associated with the decreased odds ratio (OR) for the rates of positive pressure ventilation immediately after birth, NICU admission, minor assisted ventilators such as nasal CPAP and/or high-flow therapy, and composite respiratory morbidity. As the interval from the rupture of membranes to the delivery increased, admission to the NICU was slightly increased (OR, 1.04; 95% CI, 0.1.01–1.06). The antenatal steroid administration was associated with decreased rates of mechanical ventilator use (OR, 0.32; 95% CI, 0.12–0.91) and with the rates of composite respiratory morbidity (OR, 0.39; 95% CI, 0.17–0.91).
Discussion
1. Principle findings of the study
1) The proportions of neonates who had received assisted ventilation including nasal CPAP, high-flow therapy, and mechanical ventilator were all significantly decreased as the gestational age at delivery advanced (P-trend <0.05 for all) in late preterm births after PROM. 2) The incidences of RDS were 14%, 7%, and 3% for preterm births in the 34th, 35th, and 36th week of gestation (P-trend =0.007). 3) The gestational age at delivery was associated with the rates of positive pressure ventilation immediately after birth, NICU admission, minor assisted ventilators such as nasal CPAP and/or high-flow therapy, and composite respiratory morbidity in preterm births with PROM after 34 weeks of gestation when analyzed by multivariate logistic regression. 4) The interval from PROM to delivery was independently associated with the rate of NICU admission (OR, 1.04; 95% CI, 1.01–1.06).
2. Concerns about optimal timing of delivery in the late preterm period after PROM
A survey once reported about 70% of physicians prefer to proceed to delivery when a patient presents with PROM after 34 weeks of gestation.26 Late preterm neonates have been considered sufficiently mature to be treated similarly to term infants. While many of these infants have shown positive outcomes, evidence suggesting significant maturation occurs during the last weeks of gestation has been reported and supports the considerable risk of adverse outcomes in neonates born before 37 weeks of gestation.2728
Most patients and their family members want to prolong pregnancy until the term period. Physicians suggest proceeding to delivery for preterm PROM patients in the late preterm period with an explanation of the complications such as chorioamnionitis and the reassurance of better morbidity than those in earlier gestation. However, if the neonates are admitted to the NICU and receive assisted ventilation, patients tend to be suspicious about the decision to delivery.
This study revealed, even in the late preterm period, gestational age at birth is a critical factor for neonatal morbidities and assisted ventilation use in preterm births complicated with PROM. A number of guidelines recommend not to prolong pregnancy after 34 weeks of gestation in patients with PROM to avoid the development of chorioamnionitis and further neonatal complications such as early-onset sepsis. However, this study demonstrated relatively high rates of assisted ventilation use and neonatal respiratory problems including major and minor ones. This result carefully suggests that expectant management rather than indicated delivery for late preterm patients with PROM would decrease the chance of respiratory complications if close monitoring for signs of chorioamnionitis such as fever is combined with it.
Indeed, current studies have challenged the traditional recommendations with reporting better or similar outcomes for expectant management in late preterm PROM patients when compared with indicated delivery immediately after 34 weeks of gestation. van der Ham et al.,25 demonstrated that the induction of labor did not reduce the risk of neonatal sepsis after PROM. The trial advocated expectant management with the identification of a high-risk subgroup for infection in later preterm PROM because it could potentially decrease neonatal complications from prematurity and the costs for the intensive care of neonates.29
There are a few studies showing the adverse outcomes of expectant management in later preterm PROM patients. Nayot et al.,3 reported no clear benefit of expectant management compared to elective induction of delivery in patients who had presented PROM after 34 weeks of gestation. Moreover, they demonstrated a significant increase in the incidence of necrotizing enterocolitis and longer admission days in the expectant management group than in the indicated delivery group.
3. The detailed information for counseling patients who present with PROM in late preterm and have a pending delivery
The rates of receiving positive pressure ventilator immediately after delivery were 24%, 8%, and 3% in neonates born in the 34-, 35-, and 36-week, respectively. The proportion of intubation at the delivery room was about 3% in preterm births in the 34th week and decreased to under 1% in the 35th and 36th week of gestation. The rates of relatively non-invasive assisted ventilation such as nasal CPAP and/or high-flow therapy were 23% and 6% for neonates born in the 34th week. Both the rates decreased below 10% and 1% when the gestational age at delivery advanced to 35 and 36 weeks of gestation. The mechanical ventilator use was 12%, 7%, and 3% for the 34th, 35th, and 36th week, respectively.
The rates of respiratory morbidity decreased when born in the 34th, 35th, and 36th week (18%, 8%, and 4%, respectively). The incidences of RDS, one of the most serious neonatal respiratory complications, decreased by about half (from 14% to 7%) when compared between the 34th and 35th week of gestation. Apnea is a rather minor respiratory complication; nevertheless, close monitoring is likely needed when presented. The known incidence of apnea is 4–7% for late preterm and less than 1–2% in term neonates.303132 Our study showed that the rates of frequent apnea were 3%, 1%, and 0% for neonates born in the 34th, 35th, and 36th week, respectively.
4. Strengths and limitations
The inevitable limitation of this study is its retrospective nature; however, the study population is relatively well-purified and restricted to a single tertiary center. All the studies done to identify neonatal respiratory outcomes in late preterm births with PROM were designed with the inclusion criteria focusing on maternal status. Therefore, adjusting for various factors was necessary. This study was done with only babies who were born in the late preterm period, meaning the outcomes were analyzed in late preterm neonates themselves, not in all the babies from mothers who presented with PROM. The proportions of each assisted ventilator care or respiratory morbidities including minor problems such as apnea will be a beneficial information for clinicians who need to counsel with patients since those data are lack in late preterm babies.
Pasquier et al.,33 reported similar results with our research on late preterm PROM patients. Those authors concluded that adverse neonatal outcomes were inversely related to gestational age at the time of PROM; however, the inclusion criteria for the study population were PROM cases from 24 weeks of gestation.33 Another study showed a higher rate of chorioamnionitis and neonatal sepsis in patients who had received expectant management compared to those with indicated delivery with prolongation of the latency period.34 The gestational age of PROM in this study was from 32 to 34 weeks of gestation.
Although late preterm births seem to be less severe than that of earlier gestation, gestational age at delivery is still an important factor for neonatal respiratory complications and for the use of assisted ventilation, even when the pregnancy is complicated with PROM.
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