Manuck, Tracy A. MD1; Eller, Alexandra G. MD1; Esplin, M Sean MD1; Stoddard, Gregory J. MPH2; Varner, Michael W. MD1; Silver, Robert M. MD1
Preterm premature rupture of membranes (PROM) occurring before or at the limits of viability, defined as rupture of membranes less than 24.0 weeks of gestation, complicates less than 1% of all pregnancies.1 Traditionally, incomplete fetal lung development (pulmonary hypoplasia) has been regarded as the largest obstacle to survival in neonates affected by early preterm PROM.2 During the canalicular phase of lung development, between 18 and 26 weeks of gestation, respiratory bronchioles, alveolar ducts, and primitive alveoli are formed, surfactant production begins, and exchange of carbon dioxide and oxygen necessary to sustain extrauterine life becomes possible.3,4 The presence of at least a small amount of amniotic fluid seems to be necessary for fetal lung distention and development during this critical period.3,5
Women who experience preterm PROM less than 24.0 weeks of gestation without overt intrauterine infection are offered either active management and delivery or expectant management. It is widely accepted that expectant management of these pregnancies results in a high rate of chorioamnionitis, a relatively poor chance of neonatal survival, and a high rate of severe long-term neonatal morbidity among surviving infants.6
Although there are many articles addressing preterm PROM occurring after 24 weeks of gestation, there are few regarding outcomes when amniorrhexis occurs before 24 weeks. Also, there have been considerable recent advances in neonatal care, with resultant improved outcomes at earlier gestations.7,8 Thus, there are few pertinent data available to counsel women with early preterm PROM. Our objective was to assess contemporary neonatal outcomes in expectantly managed cases of preterm PROM less than 24.0 weeks of gestation. Additionally, we sought to identify factors that are associated with improved outcomes.
MATERIALS AND METHODS
Patients with preterm PROM at less than 24 0/7 weeks of gestation were identified by an International Classification of Diseases, 9th Revision code search of outpatient and inpatient medical records at two tertiary care referral centers, from January 2001 through December 2007. Maternal and neonatal medical records were reviewed to obtain demographic information, medical histories, and clinical course. This study was approved by the institutional review boards at the University of Utah Health Sciences Center and Intermountain Healthcare, both in Salt Lake City, Utah.
Patients with pooling of amniotic fluid on speculum examination, a positive Nitrazine (Bristol-Myers Squibb, Princeton, NJ) or ferning test, or the subjective complaints of loss of fluid from the vagina combined with decreased amniotic fluid index (AFI) less than 5.0 cm on ultrasonography were diagnosed with preterm PROM. Gestational age was determined from the last menstrual period if it agreed with an ultrasound estimation within 7 days (first trimester) or within 10 days (second trimester); otherwise, the pregnancy was dated ultrasonographically.
Patients were counseled by a maternal–fetal medicine specialist regarding the risks and benefits of expectant management compared with pregnancy termination. Women who elected expectant management and achieved a minimum latency period of 12 hours were included. Patients were excluded if they elected active management/delivery, were carrying a fetus with anomalies, presented with chorioamnionitis, experienced preterm PROM within 14 days of either amniocentesis or cervical cerclage placement, were carrying multiple gestations, or had an intrauterine fetal demise at the time of presentation. Patients who labored and delivered within 12 hours of preterm PROM were also excluded, to avoid inclusion of patients who experienced preterm PROM secondary to advanced cervical dilation.
Neonatal survival without major morbidities was the primary outcome measure. Composite severe neonatal morbidity included grade III or grade IV hemorrhage, periventricular leukomalacia, pulmonary hypoplasia, bronchopulmonary dysplasia, or necrotizing enterocolitis requiring surgical treatment.
The majority of patients experiencing preterm PROM at less than 22 weeks of gestation were initially observed in the hospital for 1–2 days for evidence of chorioamnionitis and preterm labor. They were then managed as outpatients until 23–25 weeks of gestation, when they were readmitted for hospital bed rest, intramuscular steroid administration, and intensive antenatal surveillance. The decision to administer latency antibiotics was made at the discretion of the individual maternal–fetal medicine specialist; the majority of patients receiving latency antibiotics received ampicillin with or without erythromycin for a total of 7 days, per previously reported regimens.9 Tocolysis was used infrequently and only if deemed necessary during transport from an outlying facility; these medications were discontinued upon arrival at our tertiary care centers. Receipt of latency antibiotics and tocolytics were not included in the analysis because of a bias toward their use in pregnancies reaching later gestational ages.
All patients were monitored with serial ultrasonograms to evaluate growth and AFI. A four-quadrant AFI was obtained every 2–10 days. The initial AFI as well as the amniotic fluid nadir, that is, the lowest documented AFI after preterm PROM, were also recorded. The presence of “absolute anhydramnios,” defined as no measurable amniotic fluid (AFI=0) at any time after preterm PROM, was also noted. Routine cultures for group B streptococci were obtained at 23–24 weeks of gestation. Patients were treated with penicillin during active labor if cultures were positive.
Chorioamnionitis was diagnosed if patients met either clinical or histologic criteria. Clinical chorioamnionitis was defined as maternal temperature more than 38.0°C and fundal tenderness on examination; histologically, the diagnosis was made if acute chorioamnionitis or funisitis or both were recorded in placental pathology reports. Placental abruption was defined as vaginal bleeding out of proportion to that which would be expected from cervical change or digital examination in the absence of other identifiable causes of vaginal bleeding. The placental abruption was classified as acute if vaginal bleeding occurred within 24 hours of delivery, and chronic if it occurred remote from delivery (more than 24 hours) and there were at least two episodes of bleeding.
Screening cranial ultrasonography on all infants delivered at less than 32 weeks of gestation was performed at 1 week of age; those infants delivered at less than 29 weeks of gestation had a second cranial ultrasonogram at approximately 1 month of age, regardless of the results of the initial ultrasonography. Intraventricular hemorrhages were graded I–IV using criteria defined by Papile et al.10
Joint contractures were defined as the presence of persistent positional deformities of one or more extremities without any other identifiable causes. Necrotizing enterocolitis was diagnosed based on clinical findings of abdominal distension, hematochezia, worsening clinical status, and abnormal gaseous abdominal X-ray patterns (definitive necrotizing enterocolitis based on stage 2 or greater Bell’s criteria11). The decision for surgical treatment of necrotizing enterocolitis was made at the discretion of the attending pediatric surgeon. Pulmonary hypoplasia was defined as either a less than eight-rib lung expansion on chest X-ray or clinical diagnosis made by the attending neonatologist secondary to difficulty ventilating, with chest X-ray findings suggestive of poor aeration.12
Neonates requiring supplemental oxygen (Fio2 greater than 25.0%, corrected for partial pressure of oxygen at moderate altitude in Salt Lake City, UT), high flow nasal cannula oxygen (flow rate more than 1 L/min), positive airway pressure, or ventilator support at 36 weeks postconceptual age were diagnosed with bronchopulmonary dysplasia.13,14
Analyses of characteristics of patients with an infant surviving with and without major neonatal morbidity were compared using Student t test, χ2, and Fisher exact test where appropriate. Time-specific probability estimates of morbidity and mortality were calculated using a modified Kaplan-Meier approach. Patients were grouped by gestational age at the time of preterm PROM, and each gestational age group was analyzed in 2-week increments after rupture. The number of patients from each preterm PROM gestational age group who experienced death or morbidity during each subsequent 2-week increment were divided by the number of patients still being followed. If there were no events (deaths or diagnoses of morbidity) during a specific time period, the risks from the earlier time interval were carried forward, consistent with the Kaplan-Meier approach.15
Multivariable Cox regression was used to assess factors associated with fetal death, and multivariable logistic regression was used to evaluate the independent effects of variables associated with severe neonatal morbidity. In both regressions, independent variables were included in the analysis if they were statistically associated with the dependent variable at P<.20. Variables with P<.10 were retained in the final regression models.
One-way analysis of variance was used for continuous variables when three groups were compared. A χ2 and Fisher exact test were used, as appropriate, for both two-group and three-group comparisons. Statistical significance was set at P<.05. Pearson correlation coefficients are used to report linear associations between two continuous variables. Data were analyzed using Stata 10.0 (StataCorp LP, College Station, TX).
One-hundred sixty-one patients met study inclusion criteria; two patients were lost to follow-up. One hundred fifty-nine patients were analyzed. The outcome schematic, mean gestational ages at the time of preterm PROM, and mean delivery gestational ages are shown in Figure 1. Maternal demographics and characteristics are listed in Table 1.
Clinical chorioamnionitis (34%) and labor (33%) were the two most common indications for delivery. Twenty-three women (14%) were delivered after abnormal antenatal testing, and nine women (6%) were delivered secondary to an acute abruption. Two patients (1%) had documented fetal lung maturity at 33 weeks of gestation and four patients (3%) reached 34 weeks of gestation and underwent induction of labor per institutional protocol. One patient developed severe preeclampsia at 31.7 weeks of gestation, prompting delivery.
Six women (4%) experienced an intrauterine fetal demise after preterm PROM. The mean latency period between rupture and diagnosis of the intrauterine fetal demise was 12 (range 1–37) days. Additionally, seven women (4%) elected labor induction after initially choosing expectant management; these patients had a mean latency period of 19 (range 4–47) days before electing delivery.
Overall, 85 women (54%) developed clinical or histologic evidence of chorioamnionitis. Patients who developed clinical or histologic chorioamnionitis had a shorter average latency period compared with women who did not have intrauterine infection (27 compared with 43 days, P<.001); those with clinical evidence of chorioamnionitis had an even shorter latency period (24 days compared with 41 days, P<.001).
There was a high overall rate of placental abruption; 57 patients (36%) had a chronic abruption, 40 patients (25%) experienced an acute abruption, and 23 women (14%) were diagnosed with both an acute and chronic abruption. Women with a chronic abruption experienced preterm PROM approximately one week earlier than those without an abruption (20.0 compared with 21.1 weeks of gestation, P=.009). However, they did not deliver at a significantly earlier gestational age (25.6 compared with 25.5 weeks, P=.88). There was no relationship between acute abruption and gestational age at the time of rupture or time of delivery.
One hundred twelve neonates were admitted to the neonatal intensive care unit; their characteristics are shown in Table 2. Of the 112 infants admitted to neonatal intensive care, 89 (56.0% of all newborns) survived; 43 (48.3% of survivors, 27.0% of all newborns) had no major neonatal morbidities. Pulmonary hypoplasia was diagnosed in 14 of 112 (13%); 9 of these 14 (64%) neonates died; none had autopsies performed. Neonates with pulmonary hypoplasia experienced preterm PROM approximately 2 weeks earlier when compared with neonates who did not develop pulmonary hypoplasia (18.9 compared with 20.9 weeks of gestation, P=.006). Each additional week of gestational age at the time of rupture decreased the risk of pulmonary hypoplasia by 21% (95% confidence interval [CI] 38–97%, P=.025). Joint contractures were noted in 8 of 112 (7%) neonates. Contraction deformities and pulmonary hypoplasia are both presumptive sequelae of clinically significant oligohydramnios; however, there did not seem to be a relationship between the development of contractures and diagnosis of pulmonary hypoplasia (r=0.13, P=.13).
Women whose neonates survived had an average postrupture AFI of 3.4 cm compared with 1.8 cm in pregnancies with neonates who did not survive (P<.001). Surviving neonates also had a lower incidence of anhydramnios (32% compared with 53%, P=.014). Furthermore, 57% of neonates diagnosed with pulmonary hypoplasia had anhydramnios at some point, and 71% had an average AFI less than 2 cm. Although AFI correlated with outcomes, the sensitivity and specificity were low. For example, the presence of anhydramnios was only 43% sensitive (95% CI 33–53%) and 64% specific (95% CI 47–78%) in predicting neonates with major morbidities.
Table 3 and 4 provide information regarding the chance of survival and survival without major morbidities, respectively, stratified by gestational age at the time of preterm PROM and the current gestational age of the pregnancy. These tables demonstrate that the probability of neonatal death and major morbidity both decrease with increasing latency. For example, a woman with preterm PROM at 18 weeks of gestation who remains pregnant at 22 weeks of gestation still has a 42% chance that her fetus will deliver before viability or reach a viable gestational age and die in the neonatal intensive care unit; while high, this probability is decreased from a 57% chance of death at the time of preterm PROM before attaining any latency (Table 3). Similarly, the same hypothetical patient’s newborn had a mere 20% chance of surviving to viability without major morbidity at the time of preterm PROM; these chances are increased to 27% if she remains pregnant at 22 weeks of gestation (Table 4).
Results of Cox regression (mortality) and logistic regression (composite major neonatal morbidity) are displayed in Tables 5 and 6. The number of latency days was not separately evaluated in the regression models because of a high degree of correlation with delivery gestational age (r=0.81, P<.001).
Maternal complications were uncommon. There were no cases of maternal sepsis and two patients with peripartum pulmonary emboli. Both patients responded well to medical treatment and were discharged within the first 8 days postpartum. There were no maternal deaths.
Outcomes in patients remaining pregnant at least 12 hours after early preterm PROM in our study are substantially better than previously reported. There are several possible explanations for improved outcomes in our study compared with other investigators. Factors such as small sample size16–19 and neonatal care before widespread corticosteroid and surfactant administration20–24 may have contributed to relatively poor outcomes in previous studies. Conversely, including patients with preterm PROM at later gestational ages20,21,25,26 and all fetuses in a multiple gestation16,20,25 may create bias toward better outcomes. Although our study design does not permit us to address this issue directly, our relatively good outcomes may in part be a result of improved obstetric and neonatal care.7,8
It is difficult to determine an exact “cutoff” point in gestation below which survival, or survival without major neonatal morbidity, is hopeless. However, in our cohort, there were no survivors if preterm PROM occurred earlier than 16 weeks of gestation. It is likely that when severe oligohydramnios or anhydramnios is present before the canalicular stage of lung development, lung tissue development compatible with survival is unlikely.
Our findings of poor outcome associated with the diagnosis of pulmonary hypoplasia are similar to previous reports.23,25,27 Unfortunately, the AFI remains limited in its usefulness to predict which neonates will ultimately develop pulmonary hypoplasia or morbidity or both. Although lower values are generally associated with worse prognosis, the predictive value is low, and a discrimination level of 0.5–1.0 cm is technically difficult and subject to interobserver variation.
Both gestational age at delivery and gestational age at the time of preterm PROM were important predictors of survival without significant neonatal morbidity, although the gestational age at the time of preterm PROM was not predictive of neonatal mortality. Delivery gestational age was the factor that was most predictive of both neonatal survival and neonatal survival without major morbidity, consistent with most studies of infants born at the threshold of viability for various indications.8,20,28,29
Early onset sepsis (diagnosed in the first week of life with positive blood cultures) was predictive of adverse outcomes; of 14 infants who developed sepsis during the first week of life, six died, seven experienced major neonatal morbidity, and only one survived without major neonatal morbidity. Unfortunately, the correlation between early onset neonatal sepsis and chorioamnionitis was imperfect (r=0.15, P=.09). Seventy-one percent of neonates with early onset sepsis were delivered from women with clinical or histologic evidence of chorioamnionitis, but 48% of women with chorioamnionitis delivered infants that did not develop sepsis in the first week of life (P=.09).
Thus, clinical measures such as AFI and the detection of chorioamnionitis are imprecise in the prediction of neonatal outcomes after early preterm PROM. The clinician often struggles with counseling patients regarding neonatal prognosis in this difficult situation. Our tables (Tables 3 and 4) listing probabilities of morbidity and mortality at specific latency periods after previable preterm PROM are valuable in counseling women who attain latency after early preterm PROM, and provide concrete data in a circumstance when clinical predictors are inadequate.
Our study had several limitations. The retrospective design may contribute to bias. Also, both of our health care systems are large tertiary-care referral centers; thus, a preadmission selection bias may exist, because this was not a population-based study. Given the traditionally poor outcomes after preterm PROM less than 24.0 weeks of gestation, there are likely a percentage of patients who were managed by their primary obstetrician or failed initial expectant management and were not included in this analysis. Our composite serious neonatal morbidity may or may not be an appropriate surrogate for childhood developmental outcome. Further study is needed to assess longer-term developmental outcomes of early preterm PROM survivors.
In conclusion, this study presents outcomes on a large cohort of patients with singleton gestations who achieve at least 12 hours of latency after preterm PROM less than 24.0 weeks of gestation. Serious maternal complications were uncommon. Our data are noteworthy for an overall neonatal survival rate of 56%, and nearly one half of surviving infants did not have severe neonatal morbidities.
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© 2009 by The American College of Obstetricians and Gynecologists.