To determine factors associated with latency time to birth after preterm premature rupture of membranes (PPROM) and the impact on neonatal outcomes.
Data on singleton pregnancies with PPROM (n=1535 infants) were prospectively collected in a computerized perinatal/neonatal database at a tertiary care perinatal center. Latency was characterized as ⩽72h versus >72 h after PPROM.
The percentage of women with latency to birth >72 h decreased from 67% in very preterm (gestational age (GA) 25 to 28 weeks) to 10% in late preterm women (GA 33 to 36 weeks). PPROM women with latency ⩽72 h were more likely to have pregnancy-induced hypertension and birth weight <3%; PPROM women with latency >72 h were more likely to have received steroids and develop clinical chorioamnionitis. PPROM <32 weeks GA with latency ⩽72 h was associated with a two-fold higher incidence of severe neonatal morbidity, while PPROM between 29 to 34 weeks GA and latency ⩽72 h was associated with a higher incidence of moderate neonatal morbidity.
A latency period >72 h was associated with a decreased incidence of adverse neonatal outcomes up to 32 weeks GA for severe and 34 weeks GA for moderate morbidity indices.
Preterm birth continues to be a leading cause of neonatal morbidity and mortality, with preterm premature rupture of membranes (PPROM) as the primary etiology in ∼25–30% of all preterm births.1, 2 The latency time between rupture of membranes and birth tends to be longer when PPROM occurs at an earlier gestational age (GA),2 allowing for administration of corticosteroids and antibiotics to the GA group that is likely to benefit most. However, despite the presumed benefits from these therapies, PPROM infants have a higher incidence of neonatal morbidity than preterm infants born at the same GA without PPROM.3, 4 This increase in neonatal morbidity has been attributed to an increase in perinatal complications such as umbilical cord compression and cord prolapse, placental abruption and chorioamnionitis.2, 5, 6 Additionally, fetal growth restriction, neonatal chronic lung disease and brain injury with adverse long-term outcomes have been reported to occur with higher incidences in PPROM pregnancies compared with preterm births due to other etiologies.4, 6, 7
Although observed increases in maternal and neonatal morbidity with ruptured membranes >24 h in term pregnancy have led to a consensus regarding induction of labor as standard of care,8 there is currently no consensus regarding the optimal GA for labor induction and delivery after PPROM.9, 10, 11 Several studies have shown increased latency and increased rates of chorioamnionitis in late preterm PPROM women managed expectantly, but found no differences in major neonatal morbidity and mortality, regardless of whether testing for pulmonary maturity was performed.12, 13, 14, 15 A meta-analysis of these studies recommended an approach of immediate induction of labor for all PPROM women >30 weeks GA or with confirmed pulmonary maturity, although this was mainly shown to benefit maternal morbidity rather than improving neonatal outcome.16 Long-term follow-up of infants born after PPROM demonstrated that the incidence of significant neurological disorders at 2 years of age was not modified by the length of the latency period17 but more so by GA at birth, suggesting that an aggressive approach to PPROM after 30 weeks GA does not have a negative impact on neonatal and child development and may reduce fetal risks associated with increased latency to birth. Somewhat less aggressive are the recent clinical guidelines published by the American College of Obstetrics and Gynecology (ACOG) with recommendations for expectant management of PPROM; ACOG advises corticosteroids and antibiotics at GAs between 24 to 31 weeks, expectant management between 32 to 33 weeks unless pulmonary maturity has been confirmed, and induction of labor at a GA of 34 weeks or greater.18
The central question of management of a pregnancy complicated by PPROM, however, remains as to whether and at what GA the risks associated with prematurity are outweighed by the risks associated with prolonged latency. We therefore used the prospectively collected perinatal and neonatal databases of a large tertiary referral center in London, Ontario, to delineate the impact of GA at PPROM and latency time until birth on perinatal complications and neonatal outcome. The current study was designed to compare latency from time of PPROM to birth of ⩽72 vs >72 h while controlling for factors that may impact on latency time and adverse outcomes. This design attempts to mimic a situation where ‘active management’ with elective labor induction occurs after the administration of steroids resulting in latency ⩽72 h, as compared with ‘expectant’ management, with maternal/fetal monitoring and prolongation of pregnancy resulting in latency >72 h.
Computerized perinatal and neonatal databases are maintained by St Joseph's Health Care, London, Ontario, Canada, and data for all births that occur at the hospital are prospectively entered by a dedicated research assistant from the medical chart, delivery records and neonatal records. The hospital is the tertiary care facility for south-western Ontario and serves a predominantly Caucasian population of ∼1.5 million people. Information that is collected for this retrospective cohort study includes maternal medical problems, pregnancy complications, obstetrical history and perinatal outcomes.
The present study population was formed on the basis of the following inclusion criteria: date of birth between 1 January, 1996 and 31 December, 2005; singleton gestation with no major congenital anomalies and a diagnosis of PPROM between 25 and 36 weeks GA with membrane rupture 1 h or more before the onset of labor. PPROM was determined by patient history and confirmed as indicated by sterile speculum exam with vaginal pooling of amniotic fluid. The database was then used to obtain selected variables for this study population providing for the calculation of latency time from membrane rupture to time of delivery, the assessment of pregnancy-related variables that may impact on latency time and the assessment of latency time in relation to a spectrum of maternal/neonatal outcomes. The study design and data collection were approved by and followed the guidelines of The University of Western Ontario Research Ethics Board for Health Sciences Research Involving Human Subjects (no. 12561E).
This study aims to determine at which GA aggressive management of PPROM, with induction of labor or cesarean section 48 h after steroid administration, has a favorable outcome compared with expectant management. To achieve this, we analyzed the temporal relation between PPROM and delivery as if it were a causal relation and the result of the intervention—the decision to deliver. All pregnancies with PPROM were therefore first stratified into three main groups based upon GA at presentation with PPROM: (1) very preterm with PPROM between 25 and 28 completed weeks, (2) preterm with PPROM between 29 and 32 completed weeks, and (3) late preterm with PPROM between 33 and 36 completed weeks. Each of these populations was analyzed independently and further stratified into two groups; a ‘no intervention’ group with a latency >72 h, and an ‘intervention’ group, where a decision to deliver by induction or Cesarean Section would likely lead to delivery within 72 h, a time frame that allows for induction time after the optimal effect of antenatal steroid administration is reached.
Pregnancy variables of interest in our analysis included factors such as GA at PPROM, maternal hypertension, placental abruption, clinical chorioamnionitis, antenatal steroid administration, and whether the patient had a spontaneous onset of labor or was electively delivered. Perinatal outcomes included GA at birth, fetal gender, birth weight, presence or absence of growth restriction with birth weight <3%, presence or absence of respiratory distress syndrome (RDS), bronchopulmonary dysplasia, intraventricular hemorrhage (IVH), periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity (ROP), neonatal sepsis, perinatal death and neonatal stay in the Neonatal Intensive Care Unit (NICU) as defined by accepted international classifications.19, 20, 21
Adverse neonatal outcomes were additionally combined in a moderate morbidity index defined as one or more of the following outcomes: RDS, IVH grades 1 or 2, ROP grades 1 or 2 or neonatal sepsis and a severe morbidity index defined as one or more of IVH grades 3 or 4, periventricular leukomalacia, necrotizing enterocolitis, ROP grades 3 or 4, bronchopulmonary dysplasia or perinatal death. These morbidity indices were designed to address the clinical impact of a neonatal outcome that either has a major effect on infant health (severe morbidity index), or a minor effect with less impact on long-term health (moderate morbidity index). Combining separate neonatal morbidities into two groups based on clinical impact allows for assessment of risk for neonatal complications in GA groups in which the incidence of individual complications is low.
Information on antenatal tocolytics (usually with indomethacin) and prophylactic antibiotic administration was not obtained as this is not readily available from the database. However, most PPROM women would not have received tocolytics, as per our standard protocols, and after June 1999 the majority of women would have received antenatal antibiotics as standard of care, using the protocol reported by Mercer et al.22
Categorical variables were analyzed initially using χ2-test; t-tests were utilized for continuous variables. Results determined to be significant at P<0.15 were then entered into logistic regression analyses for binary variables and linear regression for continuous variables, with our neonatal morbidity indices as the dependent variables and the maternal and obstetrical factors and independent variables. To determine the relationships of the maternal and obstetrical variables to latency, a second round of models was run with latency as the dependent variable, even though as a variable it is ‘time-related’ to the birth and may predetermine the neonatal outcomes. Of the pregnancy-related variables that were assessed for their effect on latency time, GA at PPROM, pregnancy-induced hypertension and clinical chorioamnionitis were found to be significantly associated, and were entered into the logistic (chorioamnionitis) or linear regression analysis (GA at PPROM). Steroid administration and pregnancy-induced hypertension were not entered into the regression analysis because of their causal relation to latency time or neonatal outcome.
Characteristics of the study population
Between 1 January, 1996 and 31 December, 2005, there were 1535 singleton infants without major anomalies born at St Joseph's Health Care with a diagnosis of PPROM between 24 completed weeks and 36 completed weeks. Over this time period there were 35 346 total counted births, giving a resultant PPROM rate for our study population of 4.3%, which is higher than the commonly quoted incidence of 3%,1, 2 in keeping with our center's tertiary care status. Of these women, 146 or 9.5% were very preterm (25 to 28 weeks), 293 or 19.1% were preterm (29 to 32 weeks), and 1098 or 71.5% were late preterm (33 to 36 weeks) at the time of membrane rupture (Figure 1). These three PPROM patient populations in turn showed a decrease in the percentage of women with latency time >72 h, from 67% in the very preterm, to 42% in the preterm and to 10% in the late preterm populations (Figure 1).
Pregnancy-related variables and latency time
In the preterm and late preterm groups, pregnancy-related variables that were assessed for their impact on latency time, GA at PPROM, pre-eclampsia, clinical chorioamnionitis and steroid administration were found to be significantly associated as shown in Table 1. Effects showed a similar trend in the very preterm group, but significance was not reached for any of the variables because of the small number of patients in this group, with the exception of maternal length of stay. Not surprisingly given the tendency to have a shorter latency with advancing GA, women with a latency time ⩽72 h on average had more advanced GAs at the time of PPROM. The incidence of IUGR (preterm; birth weight <3%, P<0.05; Table 2) and pregnancy-induced hypertension (preterm and late preterm, P<0.01; Table 1) were also found to be higher in PPROM women with latency time ⩽72 h suggesting a contributory role in their PPROM and/or labor onset. As expected, preterm women with latency time >72 h on average were more likely to receive steroids, also impacting the relationship to neonatal outcomes. The incidence of clinical chorioamnionitis was increased in the very preterm and preterm PPROM patient populations, with latency time >72 h potentially impacting on the neonatal outcomes of interest.
Latency time and neonatal outcomes
The impact of latency time ⩽72 versus >72 h on the neonatal outcomes studied, adjusting for the effect modification of the pregnancy-related variables previously noted, are shown in Table 2 and Figures 2, 3, 4. As expected, given the study design, the GA at birth was increased with latency time >72 versus ⩽72 h. The prolongation of pregnancy after PPROM was 17.4 versus 1.4 days for the very preterm, 13.0 versus 1.1 days for the preterm and 8.3 versus 0.7 days for the late preterm populations, with a corresponding increase in birth weights.
Accordingly, the incidence of neonatal RDS, bronchopulmonary dysplasia, IVH and ROP were all decreased with latency time >72 h, for the most part in the very preterm and preterm PPROM patient populations, and in keeping with the degree of prematurity as a primary determinant for these outcomes. Specifically, in the very preterm population, a decrease was observed in incidence of bronchopulmonary dysplasia and ROP, while in the preterm population latency time >72 h was associated with a decrease in the incidence in RDS and IVH. In the late preterm infants, incidences of RDS reached statistical significance despite an overall low occurrence of neonatal complications. Where significance was not reached, trends were consistent in all GA groups, consistent with an overall decrease in incidence of neonatal complications with latency time >72 h. However, the incidence of neonatal necrotizing enterocolitis was significantly increased with latency time >72 h in the late preterm neonates and showed a similar trend in the preterm infants.
Moderate and severe morbidity indexes were calculated to further assess the impact of latency time after PPROM on adverse neonatal outcome, including a re-analysis of the late preterm data stratified into PPROM at 33 to 34 weeks and 35 to 36 weeks. The moderate morbidity index, reflecting one or more of what were deemed to be moderate neonatal morbidities, whereas uniformly high for the very preterm neonates, was significantly decreased for both the preterm and the late preterm neonates with latency time >72 h versus ⩽72 h, 67 versus 49% (P<0.01) and 9.1 versus 4.4% (P<0.01), respectively (Figure 2). However, this decrease in moderate morbidity index for the late preterm neonates was mostly secondary to PPROM at 33 to 34 weeks (15.9 versus 3.8%, P=0.01) and was not significant after PPROM at 35 to 36 weeks (4.0 versus 0, P=0.9; Figure 2). The severe morbidity index, reflecting one or more of what were deemed to be severe neonatal morbidities, was also significantly decreased for both the very preterm and the preterm neonates with latency time >72 h versus ⩽72 h, 65 versus 35%, P<0.001 and 9.4 versus 4.9%, P=0.05 (Figure 3). Conversely, the severe morbidity index was marginally increased in the late preterm neonates with latency >72 h; this was secondary to PPROM at 35 to 36 weeks although this was not statistically significant (Figure 3).
Neonatal length of NICU stay was significantly decreased for the very preterm, preterm and late preterm 33 to 34 weeks PPROM neonates with latency >72 h, but not for the late preterm 35 to 36 weeks PPROM neonates, where neonatal length of NICU stay was instead marginally increased (Figure 4b).
We determined the impact of latency time on maternal and neonatal outcome, in a large cohort of singleton pregnancies and determined a benefit for infant outcome with latency > 72 h up to a GA of 34 weeks for moderate morbidity and up to 32 weeks for severe morbidity. After 34 weeks, no clear benefit of expectant management could be demonstrated and a significant increase in the incidence of necrotizing enterocolitis, a trend in increased severe morbidity and longer NICU length of stay were observed, supporting an approach to elective induction of women presenting with PPROM after 34 weeks GA.
Moderate neonatal morbidities, which are more common clinical outcomes, showed an increased incidence in all three GA populations with a latency ⩽72 h. This was statistically significant in both preterm and late preterm infants; in late preterm infants, a shortened latency period was associated with approximately a fourfold increase in moderate morbidity in the 33 to 34 weeks GA group. To minimize moderate morbidity, our data support expectant management until 34 completed weeks. This, however, needs to be viewed against a trend toward increased NICU length of stay, likely caused by small number of infants suffering severe complications against this background of low morbidity. To minimize severe morbidity, our data support expectant management until 32 completed weeks and suggest inducing labor at 33 weeks GA.
The study design has an inherent bias in the assumption that the two latency groups are similar and that the cause of a short latency to birth does not impact on maternal or neonatal outcome. This is likely not the case; latency is shorter when PPROM is a symptom of preterm labor associated with placental problems, infection, IUGR or preeclampsia, and these comorbidities can affect maternal and neonatal outcome.1 For this reason, one needs to interpret our results with caution when outcome is more favorable in the groups with longer latency, as is observed up to a GA of 32 weeks. It is however widely acknowledged that up to a GA of 28 to 32 weeks, neonatal outcome is largely dependent on GA at birth and no prospective study recommends elective delivery after PPROM before a GA of 30 weeks is reached. The opposite effect is observed in the late preterm group, where outcome is negatively affected by longer latency, despite an advance in GA at birth and comorbidities leading to a shorter latency time. The observed increase in neonatal morbidity and NICU length of stay in our analysis therefore likely reflects true consequences of a longer latency to birth, observed with expectant management after PPROM.
At the late GA of 34 to 36 weeks, many authorities recommend aggressive management based on the grounds that there is little to gain from a small increase in maturity, while increased risk of infection associated with a delay of birth may outweigh this. These conclusions are derived from observational studies like ours and although randomized controlled trials are underway (PPROMT, Australia, ISRCTN44485060, Safety and Efficacy Study of Intentional Delivery in Women With PPROM, Canada, NCT00259519), inclusion of large numbers of women is hampered by the natural tendency to deliver within 72 h after PPROM, which in our population occurred in 90% of women. Additionally, while aggressive management protocols call for induction of labor before term to avoid risk associated with chorioamnionitis, recent evidence suggests that long-term outcomes of late preterm infants may not be as favorable as was previously thought. Recent evidence suggests that healthy infants born at 34 to 36 weeks are still physiologically immature and have increased incidences of short-term respiratory, neurological, metabolical and immunological complications,23 as well as long-term (school age) neurological and behavioral problems and developmental delays.24, 25, 26 Counseling of women with late preterm PPROM should include discussion of these findings, and prospective studies looking into the management of PPROM should include assessment of these long-term effects.
A limitation of our study is the lack of availability of data regarding antibiotic use. Although after June 1999 the majority of women would have received antenatal antibiotics as standard of care,22 its impact on outcome could not be studied. This is the consequence of insufficient coding regarding the timing and reason for antibiotic administration; no distinction could be made in the database in this time period between antepartum prophylaxis (Mercer), intrapartum (GBS prophylaxis in labor, routine throughout the study period) or therapeutic (chorioamnionitis) antibiotic use. There is good evidence that antibiotic use after PPROM prolongs pregnancy, reduces incidence of chorioamnionitis and improves neonatal outcome.27, 28, 29, 30 However, this evidence has mainly been collected through studies that were limited to pregnancies <34 weeks GA, did not provide distinction between early and late preterm PROM and calculated mean GAs at PPROM of ∼30 weeks.28, 30 Routine administration of antibiotics in late preterm PROM was not practised in our center during the study time but is commonly practised in many centers that allow for expectant management after 34 weeks. Antibiotic prophylaxis in late preterm PROM, if beneficial, could have alleviated the observed increase in clinical chorioamnionitis, the trend for increase in severe neonatal morbidity and significant longer NICU length of stay in our women with latency >72 h. Our study highlights that when expectant management >34 weeks GA does not include antibiotic use, there is a risk for increasing morbidity with prolonging the late preterm pregnancy with PPROM, for the benefit of a small gain in maturity.
In summary, the decision for induction of birth versus expectant management would depend on how one evaluates a slightly higher incidence of an uncommon but severe neonatal outcome in comparison with a significant decrease in incidence of a more benign neonatal outcome, but with potential long-term developmental issues. Our results demonstrate that both moderate and severe morbidity are minimized by conservative management of PPROM up to 32 completed weeks. However, after 32 weeks GA it becomes more difficult to deduce a conclusion. Continuing a conservative approach would clearly minimize moderate morbidity, but may increase the incidence of severe morbidity, which has low background prevalence at such an advanced GA.
There are currently no official Canadian guidelines for the clinical management of PPROM. A common approach is the immediate induction once pulmonary maturity is confirmed: this would be after a course of corticosteroids in stable PPROM between 32 to 34 weeks GA or any PPROM after 34 weeks GA.31, 32, 33 Although the American College of Obstetrics and Gynecology guideline strongly favours induction of labor after 34 weeks gestation,18 this practice is not yet universally accepted and 42% of the 508 maternal-fetal medicine specialists surveyed in the US continue expectant management beyond this GA.9 Clearly there remains a gray zone between 32 to 34 weeks GA that requires further investigation. For management of late-preterm PPROM, a sufficiently large and updated randomized control trial with assessment of long-term outcome is needed to help delineate guidelines for obstetricians who regularly face the challenge of managing the complexities of this clinical population.
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We thank Dr Larry Stitt for statistical assistance, Gail Schmidt and Maria Sinacori for technical assistance, and Dr Renato Natale for his support of the perinatal database. Dr Dan Nayot received a Schulich Research Opportunities Program grant for his work on this project and Dr Barbra de Vrijer was supported by the Strategic Training Initiative in Research in the Reproductive Health Sciences (STIRRHS). Bryan S Richardson is the recipient of the Canada Research Chair in Fetal and Neonatal Health and Development. This paper has been presented SOGC 63rd Annual Clinical Meeting, 2007 (oral), and at the Society for Gynecological Investigation 55th Annual Meeting, 2008 (poster). Research was supported by the Schulich Research Opportunities Program, the Strategic Training Initiative in Research in the Reproductive Health Sciences (STIRRHS), and the Canada Research Chair in Fetal and Neonatal Health and Development.
Contribution to Authorship
Dr Dan Nayot contributed to the conception and design of the study, analyzed the data and prepared the manuscript. Drs Barbra de Vrijer and Debbie Penava, Orlando Da Silva and Bryan Richardson contributed to the conception and design of the study, guided the data analysis and helped critically revise the manuscript. All authors gave final approval to the manuscript for submission.
Details of Ethics Approval
This project was approved by the Health Sciences Research Ethics Board at the University of Western Ontario, London, Ontario, Canada (HSREB 12561E).
The authors declare no conflict of interest.
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Nayot, D., Penava, D., Da Silva, O. et al. Neonatal outcomes are associated with latency after preterm premature rupture of membranes. J Perinatol 32, 970–977 (2012). https://doi.org/10.1038/jp.2012.15
Risk factors and perinatal outcomes associated with latency in preterm premature rupture of membranes between 24 and 34 weeks of gestation
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