Neonatal Outcomes Are Associated with Latency After Preterm Premature Rupture of Membranes

Home , Chorioamnionitis

Journal of Perinatology (2012) 32, 970–977 r 2012 Nature America, Inc. All rights reserved. 0743-8346/12 www.nature.com/jp ORIGINAL ARTICLE Neonatal outcomes are associated with latency after preterm premature rupture of membranes

D Nayot1, D Penava1, O Da Silva2,3, BS Richardson1,3 and B de Vrijer1 1Department of Obstetrics and Gynaecology, Children Health Research Institute, University of Western Ontario, London, ON, Canada; 2Department of Pediatrics, Children Health Research Institute, University of Western Ontario, London, ON, Canada and 3Physiology/Pharmacology, Children Health Research Institute, University of Western Ontario, London, ON, Canada

births.1,2 The latency time between rupture of membranes and birth Objective: To determine factors associated with latency time to birth after tends to be longer when PPROM occurs at an earlier gestational age preterm premature rupture of membranes (PPROM) and the impact on (GA),2 allowing for administration of corticosteroids and antibiotics neonatal outcomes. to the GA group that is likely to benefit most. However, despite the Study Design: Data on singleton pregnancies with PPROM (n ¼ 1535 presumed benefits from these therapies, PPROM infants have a infants) were prospectively collected in a computerized perinatal/neonatal higher incidence of neonatal morbidity than preterm infants born at 3,4 database at a tertiary care perinatal center. Latency was characterized as the same GA without PPROM. This increase in neonatal morbidity p72h versus >72 h after PPROM. has been attributed to an increase in perinatal complications such as umbilical cord compression and cord prolapse, placental abruption Result: The percentage of women with latency to birth >72 h decreased and chorioamnionitis.2,5,6 Additionally, fetal growth restriction, from 67% in very preterm (gestational age (GA) 25 to 28 weeks) to 10% in neonatal chronic lung disease and brain injury with adverse late preterm women (GA 33 to 36 weeks). PPROM women with latency long-term outcomes have been reported to occur with higher 72 h were more likely to have pregnancy-induced hypertension and p incidences in PPROM pregnancies compared with preterm births due birth weight <3%; PPROM women with latency >72 h were more likely to other etiologies.4,6,7 to have received steroids and develop clinical chorioamnionitis. PPROM Although observed increases in maternal and neonatal <32 weeks GA with latency 72 h was associated with a two-fold higher p morbidity with ruptured membranes >24 h in term pregnancy incidence of severe neonatal morbidity, while PPROM between 29 to 34 have led to a consensus regarding induction of labor as standard of weeks GA and latency 72 h was associated with a higher incidence of p care,8 there is currently no consensus regarding the optimal GA for moderate neonatal morbidity. labor induction and delivery after PPROM.9–11 Several studies have Conclusion: A latency period >72 h was associated with a decreased shown increased latency and increased rates of chorioamnionitis in incidence of adverse neonatal outcomes up to 32 weeks GA for severe and late preterm PPROM women managed expectantly, but found no 34 weeks GA for moderate morbidity indices. differences in major neonatal morbidity and mortality, regardless Journal of Perinatology (2012) 32, 970–977; doi:10.1038/jp.2012.15; of whether testing for pulmonary maturity was performed.12–15 published online 15 March 2012 A meta-analysis of these studies recommended an approach of immediate induction of labor for all PPROM women >30 weeks Keywords: PPROM; pregnancy; morbidity GA or with confirmed pulmonary maturity, although this was mainly shown to benefit maternal morbidity rather than improving 16 Introduction neonatal outcome. Long-term follow-up of infants born after PPROM demonstrated that the incidence of significant neurological Preterm birth continues to be a leading cause of neonatal morbidity disorders at 2 years of age was not modified by the length of the and mortality, with preterm premature rupture of membranes latency period17 but more so by GA at birth, suggesting that an B (PPROM)astheprimaryetiologyin 25–30% of all preterm aggressive approach to PPROM after 30 weeks GA does not have a Correspondence: Dr B de Vrijer, Department of Obstetrics and Gynaecology, University of negative impact on neonatal and child development and may Western Ontario, London Health Sciences Center, Victoria Hospital, 800 Commisioners Road reduce fetal risks associated with increased latency to birth. E, Room B2-412, London, ON, Canada N6A 5W9. Somewhat less aggressive are the recent clinical guidelines E-mail: [email protected] Received 21 September 2011; revised 24 January 2012; accepted 6 February 2012; published published by the American College of Obstetrics and Gynecology online 15 March 2012 (ACOG) with recommendations for expectant management of Neonatal outcomes after PPROM D Nayot et al 971

PPROM; ACOG advises corticosteroids and antibiotics at GAs compared with expectant management. To achieve this, we between 24 to 31 weeks, expectant management between 32 to analyzed the temporal relation between PPROM and delivery as if it 33 weeks unless pulmonary maturity has been confirmed, and were a causal relation and the result of the interventionFthe induction of labor at a GA of 34 weeks or greater.18 decision to deliver. All pregnancies with PPROM were therefore first The central question of management of a pregnancy complicated stratified into three main groups based upon GA at presentation by PPROM, however, remains as to whether and at what GA the risks with PPROM: (1) very preterm with PPROM between 25 and 28 associated with prematurity are outweighed by the risks associated completed weeks, (2) preterm with PPROM between 29 and 32 with prolonged latency. We therefore used the prospectively collected completed weeks, and (3) late preterm with PPROM between 33 perinatal and neonatal databases of a large tertiary referral center in and 36 completed weeks. Each of these populations was analyzed London, Ontario, to delineate the impact of GA at PPROM and independently and further stratified into two groups; a ‘no latency time until birth on perinatal complications and neonatal intervention’ group with a latency >72 h, and an ‘intervention’ outcome. The current study was designed to compare latency from group, where a decision to deliver by induction or Cesarean Section time of PPROM to birth of p72 vs >72 h while controlling for would likely lead to delivery within 72 h, a time frame that allows factors that may impact on latency time and adverse outcomes. This for induction time after the optimal effect of antenatal steroid design attempts to mimic a situation where ‘active management’ administration is reached. with elective labor induction occurs after the administration of Pregnancy variables of interest in our analysis included factors steroids resulting in latency p72 h, as compared with ‘expectant’ such as GA at PPROM, maternal hypertension, placental abruption, management, with maternal/fetal monitoring and prolongation of clinical chorioamnionitis, antenatal steroid administration, and pregnancy resulting in latency >72 h. 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 Methods birth weight <3%, presence or absence of respiratory distress Computerized perinatal and neonatal databases are maintained by syndrome (RDS), bronchopulmonary dysplasia, intraventricular St Joseph’s Health Care, London, Ontario, Canada, and data for all hemorrhage (IVH), periventricular leukomalacia, necrotizing births that occur at the hospital are prospectively entered by a enterocolitis, retinopathy of prematurity (ROP), neonatal sepsis, dedicated research assistant from the medical chart, delivery perinatal death and neonatal stay in the Neonatal Intensive Care records and neonatal records. The hospital is the tertiary care Unit (NICU) as defined by accepted international classifications.19–21 facility for south-western Ontario and serves a predominantly Adverse neonatal outcomes were additionally combined in a Caucasian population of B1.5 million people. Information that is moderate morbidity index defined as one or more of the following collected for this retrospective cohort study includes maternal outcomes: RDS, IVH grades 1 or 2, ROP grades 1 or 2 or neonatal medical problems, pregnancy complications, obstetrical history and sepsis and a severe morbidity index defined as one or more of IVH perinatal outcomes. grades 3 or 4, periventricular leukomalacia, necrotizing enterocolitis, The present study population was formed on the basis of the ROP grades 3 or 4, bronchopulmonary dysplasia or perinatal death. following inclusion criteria: date of birth between 1 January, 1996 These morbidity indices were designed to address the clinical impact and 31 December, 2005; singleton gestation with no major of a neonatal outcome that either has a major effect on infant congenital anomalies and a diagnosis of PPROM between 25 and health (severe morbidity index), or a minor effect with less impact 36 weeks GA with membrane rupture 1 h or more before the onset on long-term health (moderate morbidity index). Combining of labor. PPROM was determined by patient history and confirmed separate neonatal morbidities into two groups based on clinical as indicated by sterile speculum exam with vaginal pooling of impact allows for assessment of risk for neonatal complications in amniotic fluid. The database was then used to obtain selected GA groups in which the incidence of individual complications is low. variables for this study population providing for the calculation of Information on antenatal tocolytics (usually with latency time from membrane rupture to time of delivery, the indomethacin) and prophylactic antibiotic administration was not assessment of pregnancy-related variables that may impact on obtained as this is not readily available from the database. latency time and the assessment of latency time in relation to a However, most PPROM women would not have received tocolytics, spectrum of maternal/neonatal outcomes. The study design and as per our standard protocols, and after June 1999 the majority of data collection were approved by and followed the guidelines of The women would have received antenatal antibiotics as standard of University of Western Ontario Research Ethics Board for Health care, using the protocol reported by Mercer et al.22 Sciences Research Involving Human Subjects (no. 12561E). This study aims to determine at which GA aggressive Data analysis management of PPROM, with induction of labor or cesarean Categorical variables were analyzed initially using w2-test; t-tests section 48 h after steroid administration, has a favorable outcome were utilized for continuous variables. Results determined to be

Journal of Perinatology Neonatal outcomes after PPROM D Nayot et al 972 significant at P<0.15 were then entered into logistic regression Pregnancy-related variables and latency time analyses for binary variables and linear regression for con- In the preterm and late preterm groups, pregnancy-related tinuous variables, with our neonatal morbidity indices as the variables that were assessed for their impact on latency time, GA at dependent variables and the maternal and obstetrical factors and PPROM, pre-eclampsia, clinical chorioamnionitis and steroid independent variables. To determine the relationships of the administration were found to be significantly associated as shown maternal and obstetrical variables to latency, a second round of in Table 1. Effects showed a similar trend in the very preterm models was run with latency as the dependent variable, even though group, but significance was not reached for any of the variables as a variable it is ‘time-related’ to the birth and may predetermine because of the small number of patients in this group, with the the neonatal outcomes. Of the pregnancy-related variables that were exception of maternal length of stay. Not surprisingly given the assessed for their effect on latency time, GA at PPROM, pregnancy- tendency to have a shorter latency with advancing GA, women with induced hypertension and clinical chorioamnionitis were found to a latency time p72 h on average had more advanced GAs at the be significantly associated, and were entered into the logistic time of PPROM. The incidence of IUGR (preterm; birth weight (chorioamnionitis) or linear regression analysis (GA at PPROM). <3%, P<0.05; Table 2) and pregnancy-induced hypertension Steroid administration and pregnancy-induced hypertension were (preterm and late preterm, P<0.01; Table 1) were also found to be not entered into the regression analysis because of their causal higher in PPROM women with latency time p72 h suggesting a relation to latency time or neonatal outcome. contributory role in their PPROM and/or labor onset. As expected, preterm women with latency time >72 h on average were more

Results Table 1 Pregnancy-related variables and latency time Characteristics of the study population Between 1 January, 1996 and 31 December, 2005, there were 1535 Very preterm Preterm Late preterm singleton infants without major anomalies born at St Joseph’s p72 h >72 h p72 h >72 h p72 h >72 h Health Care with a diagnosis of PPROM between 24 completed weeks and 36 completed weeks. Over this time period there were GA at PPROM (weeks) 26.5 26.6 30.9** 30.5 35.2** 34.0 35 346 total counted births, giving a resultant PPROM rate for our PIH (%) 4.2 2.1 14.6** 2.5 13.2** 2.7 study population of 4.3%, which is higher than the commonly Abruption (%) 35.4 33.0 17.0 19.7 5.9 5.3 quoted incidence of 3%,1,2 in keeping with our center’s tertiary care Clin chorio (%) 25.0 38.1 14.6** 35.3 2.6** 10.6 status. Of these women, 146 or 9.5% were very preterm (25 to 28 Steroids (%) 83.3 86.6 67.3** 82.0 7.4 12.4 weeks), 293 or 19.1% were preterm (29 to 32 weeks), and 1098 or Elective delivery (%) 23.0 22.0 31.0 23.0 53.0 44.0 Maternal LOS (days) 6.7** 19.1 6.1** 13.9 4.4** 8.7 71.5% were late preterm (33 to 36 weeks) at the time of membrane rupture (Figure 1). These three PPROM patient populations in turn Abbreviations: Clin chorio, clinical chorioamnionitis; GA, gestational age; LOS, length of stay; PIH, pregnancy-induced hypertension; PPROM, preterm premature rupture of showed a decrease in the percentage of women with latency time membranes. >72 h, from 67% in the very preterm, to 42% in the preterm and to Data are presented as mean or % incidence. *P<0.05 and **P<0.01 latency time p72 h 10% in the late preterm populations (Figure 1). versus >72 h as determined with linear regression or logistic regression analysis.

Figure 1 Characteristics of the study population. Distribution of infants with preterm premature rupture of membranes (PPROM) between 25 to 36 weeks gestational age (GA) in combined perinatal/neonatal database, delivered between January 1996 and 31 December, 2005 (n ¼ 35 346). GA groups are deﬁned based on GA at time of rupture of membranes: Very preterm (25 to 28 weeks), preterm (GA 29 to 32 weeks) and late preterm (GA 33 to 36 weeks).

Journal of Perinatology Neonatal outcomes after PPROM D Nayot et al 973 likely to receive steroids, also impacting the relationship to prolongation of pregnancy after PPROM was 17.4 versus 1.4 days neonatal outcomes. The incidence of clinical chorioamnionitis was for the very preterm, 13.0 versus 1.1 days for the preterm and increased in the very preterm and preterm PPROM patient 8.3 versus 0.7 days for the late preterm populations, with a populations, with latency time >72 h potentially impacting on the corresponding increase in birth weights. neonatal outcomes of interest. Accordingly, the incidence of neonatal RDS, bronchopulmonary dysplasia, IVH and ROP were all decreased with latency time Latency time and neonatal outcomes >72 h, for the most part in the very preterm and preterm PPROM The impact of latency time p72 versus >72 h on the neonatal patient populations, and in keeping with the degree of prematurity outcomes studied, adjusting for the effect modification of the as a primary determinant for these outcomes. Specifically, in the pregnancy-related variables previously noted, are shown in Table 2 very preterm population, a decrease was observed in incidence and Figures 2–4. As expected, given the study design, the GA at of bronchopulmonary dysplasia and ROP, while in the preterm birth was increased with latency time >72 versus p72 h. The 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 Table 2 Latency time and neonatal outcomes low occurrence of neonatal complications. Where significance was Very preterm Preterm Late preterm not reached, trends were consistent in all GA groups, consistent with an overall decrease in incidence of neonatal complications p72 h >72 h p72 h >72 h p72 h >72 h with latency time >72 h. However, the incidence of neonatal GA at delivery (weeks) 26.7* 29.1 31.1** 32.4 35.3** 35.2 necrotizing enterocolitis was significantly increased with latency Male gender (%) 44.0 57.0 58.0 57.0 53.0 58.0 time >72 h in the late preterm neonates and showed a similar Birth weight (grams) 1016.0** 1392.0 1743.0** 2004.0 2697.0** 2604.0 trend in the preterm infants. Birth weight <3% (%) 10.4 4.1 10.5* 2.5 4.5 2.7 Moderate and severe morbidity indexes were calculated to RDS (%) 72.3 66.7 37.1** 18.9 6.0** 0.9 further assess the impact of latency time after PPROM on adverse BPD (%) 54.4** 25.5 2.9 0.0 0.1 0.0 neonatal outcome, including a re-analysis of the late preterm data IVH (%) 58.1 38.5 25.9* 12.2 1.0 0.0 stratified into PPROM at 33 to 34 weeks and 35 to 36 weeks. The PVL (%) 4.3 4.2 1.2 0.0 0.0 0.0 moderate morbidity index, reflecting one or more of what were NEC (%) 6.4 4.2 2.4 4.9 0.2* 1.8 ROP (%) 42.6* 23.2 4.2 1.0 0.1 0.0 deemed to be moderate neonatal morbidities, whereas uniformly Neonatal sepsis (%) 25.5 26.0 9.4 5.7 0.8 1.8 high for the very preterm neonates, was significantly decreased for Perinatal death (%) 6.3 9.3 3.6 1.6 0.8 0.0 both the preterm and the late preterm neonates with latency time Neonatal LOS (days) 53.4** 37.5 23.4** 17.2 4.5** 5.2 >72 h versus p72 h, 67 versus 49% (P<0.01) and 9.1 versus 4.4% (P<0.01), respectively (Figure 2). However, this decrease in Abbreviations: BPD, bronchopulmonary dysplasia; GA, gestational age; IVH, intraventricular hemorrhage; LOS, length of stay; NEC, necrotizing enterocolitis; PVL, moderate morbidity index for the late preterm neonates was mostly periventricular leukomalacia; RDS, respiratory distress syndrome; ROP, retinopathy of secondary to PPROM at 33 to 34 weeks (15.9 versus 3.8%, prematurity. P ¼ 0.01) and was not significant after PPROM at 35 to 36 weeks Data are presented as mean or % incidence. *P<0.05 and **P<0.01 latency time p72 h versus >72 h as determined with linear regression or logistic regression analysis (4.0 versus 0, P ¼ 0.9; Figure 2). The severe morbidity index, adjusting for gestational age at PPROM and chorioamnionitis. reflecting one or more of what were deemed to be severe neonatal

Figure 2 Moderate morbidity index and gestational age at preterm premature rupture of membranes (PPROM). Data are presented as % incidence of infants with PPROM. Moderate morbidity index is deﬁned as one or more of respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH) grades 1 and 2, retinopathy of prematurity (ROP) grades 1 and 2, or neonatal sepsis.

Journal of Perinatology Neonatal outcomes after PPROM D Nayot et al 974

Figure 3 Severe morbidity index and gestational age at preterm premature rupture of membranes (PPROM). Data are presented as % incidence of infants with PPROM. Severe morbidity index is deﬁned as one or more of bronchopulmonary dysplasia, intraventricular hemorrhage (IVH) grades 3 and 4, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity (ROP) grades 3 and 4, or perinatal death.

Figure 4 Maternal (a) and neonatal (b) length of stay and gestational age at preterm premature rupture of membranes (PPROM). Data are presented as total length of stay (days) on antentatal, delivery and post partum ward for mothers and in Level 3 Neonatal Intensive Care Unit (NICU) in tertiary care hospital for infants. morbidities, was also significantly decreased for both the very weeks PPROM neonates, where neonatal length of NICU stay was preterm and the preterm neonates with latency time >72 h versus instead marginally increased (Figure 4b). p72 h, 65 versus 35%, P<0.001 and 9.4 versus 4.9%, P ¼ 0.05 (Figure 3). Conversely, the severe morbidity index was marginally increased in the late preterm neonates with latency >72 h; this was Discussion secondary to PPROM at 35 to 36 weeks although this was not We determined the impact of latency time on maternal and statistically significant (Figure 3). neonatal outcome, in a large cohort of singleton pregnancies and Neonatal length of NICU stay was significantly decreased for the determined a benefit for infant outcome with latency > 72 h up to very preterm, preterm and late preterm 33 to 34 weeks PPROM a GA of 34 weeks for moderate morbidity and up to 32 weeks for neonates with latency >72 h, but not for the late preterm 35 to 36 severe morbidity. After 34 weeks, no clear benefit of expectant

Journal of Perinatology Neonatal outcomes after PPROM D Nayot et al 975 management could be demonstrated and a significant increase in term to avoid risk associated with chorioamnionitis, recent the incidence of necrotizing enterocolitis, a trend in increased evidence suggests that long-term outcomes of late preterm infants severe morbidity and longer NICU length of stay were observed, may not be as favorable as was previously thought. Recent evidence supporting an approach to elective induction of women presenting suggests that healthy infants born at 34 to 36 weeks are still with PPROM after 34 weeks GA. physiologically immature and have increased incidences of short- Moderate neonatal morbidities, which are more common term respiratory, neurological, metabolical and immunological clinical outcomes, showed an increased incidence in all three GA complications,23 as well as long-term (school age) neurological populations with a latency p72 h. This was statistically significant and behavioral problems and developmental delays.24–26 in both preterm and late preterm infants; in late preterm infants, a Counseling of women with late preterm PPROM should include shortened latency period was associated with approximately a discussion of these findings, and prospective studies looking into fourfold increase in moderate morbidity in the 33 to 34 weeks GA the management of PPROM should include assessment of these group. To minimize moderate morbidity, our data support long-term effects. expectant management until 34 completed weeks. This, however, A limitation of our study is the lack of availability of data needs to be viewed against a trend toward increased NICU length of regarding antibiotic use. Although after June 1999 the majority of stay, likely caused by small number of infants suffering severe women would have received antenatal antibiotics as standard of complications against this background of low morbidity. To care,22 its impact on outcome could not be studied. This is the minimize severe morbidity, our data support expectant consequence of insufficient coding regarding the timing and management until 32 completed weeks and suggest inducing labor reason for antibiotic administration; no distinction could be made at 33 weeks GA. in the database in this time period between antepartum prophylaxis The study design has an inherent bias in the assumption that (Mercer), intrapartum (GBS prophylaxis in labor, routine the two latency groups are similar and that the cause of a short throughout the study period) or therapeutic (chorioamnionitis) latency to birth does not impact on maternal or neonatal outcome. antibiotic use. There is good evidence that antibiotic use after This is likely not the case; latency is shorter when PPROM is a PPROM prolongs pregnancy, reduces incidence of chorioamnionitis symptom of preterm labor associated with placental problems, and improves neonatal outcome.27–30 However, this evidence has infection, IUGR or preeclampsia, and these comorbidities can affect mainly been collected through studies that were limited to maternal and neonatal outcome.1 For this reason, one needs to pregnancies <34 weeks GA, did not provide distinction between interpret our results with caution when outcome is more favorable early and late preterm PROM and calculated mean GAs at PPROM in the groups with longer latency, as is observed up to a GA of 32 of B30 weeks.28,30 Routine administration of antibiotics in late weeks. It is however widely acknowledged that up to a GA of 28 to preterm PROM was not practised in our center during the study 32 weeks, neonatal outcome is largely dependent on GA at birth time but is commonly practised in many centers that allow for and no prospective study recommends elective delivery after expectant management after 34 weeks. Antibiotic prophylaxis in PPROM before a GA of 30 weeks is reached. The opposite effect is late preterm PROM, if beneficial, could have alleviated the observed observed in the late preterm group, where outcome is negatively increase in clinical chorioamnionitis, the trend for increase in affected by longer latency, despite an advance in GA at birth and severe neonatal morbidity and significant longer NICU length of comorbidities leading to a shorter latency time. The observed stay in our women with latency >72 h. Our study highlights that increase in neonatal morbidity and NICU length of stay in our when expectant management >34 weeks GA does not include analysis therefore likely reflects true consequences of a longer antibiotic use, there is a risk for increasing morbidity with latency to birth, observed with expectant management after prolonging the late preterm pregnancy with PPROM, for the benefit PPROM. of a small gain in maturity. At the late GA of 34 to 36 weeks, many authorities recommend In summary, the decision for induction of birth versus expectant aggressive management based on the grounds that there is little to management would depend on how one evaluates a slightly higher gain from a small increase in maturity, while increased risk of incidence of an uncommon but severe neonatal outcome in infection associated with a delay of birth may outweigh this. These comparison with a significant decrease in incidence of a more conclusions are derived from observational studies like ours and benign neonatal outcome, but with potential long-term although randomized controlled trials are underway (PPROMT, developmental issues. Our results demonstrate that both moderate Australia, ISRCTN44485060, Safety and Efficacy Study of and severe morbidity are minimized by conservative management Intentional Delivery in Women With PPROM, Canada, of PPROM up to 32 completed weeks. However, after 32 weeks GA it NCT00259519), inclusion of large numbers of women is hampered becomes more difficult to deduce a conclusion. Continuing a by the natural tendency to deliver within 72 h after PPROM, which conservative approach would clearly minimize moderate morbidity, in our population occurred in 90% of women. Additionally, while but may increase the incidence of severe morbidity, which has low aggressive management protocols call for induction of labor before background prevalence at such an advanced GA.

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There are currently no official Canadian guidelines for the 2 Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol 2003; clinical management of PPROM. A common approach is the 101(1): 178–193. immediate induction once pulmonary maturity is confirmed: this 3 Spinillo A, Capuzzo E, Stronati M, Ometto A, Orcesi S, Fazzi E. Effect of preterm would be after a course of corticosteroids in stable PPROM between premature rupture of membranes on neurodevelopmental outcome: follow up at two 31–33 years of age. Br J Obstet Gynaecol 1995; 102(11): 882–887. 32 to 34 weeks GA or any PPROM after 34 weeks GA. Although 4 Dammann O, Allred EN, Veelken N. Increased risk of spastic diplegia among very low the American College of Obstetrics and Gynecology guideline birth weight children after preterm labor or prelabor rupture of membranes. J Pediatr strongly favours induction of labor after 34 weeks gestation,18 this 1998; 132(3 Pt 1): 531–535. practice is not yet universally accepted and 42% of the 508 5 Ananth CV, Oyelese Y, Srinivas N, Yeo L, Vintzileos AM. Preterm premature rupture of maternal-fetal medicine specialists surveyed in the US continue membranes, intrauterine infection, and oligohydramnios: risk factors for placental 9 abruption. Obstet Gynecol 2004; 104(1): 71–77. expectant management beyond this GA. Clearly there remains a 6 Kurkinen-Raty M, Koivisto M, Jouppila P. Perinatal and neonatal outcome and late gray zone between 32 to 34 weeks GA that requires further pulmonary sequelae in infants born after preterm premature rupture of membranes. investigation. For management of late-preterm PPROM, a Obstet Gynecol 1998; 92(3): 408–415. sufficiently large and updated randomized control trial with 7 Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case-control study of assessment of long-term outcome is needed to help delineate antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton guidelines for obstetricians who regularly face the challenge of babies. Lancet 1995; 346(8988): 1449–1454. 8 Hannah ME, Ohlsson A, Farine D, Hewson SA, Hodnett ED, Myhr TL et al. Induction of managing the complexities of this clinical population. labor compared with expectant management for prelabor rupture of the membranes at term. N Engl J Med 1996; 334(16): 1005–1010. 9 Ramsey PS, Nuthalapaty FS, Lu G, Ramin S, Nuthalapaty ES, Ramin KD. Contemporary Conflict of interest management of preterm premature rupture of membranes (PPROM): a survey of maternal-fetal medicine providers. Am J Obstet Gynecol 2004; 191(4): 1497–1502. The authors declare no conflict of interest. 10 Healy AJ, Veille JC, Sciscione A, McNutt LA, Dexter SC. The timing of elective delivery in preterm premature rupture of the membranes: a survey of members of the Society of Maternal-Fetal Medicine. Am J Obstet Gynecol 2004; 190(5): 1479–1481. Acknowledgments 11 Smith G, Rafuse C, Anand N, Brennan B, Connors G, Crane J et al. Prevalence, management, and outcomes of preterm prelabour rupture of the membranes of women We thank Dr Larry Stitt for statistical assistance, Gail Schmidt and Maria Sinacori in Canada. J Obstet Gynaecol Can 2005; 27(6): 547–553. for technical assistance, and Dr Renato Natale for his support of the perinatal 12 Spinnato JA, Shaver DC, Bray EM, Lipshitz J. Preterm premature rupture of the database. Dr Dan Nayot received a Schulich Research Opportunities Program membranes with fetal pulmonary maturity present: a prospective study. Obstet Gynecol grant for his work on this project and Dr Barbra de Vrijer was supported by the 1987; 69(2): 196–201. Strategic Training Initiative in Research in the Reproductive Health Sciences 13 Mercer BM, Crocker LG, Boe NM, Sibai BM. Induction versus expectant management in (STIRRHS). Bryan S Richardson is the recipient of the Canada Research Chair in premature rupture of the membranes with mature amniotic fluid at 32 to 36 weeks: a Fetal and Neonatal Health and Development. This paper has been presented SOGC randomized trial. Am J Obstet Gynecol 1993; 169(4): 775–782. 63rd Annual Clinical Meeting, 2007 (oral), and at the Society for Gynecological 14 Cox SM, Leveno KJ. Intentional delivery versus expectant management with preterm Investigation 55th Annual Meeting, 2008 (poster). Research was supported by the ruptured membranes at 30 to 34 weeks’ gestation. Obstet Gynecol 1995; 86(6): 875–879. 15 Naef III RW, Allbert JR, Ross EL, Weber BM, Martin RW, Morrison JC. Premature Schulich Research Opportunities Program, the Strategic Training Initiative in rupture of membranes at 34 to 37 weeks0 gestation: aggressive versus conservative Research in the Reproductive Health Sciences (STIRRHS), and the Canada management. Am J Obstet Gynecol 1998; 178(1 Pt 1): 126–130. Research Chair in Fetal and Neonatal Health and Development. 16 Hartling L, Chari R, Friesen C, Vandermeer B, Lacaze-Masmonteil T. A systematic review of intentional delivery in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med 2006; 19(3): 177–187. Contribution to Authorship 17 Pasquier JC, Bujold E, Rabilloud M, Picaud JC, Ecochard R, Claris O et al. Effect of Dr Dan Nayot contributed to the conception and design of the study, analyzed the latency period after premature rupture of membranes on 2 years infant mortality data and prepared the manuscript. Drs Barbra de Vrijer and Debbie Penava, (DOMINOS study). Eur J Obstet Gynecol Reprod Biol 2007; 135(1): 21–27. Orlando Da Silva and Bryan Richardson contributed to the conception and design 18 ACOG Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 80: of the study, guided the data analysis and helped critically revise the manuscript. premature rupture of membranes. Clinical management guidelines for obstetrician- gynecologists. Obstet Gynecol 2007; 109(4): 1007–1019. All authors gave final approval to the manuscript for submission. 19 An international classification of retinopathy of prematurity. Pediatrics 1984; 74(1): Details of Ethics Approval 127–133. 20 Bell MJ. Neonatal necrotizing enterocolitis. N Engl J Med 1978; 298(5): 281–282. This project was approved by the Health Sciences Research Ethics Board at the 21 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal University of Western Ontario, London, Ontario, Canada (HSREB 12561E). and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm. 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