Journal of Obstetrics and Gynaecology, 2015; Early Online: 1–6 © 2015 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2014.990432
ORIGINAL ARTICLE
Conservative management of preterm premature rupture of membranes beyond 32 weeks’ gestation: Is it worthwhile? Z. Tsafrir1, G. Margolis1, Y. Cohen1, A. Cohen1, I. Laskov1, I. Levin1, D. Mandel2 & A. Many1 1The Department of Gynecology and 2Neonatal Intensive Care Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, Sackler Faculty
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of Medicine, Tel-Aviv University, Tel Aviv, Israel
We aimed to investigate whether conservative management of preterm premature rupture of membranes (PPROM) at 32–34 weeks’ gestation improves outcome. In this retrospective analysis of singleton pregnancies, the study group included patients with PPROM at 28–34 weeks’ gestation and the control group included patients presented with spontaneous preterm delivery at 28–34 weeks’ gestation. Both groups were subdivided according to gestational age – early (28–31 weeks’ gestation) versus late (32–34 weeks’ gestation). Adverse neonatal outcome included neonatal death, intraventricular haemorrhage grade 3/4, respiratory distress syndrome, periventricular leucomalacia and neonatal sepsis. The study and control groups included 94 and 86 women, respectively. The study group had a lower incidence of adverse neonatal outcome at the earlier weeks (28–31), compared with the control group at the same gestational age. In contrast, at 32–34 weeks’ gestation no difference in the risk for adverse neonatal outcome was noticed. Additionally, within the study group, chorioamnionitis rate was significantly higher among those who delivered at 32–34 weeks’ gestation (p ⬍ 0.01). No advantage for conservative management of PPROM was demonstrated beyond 31 weeks’ gestation. Moreover, conservative management of PPROM at 32–34 weeks’ gestation may expose both mother and neonate to infectious morbidity. Keywords: Conservative management, chorioamnionitis, outcome, preterm premature rupture of membranes
Introduction Preterm premature rupture of membranes (PPROM) accounts for nearly 3% of all pregnancies and is a leading cause of maternal and perinatal morbidity and mortality (Mercer 2003; ACOG 2007). There is an inverse correlation between the frequency and severity of neonatal complications after PROM and the gestational age at membrane rupture and at delivery (Locatelli et al. 2005). The appropriate management in the event of PPROM is controversial (Ramsey et al. 2004). Expectant management is justified in order to decrease gestational age-related morbidity associated with prematurity. Accumulated experience in the last decade established the benefit of administering prophylactic glucocorticoids and antibiotics before 32 weeks’ gestation in preventing neonatal morbidity and mortality, especially respiratory distress syndrome (RDS), intraventricular haemorrhage (IVH),
necrotising enterocolitis (NEC) and neonatal sepsis (Egarter et al. 1996; Lewis et al. 1996; Pattinson et al. 1999; Kenyon et al. 2003). In addition, prophylactic antibiotic treatment assists in reducing the likelihood of chorioamnionitis and delays delivery, thereby allowing sufficient time for the administration of prophylactic prenatal corticosteroids (Mercer et al. 1997; Kenyon et al. 2001; RCOG 2006). However, an extended latency period may increase the risk of chorioamnionitis, thereby exposing the foetus to an unfavourable intrauterine environment, which is associated with adverse neonatal outcomes, including cerebral palsy, lung injury, NEC and early neonatal sepsis. Other complications associated with conservative management include cord compression due to oligohydramnios and umbilical cord prolapse, especially in cases of malpresentation. There is a consensus on the need for expeditious delivery in the following scenarios, regardless of gestational age: (1) overt chorioamnionitis, (2) abruptio placenta, (3) foetal distress and (4) advanced labour. In the event of foetal malpresentation and significant cervical dilatation, it may be justified to operate without delay. Furthermore, induction of labour is the accepted policy when PPROM occurs at or beyond 34 weeks’ gestation, or in the cases of PPROM which had been managed expectantly and reached 34 weeks’ gestation (ACOG 2007). The American Congress of Obstetricians and Gynecologists (ACOG) recommends conservative management with the administration of glucocorticoids and antibiotics up to 33 weeks’ gestation (ACOG 2007). However, the Royal College of Obstetricians and Gynecologists (RCOG) states that delivery should be considered at 34 weeks’ gestation (RCOG 2006). There is also wide agreement that in the absence of any of the indications mentioned above, women who present with PPROM remote from term (i.e. ⬍ 32 weeks’ gestation) should be treated expectantly. In cases of PPROM at 32–34 weeks’ gestation, however, the optimal management is controversial. We performed this retrospective analysis in order to determine whether expectant management in PPROM at 32–34 weeks’ gestation is beneficial.
Materials and methods This retrospective cohort analysis was conducted on all singleton pregnancies that were delivered at 280/7–346/7 weeks’ gestation between 2004 and 2011 in a single tertiary centre. The study group was comprised of women who presented with PPROM. The control group included randomly selected women who presented with spontaneous preterm labour (SPTL) and
Correspondence: Ziv Tsafrir, MD, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. Tel: ⫹ 972-3-6925604. Fax: ⫹ 972-3-6925687 and Current address: 7632 Goshen Dr. West Bloomfield, Michigan 48322, USA. Tel: ⫹ 1-248-859-5255, 1-248826-3782, 1-313-6734757. Fax: ⫹ 1-248-325-0094. E-mail: [email protected]
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Z. Tsafrir et al.
intact membranes, during the same study period. Both groups were divided according to gestational age at delivery: early (280/7–316/7) and late (320/7–336/7). Patients who presented with PPROM or SPTL and gave birth before the completion of 34 weeks’ gestation (i.e. ⬍ 35 weeks’ gestation) were included in the ‘late’ group as well. We excluded all pregnancies with known foetal malformations, multiple foetuses, stillbirths, placenta previa, women who presented with abruptio placenta and cases in which a decision to deliver was made due to other maternal or foetal indications. Women who delivered within 24 h of PPROM were also excluded from the study group. This study was approved by the Institutional Review Board. PPROM was defined as spontaneous rupture of membranes (ROM) occurring before the onset of active labour and at ⬍ 340/7 weeks’ gestation. ROM was diagnosed by the observation of persistent vaginal pooling on sterile speculum examination. Gestational age was determined by the last menstrual period, and confirmed by first-trimester ultrasound. The latency period was defined as ‘the time interval between ROM and time of delivery’. Clinical chorioamnionitis was defined as ‘the presence of uterine tenderness and/or foul-smelling amniotic fluid, maternal fever (⬎ 38.0°C), leucocytosis or foetal tachycardia’. All women who presented with PPROM at ⬍ 340/7 weeks’ gestation were managed by a standardised protocol as follows: (1) inpatient management after excluding cases of active labour, chorioamnionitis, placental abruption or foetal compromise; (2) intramuscular administration of betamethasone (12 mg, 2 doses 12 h apart) and prophylactic antibiotics (ampicillin and azithromycin) based on the ACOG and RCOG guidelines (ACOG, 2007; RCOG, 2006); (3) urine culture upon admission; and (4) monitoring of maternal and foetal status for signs of chorioamnionitis, labour and/or foetal compromise. The routine follow-up included daily measurement of vital signs, examination for uterine tenderness, nonstress test three times daily, complete blood count every other day, biophysical profile twice a week and estimation of foetal weight every 2 weeks. Vaginal examination was avoided unless the patient was symptomatic or complained of contractions. Indications for rejecting expectant management were chorioamnionitis, abruption placenta, foetal compromise and active labour. Tocolysis was avoided for women who presented with PPROM. Women who presented with SPTL were given betamethasone at the time of admission to the emergency room. All the women in active labour were treated using prophylactic antibiotics intrapartum (intravenous penicillin 5 million U, followed by 2.5 million U every 4 h) to prevent vertical transmission of group B streptococci, regardless of earlier treatments. Induction of labour, when indicated, was performed by oxytocin. Data for this study were retrieved from our computerised obstetrics database as well as from neonatal intensive care unit (NICU) records. Maternal information included demographics, age, height, weight and calculated body mass index, smoking, alcohol use and medical and obstetrical history. Obstetrical information included current pregnancy follow-up, latency period, mode of delivery and complications. Clinical chorioamnionitis was confirmed by histopathological examination when available. Primary adverse neonatal outcomes included IVH, sepsis, RDS, NEC, retinopathy of prematurity, periventricular leucomalacia (PVL) and neonatal death. The composite adverse neonatal outcome was defined as ‘the presence of at least one of the followings: RDS, IVH stage ¾, PVL, sepsis and neonatal death’. Secondary neonatal outcomes included number of days in the NICU, birth weight, Apgar score, intubation/mechanical ventilation in the delivery room, hypotension, inotropic or crystalloids support, administration of indomethacin for patent ductus arteriosus
(PDA), bilirubin and haematocrit levels, phototherapy treatment, erythropoietin treatment, documented hypoglycaemia or hyponatremia, and administration of surfactants.
Statistical analysis According to our calculation with the implementation of Z-test, a sample size of 90 patients in each studied group could reveal a decrease of at least 25% in the incidence of composite adverse neonatal outcome in the study group compared with that in the control group, with a power of 80% at the 0.05 significance level. This assumption was based upon accepted differences in the literature regarding the rate of RDS, IVH stage 3/4, PVL, sepsis, and neonatal death between newborns before 32 weeks’ gestation and those at 32–34 weeks’ gestation (Mercer, 2003; Hartling et al. 2006; RCOG, 2006). Data were analysed with the Student’s t-test, the χ2 test and the Fisher’s exact test as appropriate. A multivariable logistic regression with backward elimination was performed to examine the effect of possible confounding variables that were considered risk factors for the composite neonatal outcome. Odds ratio (OR) and their 95% confidence intervals (CIs) were computed. Probability values of ⬍ 0.05 for all two-tailed tests were considered significant.
Results During 2004–2011, we had 80,384 deliveries in our medical centre. There were 1262 preterm births at 28–34 weeks’ gestation. After applying the above-mentioned exclusion criteria, we had 238 cases of PPROM, of which 94 singleton pregnancies were eligible for study entry, that is the women presented with PPROM and gave birth after more than 24 h from ROM. In addition, we had 337 cases of SPTL. The control group of 86 women was randomly selected within the same time period. After stratification by gestational age at delivery, there were 43 women in the study group who delivered between 280 and 316/7 weeks’ gestation (the early PPROM subgroup), and 51 women who delivered between 32 and 34 weeks’ gestation (the late PPROM subgroup). The control group consisted of 37 and 49 women in the early and late SPTL subgroups, respectively. Demographic and obstetric details of all four subgroups are summarised in Table I. The late PPROM subgroup had more events of urinary tract infection (UTI) compared with the late PTL subgroup (9 vs. 1; p ⬍ 0.01). Cerclage in the current pregnancy or a history of cervical procedures was present in 7/43 of early PPROM cases compared with 0/37 early SPTL cases (p ⬍ 0.01).
Neonatal outcome The rate of composite adverse neonatal outcome was significantly lower in the early PPROM subgroup than that of the early SPTL subgroup but not between the late PPROM and SPTL subgroups (Table II). In order to examine whether the better neonatal outcome in PPROM events at 28–31 weeks’ gestation could be attributed to expectant management, we used linear regression and included potential confounders that might affect neonatal outcome, i.e. maternal age, parity, caesarean section/operative delivery, chorioamnionitis and birth weight. The expectant management of PPROM at 28–31 weeks’ gestation was associated with less neonatal morbidity than preterm deliveries at 28–31 weeks’ gestation, even after adjusting for the variables mentioned above (OR: 0.34; 95% CI: 0.13–0.89). Analysis of secondary adverse neonatal outcome (Table III) revealed that more cases of PDA occurred in the early SPTL subgroup compared with those in the early PPROM subgroup (13 vs. 5; p ⫽ 0.013). In addition, fewer premature newborns in
Conservative management of PPROM
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Table I. Demographic and obstetric characteristics of pregnancies with PPROM and SPTL. Early gestational age at labour (28–31 weeks)
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Characteristics
Late gestational age at labour (32–34 weeks)
Early PPROM (n ⫽ 43)
Early SPTL (n ⫽ 37)
p value
Late PPROM (n ⫽ 51)
Late SPTL (n ⫽ 49)
p
32.7 ⫾ 6.1 20.5 ⫾ 3.5 2 (4.6) 0 4 (9.3) 3 (6.9) 15 (34.8) 10 (23.2) 2 (4.6) 7 (16.3) 2 (4.6) 3 (6.9) 7 (16.2) 5 (11.3)
31.6 ⫾ 9.0 20.4 ⫾ 3.5 2 (5.4) 0 1 (2.7) 3 (8.1) 21 (56.7) 3 (8.1) 4 (10.8) 1 (2.7) 2 (5.4) 2 (4.6) 0 (0) 3 (8.1)
0.14 0.96 0.87 N/A 0.21 0.92 0.04 0.07 0.31 0.06 0.87 0.77 ⬍ 0.01 0.6
31.6 ⫾ 5.8 21.0 ⫾ 4.6 7 (13.7) 0 5 (8.7) 5 (9.8) 21 (41.1) 14 (27.4) 8 (15.6) 5 (9.8) 3 (5.8) 9 (17.6) 3 (5.8) 5 (9.8)
31.1 ⫾ 5.1 21.1 ⫾ 3.8 6 (12.2) 1 (2) 4 (8.1) 5 (10.2) 16 (32.6) 10 (20.4) 11 (22.4) 5 (10.2) 7 (14.3) 1 (2) 5 (10.2) 3 (6.1)
0.65 0.89 0.41 N/A 0.39 0.97 0.6 0.48 0.2 0.97 0.08 ⬍ 0.01 0.21 0.25
Maternal age (years) Body mass index (kg/m2) Smoking rate Pre-gestational diabetes History of abdominal surgery History of caesarean section Nulliparous Recurrent pregnancy loss (⬎ 2 miscarriages) Previous SPTL Assisted reproductive technique Gestational diabetes UTI Cerclage in current pregnancy/history of cervical procedure Antepartum vaginal bleeding Data presented as number (%) or mean ⫾ standard deviation (SD). N/A, not applicable.
the early PPROM subgroup needed fluids or inotropic support and their mean haematocrit level was higher compared with the newborns in the early SPTL subgroup, although these differences did not reach a level of significance.
Maternal outcome Women who presented with PPROM at 32–34 weeks’ gestation suffered from a higher rate of clinical and histological chorioamnionitis, underwent more operative deliveries/caesarean sections and had prolonged length of stay in hospital compared with the control women. These differences also applied to the earlier PPROM subgroup (Table IV). There were more cases of chorioamnionitis in the PPROM group at 28–31 weeks’ gestation compared with 32–34 weeks’ gestation (15 vs. 9; p ⬍ 0.05).
Effect of a latency period In order to examine the influence of a latency period on adverse neonatal outcome of the PPROM women, we divided these patients into cases with a prolonged latency period (i.e. ⬎ 7 days) and cases with a short latency period (i.e. ⱕ 7 days). There was no significant difference in adverse outcome between the
neonates of both groups of women. These results were repeated even after applying multivariate analysis, which included latency period, maternal age, birth weight, UTI during pregnancy, current cerclage or history of cervical procedures, and chorioamnionitis. We next evaluated the effect of the duration of the latency period on the rate of chorioamnionitis in the PPROM group and found no significant difference between the women with short or long latency periods at any gestational age. The rate of neonatal sepsis among neonates who were born at 32–34 weeks’ gestation after a prolonged latency period, however, was higher compared with that of neonates who were born after a short latency period (15.3% vs. 0%; p ⫽ 0.05). This difference was not observed in PPROM cases at 28–31 weeks’ gestation. Finally, we performed a multivariate regression analysis in order to determine which risk factors for PPROM were independently or directly associated with the composite adverse neonatal outcome. The results showed that gestational age at the time of membrane rupture correlated to adverse neonatal outcome, even after adjustment for confounding factors, such as maternal age, history of vaginal bleeding, chorioamnionitis, prolonged latency period, nulliparity and the newborn’s gender.
Table II. Primary adverse neonatal outcome in PPROM and SPTL Groups. Early gestational age at labour (28–31 weeks)
Outcome Composite neonatal outcome¶ Neonatal death IVH (grade 3–4) Neonatal sepsis RDS NEC PVL ROP
Early PPROM (n ⫽ 43) 17 (39.5) 1 (2.3) 1 (2.3) 6 (13.9) 16 (37.2) 4 (9.2) 0 6 (13.9)
Early PTL (n ⫽ 37) 24 (64.9) 1 (2.7) 2(5.4) 5 (13.5) 21 (56.7) 2 (5.4) 3 (8.1) 2 (5.4)
Late gestational age at labour (32–34 weeks)
p
Late PPROM (n ⫽ 51)
Late SPTL (n ⫽ 49)
p
0.02 0.91 0.48 0.95 0.11 0.5 0.09 0.19
9 (17.6) 0 0 2 (3.9) 8 (15.6) 2 (3.9) 0 0
11 (22.4) 0 0 0 11 (22.4) 1 (2.0) 0 0
0.28 N\A N\A 0.48 0.19 0.29 N/A N/A
Data presented as number (%). RDS, respiratory distress syndrome; IVH, intraventricular haemorrhage; NEC, necrotising enterocolitis; PVL, periventricular leucomalacia; ROP, retinopathy of prematurity; N/A, not applicable. ¶Defined in the ‘Materials and methods’ section
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Z. Tsafrir et al. Table III. Secondary adverse neonatal outcome in PPROM and SPTL groups. Early gestational age at labour (28–31 weeks)
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Outcome
Late gestational age at labour (32–34 weeks)
Early PPROM (n ⫽ 43)
Early PTL (n ⫽ 37)
p
Late PPROM (n ⫽ 51)
Late SPTL (n ⫽ 49)
p
40.9 ⫾ 12.5 1477 ⫾ 285 9 (20.9) 2 (4.6) 3 (6.9) 4 (9.3) 5 (11.6) 4 (9.3) 32 (74.4) 34.4 ⫾ 4.6 13 (30) 3 (6.9) 4 (9.3)
44.9 ⫾ 15 1503 ⫾ 266 7 (18.9) 1 (2.7) 6 (16.2) 9 (24.3) 13 (35.1) 9 (24.3) 24 (64.8) 32.4 ⫾ 5.3 11(29) 2 (5.4) 3 (8.1)
0.84 0.68 1 1 0.2 0.08 0.014 0.08 0.36 0.07 0.96 0.77 0.85
18.9 ⫾ 8.3 2018 ⫾ 234 6 (11.7) 1 (1.9) 2 (3.9) 3 (5.8) 1 (1.9) 0 21 (41.2) 44.1 ⫾ 7.6 0 6 (11.8) 0
17.2 ⫾ 7.5 2148 ⫾ 305 6 (12.2) 3 (6.1) 3 (6.1) 3 (6.1) 2 (4.0) 0 17 (34.6) 42.6 ⫾ 10.6 0 4 (8.1) 0
0.88 0.73 1 0.35 0.3 0.48 0.27 N/A 0.25 0.45 N/A 0.27 N/A
Days at the NICU Birth weight(g) Apgar score ⬍ 7 at 1 min Apgar score ⬍ 7 at 5 min Hypotension at admission to NICU Fluids/inotropic agents treatment PDA Indomethacin treatment Jaundice requiring phototherapy Haematocrit upon discharge Erythropoietin treatment Hypoglycaemia Hyponatremia
Data presented as number (%) or mean ⫾ SD. NICU, neonatal intensive care unit.
Discussion
management (Van Der Ham et al. 2012). Mercer et al.’s randomised controlled study demonstrated the importance of antibiotic therapy in the event of PPROM occurring up to 32 weeks’ gestation (Mercer et al. 1997). The ACOG recommends conservative management with the administration of glucocorticoids and antibiotics up to 33 weeks’ gestation (ACOG 2007). However, the RCOG states that delivery should be considered at 34 weeks’ gestation, and that women should be informed of the increased risk of chorioamnionitis and the decreased risk of respiratory problems in the neonate (RCOG 2006). An alternative model is to compare the obstetrical and neonatal outcomes of PPROM versus SPTL. Only a few such studies were identified in our literature search. Sims et al. retrospectively compared a PPROM group of 99 neonates and an SPTL group of 267 neonates (at 24–34 weeks’ gestation). Similar to our study findings, women who presented with PPROM and delivered within 24 h were excluded, and steroid and antibiotics were administered to all PPROM patients. Their results showed that neonates in the PPROM group had a lower incidence of RDS (Sims et al. 2002). Sciscione et al. analysed the outcome of neonates with very low birth weight (⬍ 1500 g) who were delivered due to SPTL versus similar infants who were delivered due to PPROM. Their cohort is comparable to the early subgroups in our study. These authors concluded that the neonates who were delivered as a result of PPROM had a higher survival rate than those who were delivered after SPTL (Sciscione et al. 2008).
The results of our analysis demonstrate that expectant management of women presenting with PPROM at 28–31 weeks’ gestation is associated with lower rates of adverse neonatal outcome compared with cases of SPTL at the same gestational age. However, we did not detect any benefit for conservative management in the event of PPROM occurrence at 32–34 weeks’ gestation. The most appropriate model to evaluate the benefit of expectant management of a PPROM event is a prospective clinical trial in which obstetrical and neonatal outcomes of PPROM cases managed expectantly are compared with PPROM cases who were actively delivered. Hartling et al.’s meta-analysis evaluated four randomised controlled trials that were relevant to this issue. These authors concluded that while intentional delivery may be more favourable than expectant management for some maternal outcomes, there is insufficient evidence to suggest that either strategy is beneficial or harmful for the baby (Spinnato et al. 1987; Cox and Leveno 1995; Mercer et al. 1996; Naef et al. 1998; Hartling et al. 2006). Since none of those trials included glucocorticoids or systematic antibiotic treatment as part of the management, their relevance to the contemporary clinical context is called into doubt. Van Der Ham et al. randomised women who presented with PPROM between 340 and 370 weeks’ gestation to either induction of labour or expectant management. Patients in both groups received antibiotics. The authors found that induction of labour did not improve pregnancy outcomes compared with expectant Table IV. Maternal outcome in PPROM and SPTL Groups.
Early gestational age at labour (28–31 weeks)
Outcome
Late gestational age at labour (32–34 weeks)
Early PPROM (n ⫽ 43)
Early SPTL (n ⫽ 37)
p
Late PPROM (n ⫽ 51)
Late PTL (n ⫽ 49)
p
17 (39.5) 15 (34.8) 17.3 ⫾ 5.1 37.3 ⫾ 0.6 3.1 ⫾ 1.2
7 (18.9) 8 (21.6) 14.3 ⫾ 3.8 37.1 ⫾ 0.5 2.5 ⫾ 0.9
0.05 0.19 ⬍ 0.01 0.08 0.049
18 (35.2) 9 (17.6) 16.2 ⫾ 4.2 37.1 ⫾ 0.3 2.9 ⫾ 1.4
4 (8.1) 1 (2) 13.1 ⫾ 3.3 36.8 ⫾ 0.4 2.2 ⫾ 0.5
⬍ 0.01 ⬍ 0.01 0.06 ⬍ 0.01 ⬍ 0.01
Caesarean/instrumental deliveries Chorioamnionitis White blood count max (mm3) Body temperature (Co) LOS postpartum (days) Data presented as number (%) or mean ⫾ SD. LOS, length of stay; N/A, not applicable.
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Conservative management of PPROM We observed that the group of women who presented with PPROM at 32–34 weeks’ gestation (the late subgroup) had a significantly higher rate of chorioamnionitis and operative delivery or caesarean section, as well as prolonged length of post-delivery stay in hospital compared with the late SPTL subgroup. Tanir et al. also observed that histological chorioamnionitis was more common among PPROM cases compared with that among SPTL cases, but they did not stratify the outcome according to gestational week (Tanir et al. 2003). We observed an inverse correlation between gestational age at PPROM and the probability of chorioamnionitis, in accordance with other reports (Ramsey et al. 2005; Aziz et al. 2008; Test et al. 2011). We did not find any link between the length of latency period and the rate of chorioamnionitis in the PPROM group: this is in agreement with Aziz et al., but not with Test et al. and Ramsey et al., who demonstrated opposite correlations (Ramsey et al. 2005; Aziz et al. 2008; Test et al. 2011). We then scrutinised the effect of a latency period on adverse neonatal outcome and found that a prolonged latency period (i.e. ⬎ 7 days) was not associated with improved neonatal outcome. Moreover, neonates of women in the PPROM group who had an extended latency period at 32–34 weeks’ gestation suffered from higher rates of early neonatal sepsis. Our results demonstrate that the most important factor influencing neonatal outcome is gestational age at the time of ROM. In a prospective study of PPROM cases at 24–34 weeks’ gestation, Pasquier et al. did not detect any association between a latency period and neonatal outcomes. Those authors also concluded that the risk of adverse neonatal outcome is inversely related to gestational age at PPROM (Pasquier et al. 2009). Locatelli et al. found that gestational age at PPROM was independently predictive of white matter damage (Locatelli et al. 2005). The practitioner who advocates expectant management needs to find a balance between two opposing processes: as the period of latency is prolonged, the rate of adverse neonatal outcome associated with prematurity decreases, but the risk of chorioamnionitis and related neonatal complications increases. We strived to identify the definitive point at which expectant management might be counterproductive. According to our observations, expectant management of a woman with PPROM at 32–34 weeks’ gestation is not associated with improved neonatal outcome. Furthermore, we witnessed a higher rate of chorioamnionitis and neonatal sepsis in combination with a prolonged latency period among those women. We are aware of several possible limitations of this study. It has been claimed that SPTL and PPROM are associated with different pathophysiological mechanisms, whereupon a comparison of neonatal outcome between these two clinical entities may be open to question. Being limited as we were by the nature of a retrospective design, we thought that a study group comprised of SPTL cases will best reflect an alternative management, i.e. expeditious delivery. An additional weakness of this study is the lack of follow-up, thus precluding knowledge of the long-term outcome of these premature newborns, especially with regard to their neurological development. In summary, our findings demonstrate that expectant management of PPROM cases at 28–31 weeks’ gestation is associated with improved neonatal outcome in comparison to the neonatal outcome of SPTL cases at the same gestational age. This does not hold true at 32–34 weeks’ gestation. We also found higher rates of chorioamnionitis and a higher incidence of neonatal sepsis to be associated with prolonged latency rates at 32–34 weeks’ gestation, indicating that expectant management might be counterproductive and call for judicious decision-making.
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Acknowledgments We thank Esther Eshkol, the institutional medical and scientific copyeditor. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References American Congress of Obstetricians and Gynecologists: Premature rupture of membranes. 2007. ACOG Practice Bulletin No. 80. American College of Obstetrics and Gynecologists. Obstetrics and Gynecology 109: 1007–1019. Aziz N, Cheng YW, Caughey AB. 2008. Factors and outcomes associated with longer latency in premature rupture of membranes. Journal of MaternalFetal & Neonatal Medicine 21:821–825. Cox SM, Leveno KJ. 1995. Intentional delivery versus expectant management with preterm ruptured membranes at 30–34 weeks’ gestation. Obstetrics and Gynecology ;86:875–879. Egarter C, Leitich H, Karas H, Weiser F, Husselein P, Kaider A et al. 1996. Antibiotic treatment in premature rupture of membranes and neonatal morbidity: a meta-analysis. American Journal of Obstetrics and Gynecology 174:589–597. Hartling L, Chari R, Friesen C, Vandermeer B, Masmonteil TL. 2006. A systematic review of intentional delivery in women with preterm prelabor rupture of membranes. Journal of Maternal-Fetal Neonatal Medicine 19:177–187. Kenyon S, Boulvain M, Neilson J. 2003. Antibiotics for preterm rupture of membranes. Cochrane Database of Systematic Reviews Issue 2. Art No.:CD001058. DOI:10. 1002/14651858.CD001058. Kenyon SL, Taylor DJ, Tarnow-Mordi W. 2001. Broad spectrum antibiotics for preterm, pre-labor rupture of fetal membranes: the ORACLE I randomized trial. ORACLE Collaborative Group. Lancet 357:979–988. Lewis DF, Brody K, Edwards MS, Brouillette RM, Burlison S, London SN. 1996. Preterm premature ruptured ruptured membranes: a randomized trial of steroids after treatment with antibiotics. Obstetrics and Gynecology 88:801–805. Locatelli A, Ghidini A, Paterlini G, Patane L, Doria V, Zorloni C et al. 2005. Gestational age at preterm premature rupture of membranes: a risk factor for neonatal white matter damage. American Journal of Obstetrics and Gynecology 193:947–951. Mercer BM. 2003. Preterm premature rupture of the membranes. Obstetrics and Gynecology 101:178–193. Mercer BM, Crocker LG, Boe NM, Sibai BM. 1996. Induction versus expectant management in premature rupture of the membranes with mature amniotic fluid at 32–36 weeks: a randomized trial. American Journal of Obstetrics and Gynecology 169:775–778 Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Das AF, Ramsey RD et al. 1997. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. JAMA 278: 989–995. Naef RW, Allbert JR, Ross EL, Weber BH, Martin RW, Morrison JC. 1998. Premature rupture of membranes at 34 to 37 weeks’ gestation: aggressive versus conservative management. American Journal of Obstetrics and Gynecology 178:126–130. Pasquier JC, Picaud JC, Rabilloud M, Claris O, Ecochard R, Moret S et al. 2009. Neonatal outcomes after elective delivery management of preterm premature rupture of the membranes before 34 weeks’ gestation (DOMINOS study). European Journal of Obstetrics, Gynecology, and Reproductive Biology 143:18–23. Pattinson RC, Makin JD, Funk M, Delrot SD, Macdonald AP, Norman K et al. 1999. The use of dexamethasone in women with preterm premature rupture of membranes – a multicentre, double-blind, placebo-controlled, randomized trial. Dexiprom Study Group. South African Medical Journal 89:865–870. Ramsey PS, Lieman JM, Brumfield CG, Carlo W. 2005. Chorioamnionitis increases neonatal morbidity in pregnancies complicated by preterm premature rupture of membranes. American Journal of Obstetrics and Gynecology 192:1162–1166. Ramsey PS, Nuthalapaty FS, Lu G, Ramin S, Nuthalapaty ES, Ramin KD. 2004. Contemporary management of preterm premature rupture of membranes (PPROM): a survey of maternal-fetal medicine providers. American Journal of Obstetrics and Gynecology 191:1497–1502.
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Royal College of Obstetricians and Gynaecologists: Preterm Prelabour Rupture of Membranes. Gren-top Guideline No.44, November 2006. Sciscione A, Hoffman M, Paul D, Adu-Amankwa B, Sciscione J, Merriman J. 2008. Outcomes in very low birth weight (VLBW) infants who delivered as a result of preterm rupture of the membranes versus preterm labor (PTL). American Journal of Obstetrics and Gynecology 199 Supplement A:S51. Sims EJ, Vemillion ST, Soper DE. 2002. Preterm premature rupture of the membranes is associated with a reduction in neonatal respiratory distress syndrome. American Journal of Obstetrics and Gynecology 187:268–272. Spinnato JA, Shaver DC, Bray EM, Lipshitz J. 1987. Preterm premature rupture of the membranes with fetal pulmonary maturity present: a prospective study. Obstetrics and Gynecology 69:196–201.
Tanir HM, Sener T, Tekin N, Aksit A, Ardic N. 2003. Preterm premature rupture of membranes and neonatal outcome prior to 34 weeks gestation. International Journal of Gynecology and Obstetrics 82; 167–172. Test G, Levy A, Wiznitzer A, Mazor M, Holcberg G, Zlotnik A et al. 2011. Factors affecting the latency period in patients with preterm premature rupture of membranes. Archives of Gynecology and Obstetrics 283: 707–710. Van Der Ham DP, Vijgen SM, Nijhuis JG, Van Beek JJ, Opmeer BC, Mulder AL et al. 2012. Induction of labor versus expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks: a randomized controlled trial. PloS Medicine 9:e1001208.
ORIGINAL ARTICLE
Conservative management of preterm premature rupture of membranes beyond 32 weeks’ gestation: Is it worthwhile? Z. Tsafrir1, G. Margolis1, Y. Cohen1, A. Cohen1, I. Laskov1, I. Levin1, D. Mandel2 & A. Many1 1The Department of Gynecology and 2Neonatal Intensive Care Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, Sackler Faculty
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of Medicine, Tel-Aviv University, Tel Aviv, Israel
We aimed to investigate whether conservative management of preterm premature rupture of membranes (PPROM) at 32–34 weeks’ gestation improves outcome. In this retrospective analysis of singleton pregnancies, the study group included patients with PPROM at 28–34 weeks’ gestation and the control group included patients presented with spontaneous preterm delivery at 28–34 weeks’ gestation. Both groups were subdivided according to gestational age – early (28–31 weeks’ gestation) versus late (32–34 weeks’ gestation). Adverse neonatal outcome included neonatal death, intraventricular haemorrhage grade 3/4, respiratory distress syndrome, periventricular leucomalacia and neonatal sepsis. The study and control groups included 94 and 86 women, respectively. The study group had a lower incidence of adverse neonatal outcome at the earlier weeks (28–31), compared with the control group at the same gestational age. In contrast, at 32–34 weeks’ gestation no difference in the risk for adverse neonatal outcome was noticed. Additionally, within the study group, chorioamnionitis rate was significantly higher among those who delivered at 32–34 weeks’ gestation (p ⬍ 0.01). No advantage for conservative management of PPROM was demonstrated beyond 31 weeks’ gestation. Moreover, conservative management of PPROM at 32–34 weeks’ gestation may expose both mother and neonate to infectious morbidity. Keywords: Conservative management, chorioamnionitis, outcome, preterm premature rupture of membranes
Introduction Preterm premature rupture of membranes (PPROM) accounts for nearly 3% of all pregnancies and is a leading cause of maternal and perinatal morbidity and mortality (Mercer 2003; ACOG 2007). There is an inverse correlation between the frequency and severity of neonatal complications after PROM and the gestational age at membrane rupture and at delivery (Locatelli et al. 2005). The appropriate management in the event of PPROM is controversial (Ramsey et al. 2004). Expectant management is justified in order to decrease gestational age-related morbidity associated with prematurity. Accumulated experience in the last decade established the benefit of administering prophylactic glucocorticoids and antibiotics before 32 weeks’ gestation in preventing neonatal morbidity and mortality, especially respiratory distress syndrome (RDS), intraventricular haemorrhage (IVH),
necrotising enterocolitis (NEC) and neonatal sepsis (Egarter et al. 1996; Lewis et al. 1996; Pattinson et al. 1999; Kenyon et al. 2003). In addition, prophylactic antibiotic treatment assists in reducing the likelihood of chorioamnionitis and delays delivery, thereby allowing sufficient time for the administration of prophylactic prenatal corticosteroids (Mercer et al. 1997; Kenyon et al. 2001; RCOG 2006). However, an extended latency period may increase the risk of chorioamnionitis, thereby exposing the foetus to an unfavourable intrauterine environment, which is associated with adverse neonatal outcomes, including cerebral palsy, lung injury, NEC and early neonatal sepsis. Other complications associated with conservative management include cord compression due to oligohydramnios and umbilical cord prolapse, especially in cases of malpresentation. There is a consensus on the need for expeditious delivery in the following scenarios, regardless of gestational age: (1) overt chorioamnionitis, (2) abruptio placenta, (3) foetal distress and (4) advanced labour. In the event of foetal malpresentation and significant cervical dilatation, it may be justified to operate without delay. Furthermore, induction of labour is the accepted policy when PPROM occurs at or beyond 34 weeks’ gestation, or in the cases of PPROM which had been managed expectantly and reached 34 weeks’ gestation (ACOG 2007). The American Congress of Obstetricians and Gynecologists (ACOG) recommends conservative management with the administration of glucocorticoids and antibiotics up to 33 weeks’ gestation (ACOG 2007). However, the Royal College of Obstetricians and Gynecologists (RCOG) states that delivery should be considered at 34 weeks’ gestation (RCOG 2006). There is also wide agreement that in the absence of any of the indications mentioned above, women who present with PPROM remote from term (i.e. ⬍ 32 weeks’ gestation) should be treated expectantly. In cases of PPROM at 32–34 weeks’ gestation, however, the optimal management is controversial. We performed this retrospective analysis in order to determine whether expectant management in PPROM at 32–34 weeks’ gestation is beneficial.
Materials and methods This retrospective cohort analysis was conducted on all singleton pregnancies that were delivered at 280/7–346/7 weeks’ gestation between 2004 and 2011 in a single tertiary centre. The study group was comprised of women who presented with PPROM. The control group included randomly selected women who presented with spontaneous preterm labour (SPTL) and
Correspondence: Ziv Tsafrir, MD, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel. Tel: ⫹ 972-3-6925604. Fax: ⫹ 972-3-6925687 and Current address: 7632 Goshen Dr. West Bloomfield, Michigan 48322, USA. Tel: ⫹ 1-248-859-5255, 1-248826-3782, 1-313-6734757. Fax: ⫹ 1-248-325-0094. E-mail: [email protected]
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intact membranes, during the same study period. Both groups were divided according to gestational age at delivery: early (280/7–316/7) and late (320/7–336/7). Patients who presented with PPROM or SPTL and gave birth before the completion of 34 weeks’ gestation (i.e. ⬍ 35 weeks’ gestation) were included in the ‘late’ group as well. We excluded all pregnancies with known foetal malformations, multiple foetuses, stillbirths, placenta previa, women who presented with abruptio placenta and cases in which a decision to deliver was made due to other maternal or foetal indications. Women who delivered within 24 h of PPROM were also excluded from the study group. This study was approved by the Institutional Review Board. PPROM was defined as spontaneous rupture of membranes (ROM) occurring before the onset of active labour and at ⬍ 340/7 weeks’ gestation. ROM was diagnosed by the observation of persistent vaginal pooling on sterile speculum examination. Gestational age was determined by the last menstrual period, and confirmed by first-trimester ultrasound. The latency period was defined as ‘the time interval between ROM and time of delivery’. Clinical chorioamnionitis was defined as ‘the presence of uterine tenderness and/or foul-smelling amniotic fluid, maternal fever (⬎ 38.0°C), leucocytosis or foetal tachycardia’. All women who presented with PPROM at ⬍ 340/7 weeks’ gestation were managed by a standardised protocol as follows: (1) inpatient management after excluding cases of active labour, chorioamnionitis, placental abruption or foetal compromise; (2) intramuscular administration of betamethasone (12 mg, 2 doses 12 h apart) and prophylactic antibiotics (ampicillin and azithromycin) based on the ACOG and RCOG guidelines (ACOG, 2007; RCOG, 2006); (3) urine culture upon admission; and (4) monitoring of maternal and foetal status for signs of chorioamnionitis, labour and/or foetal compromise. The routine follow-up included daily measurement of vital signs, examination for uterine tenderness, nonstress test three times daily, complete blood count every other day, biophysical profile twice a week and estimation of foetal weight every 2 weeks. Vaginal examination was avoided unless the patient was symptomatic or complained of contractions. Indications for rejecting expectant management were chorioamnionitis, abruption placenta, foetal compromise and active labour. Tocolysis was avoided for women who presented with PPROM. Women who presented with SPTL were given betamethasone at the time of admission to the emergency room. All the women in active labour were treated using prophylactic antibiotics intrapartum (intravenous penicillin 5 million U, followed by 2.5 million U every 4 h) to prevent vertical transmission of group B streptococci, regardless of earlier treatments. Induction of labour, when indicated, was performed by oxytocin. Data for this study were retrieved from our computerised obstetrics database as well as from neonatal intensive care unit (NICU) records. Maternal information included demographics, age, height, weight and calculated body mass index, smoking, alcohol use and medical and obstetrical history. Obstetrical information included current pregnancy follow-up, latency period, mode of delivery and complications. Clinical chorioamnionitis was confirmed by histopathological examination when available. Primary adverse neonatal outcomes included IVH, sepsis, RDS, NEC, retinopathy of prematurity, periventricular leucomalacia (PVL) and neonatal death. The composite adverse neonatal outcome was defined as ‘the presence of at least one of the followings: RDS, IVH stage ¾, PVL, sepsis and neonatal death’. Secondary neonatal outcomes included number of days in the NICU, birth weight, Apgar score, intubation/mechanical ventilation in the delivery room, hypotension, inotropic or crystalloids support, administration of indomethacin for patent ductus arteriosus
(PDA), bilirubin and haematocrit levels, phototherapy treatment, erythropoietin treatment, documented hypoglycaemia or hyponatremia, and administration of surfactants.
Statistical analysis According to our calculation with the implementation of Z-test, a sample size of 90 patients in each studied group could reveal a decrease of at least 25% in the incidence of composite adverse neonatal outcome in the study group compared with that in the control group, with a power of 80% at the 0.05 significance level. This assumption was based upon accepted differences in the literature regarding the rate of RDS, IVH stage 3/4, PVL, sepsis, and neonatal death between newborns before 32 weeks’ gestation and those at 32–34 weeks’ gestation (Mercer, 2003; Hartling et al. 2006; RCOG, 2006). Data were analysed with the Student’s t-test, the χ2 test and the Fisher’s exact test as appropriate. A multivariable logistic regression with backward elimination was performed to examine the effect of possible confounding variables that were considered risk factors for the composite neonatal outcome. Odds ratio (OR) and their 95% confidence intervals (CIs) were computed. Probability values of ⬍ 0.05 for all two-tailed tests were considered significant.
Results During 2004–2011, we had 80,384 deliveries in our medical centre. There were 1262 preterm births at 28–34 weeks’ gestation. After applying the above-mentioned exclusion criteria, we had 238 cases of PPROM, of which 94 singleton pregnancies were eligible for study entry, that is the women presented with PPROM and gave birth after more than 24 h from ROM. In addition, we had 337 cases of SPTL. The control group of 86 women was randomly selected within the same time period. After stratification by gestational age at delivery, there were 43 women in the study group who delivered between 280 and 316/7 weeks’ gestation (the early PPROM subgroup), and 51 women who delivered between 32 and 34 weeks’ gestation (the late PPROM subgroup). The control group consisted of 37 and 49 women in the early and late SPTL subgroups, respectively. Demographic and obstetric details of all four subgroups are summarised in Table I. The late PPROM subgroup had more events of urinary tract infection (UTI) compared with the late PTL subgroup (9 vs. 1; p ⬍ 0.01). Cerclage in the current pregnancy or a history of cervical procedures was present in 7/43 of early PPROM cases compared with 0/37 early SPTL cases (p ⬍ 0.01).
Neonatal outcome The rate of composite adverse neonatal outcome was significantly lower in the early PPROM subgroup than that of the early SPTL subgroup but not between the late PPROM and SPTL subgroups (Table II). In order to examine whether the better neonatal outcome in PPROM events at 28–31 weeks’ gestation could be attributed to expectant management, we used linear regression and included potential confounders that might affect neonatal outcome, i.e. maternal age, parity, caesarean section/operative delivery, chorioamnionitis and birth weight. The expectant management of PPROM at 28–31 weeks’ gestation was associated with less neonatal morbidity than preterm deliveries at 28–31 weeks’ gestation, even after adjusting for the variables mentioned above (OR: 0.34; 95% CI: 0.13–0.89). Analysis of secondary adverse neonatal outcome (Table III) revealed that more cases of PDA occurred in the early SPTL subgroup compared with those in the early PPROM subgroup (13 vs. 5; p ⫽ 0.013). In addition, fewer premature newborns in
Conservative management of PPROM
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Table I. Demographic and obstetric characteristics of pregnancies with PPROM and SPTL. Early gestational age at labour (28–31 weeks)
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Characteristics
Late gestational age at labour (32–34 weeks)
Early PPROM (n ⫽ 43)
Early SPTL (n ⫽ 37)
p value
Late PPROM (n ⫽ 51)
Late SPTL (n ⫽ 49)
p
32.7 ⫾ 6.1 20.5 ⫾ 3.5 2 (4.6) 0 4 (9.3) 3 (6.9) 15 (34.8) 10 (23.2) 2 (4.6) 7 (16.3) 2 (4.6) 3 (6.9) 7 (16.2) 5 (11.3)
31.6 ⫾ 9.0 20.4 ⫾ 3.5 2 (5.4) 0 1 (2.7) 3 (8.1) 21 (56.7) 3 (8.1) 4 (10.8) 1 (2.7) 2 (5.4) 2 (4.6) 0 (0) 3 (8.1)
0.14 0.96 0.87 N/A 0.21 0.92 0.04 0.07 0.31 0.06 0.87 0.77 ⬍ 0.01 0.6
31.6 ⫾ 5.8 21.0 ⫾ 4.6 7 (13.7) 0 5 (8.7) 5 (9.8) 21 (41.1) 14 (27.4) 8 (15.6) 5 (9.8) 3 (5.8) 9 (17.6) 3 (5.8) 5 (9.8)
31.1 ⫾ 5.1 21.1 ⫾ 3.8 6 (12.2) 1 (2) 4 (8.1) 5 (10.2) 16 (32.6) 10 (20.4) 11 (22.4) 5 (10.2) 7 (14.3) 1 (2) 5 (10.2) 3 (6.1)
0.65 0.89 0.41 N/A 0.39 0.97 0.6 0.48 0.2 0.97 0.08 ⬍ 0.01 0.21 0.25
Maternal age (years) Body mass index (kg/m2) Smoking rate Pre-gestational diabetes History of abdominal surgery History of caesarean section Nulliparous Recurrent pregnancy loss (⬎ 2 miscarriages) Previous SPTL Assisted reproductive technique Gestational diabetes UTI Cerclage in current pregnancy/history of cervical procedure Antepartum vaginal bleeding Data presented as number (%) or mean ⫾ standard deviation (SD). N/A, not applicable.
the early PPROM subgroup needed fluids or inotropic support and their mean haematocrit level was higher compared with the newborns in the early SPTL subgroup, although these differences did not reach a level of significance.
Maternal outcome Women who presented with PPROM at 32–34 weeks’ gestation suffered from a higher rate of clinical and histological chorioamnionitis, underwent more operative deliveries/caesarean sections and had prolonged length of stay in hospital compared with the control women. These differences also applied to the earlier PPROM subgroup (Table IV). There were more cases of chorioamnionitis in the PPROM group at 28–31 weeks’ gestation compared with 32–34 weeks’ gestation (15 vs. 9; p ⬍ 0.05).
Effect of a latency period In order to examine the influence of a latency period on adverse neonatal outcome of the PPROM women, we divided these patients into cases with a prolonged latency period (i.e. ⬎ 7 days) and cases with a short latency period (i.e. ⱕ 7 days). There was no significant difference in adverse outcome between the
neonates of both groups of women. These results were repeated even after applying multivariate analysis, which included latency period, maternal age, birth weight, UTI during pregnancy, current cerclage or history of cervical procedures, and chorioamnionitis. We next evaluated the effect of the duration of the latency period on the rate of chorioamnionitis in the PPROM group and found no significant difference between the women with short or long latency periods at any gestational age. The rate of neonatal sepsis among neonates who were born at 32–34 weeks’ gestation after a prolonged latency period, however, was higher compared with that of neonates who were born after a short latency period (15.3% vs. 0%; p ⫽ 0.05). This difference was not observed in PPROM cases at 28–31 weeks’ gestation. Finally, we performed a multivariate regression analysis in order to determine which risk factors for PPROM were independently or directly associated with the composite adverse neonatal outcome. The results showed that gestational age at the time of membrane rupture correlated to adverse neonatal outcome, even after adjustment for confounding factors, such as maternal age, history of vaginal bleeding, chorioamnionitis, prolonged latency period, nulliparity and the newborn’s gender.
Table II. Primary adverse neonatal outcome in PPROM and SPTL Groups. Early gestational age at labour (28–31 weeks)
Outcome Composite neonatal outcome¶ Neonatal death IVH (grade 3–4) Neonatal sepsis RDS NEC PVL ROP
Early PPROM (n ⫽ 43) 17 (39.5) 1 (2.3) 1 (2.3) 6 (13.9) 16 (37.2) 4 (9.2) 0 6 (13.9)
Early PTL (n ⫽ 37) 24 (64.9) 1 (2.7) 2(5.4) 5 (13.5) 21 (56.7) 2 (5.4) 3 (8.1) 2 (5.4)
Late gestational age at labour (32–34 weeks)
p
Late PPROM (n ⫽ 51)
Late SPTL (n ⫽ 49)
p
0.02 0.91 0.48 0.95 0.11 0.5 0.09 0.19
9 (17.6) 0 0 2 (3.9) 8 (15.6) 2 (3.9) 0 0
11 (22.4) 0 0 0 11 (22.4) 1 (2.0) 0 0
0.28 N\A N\A 0.48 0.19 0.29 N/A N/A
Data presented as number (%). RDS, respiratory distress syndrome; IVH, intraventricular haemorrhage; NEC, necrotising enterocolitis; PVL, periventricular leucomalacia; ROP, retinopathy of prematurity; N/A, not applicable. ¶Defined in the ‘Materials and methods’ section
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Z. Tsafrir et al. Table III. Secondary adverse neonatal outcome in PPROM and SPTL groups. Early gestational age at labour (28–31 weeks)
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Outcome
Late gestational age at labour (32–34 weeks)
Early PPROM (n ⫽ 43)
Early PTL (n ⫽ 37)
p
Late PPROM (n ⫽ 51)
Late SPTL (n ⫽ 49)
p
40.9 ⫾ 12.5 1477 ⫾ 285 9 (20.9) 2 (4.6) 3 (6.9) 4 (9.3) 5 (11.6) 4 (9.3) 32 (74.4) 34.4 ⫾ 4.6 13 (30) 3 (6.9) 4 (9.3)
44.9 ⫾ 15 1503 ⫾ 266 7 (18.9) 1 (2.7) 6 (16.2) 9 (24.3) 13 (35.1) 9 (24.3) 24 (64.8) 32.4 ⫾ 5.3 11(29) 2 (5.4) 3 (8.1)
0.84 0.68 1 1 0.2 0.08 0.014 0.08 0.36 0.07 0.96 0.77 0.85
18.9 ⫾ 8.3 2018 ⫾ 234 6 (11.7) 1 (1.9) 2 (3.9) 3 (5.8) 1 (1.9) 0 21 (41.2) 44.1 ⫾ 7.6 0 6 (11.8) 0
17.2 ⫾ 7.5 2148 ⫾ 305 6 (12.2) 3 (6.1) 3 (6.1) 3 (6.1) 2 (4.0) 0 17 (34.6) 42.6 ⫾ 10.6 0 4 (8.1) 0
0.88 0.73 1 0.35 0.3 0.48 0.27 N/A 0.25 0.45 N/A 0.27 N/A
Days at the NICU Birth weight(g) Apgar score ⬍ 7 at 1 min Apgar score ⬍ 7 at 5 min Hypotension at admission to NICU Fluids/inotropic agents treatment PDA Indomethacin treatment Jaundice requiring phototherapy Haematocrit upon discharge Erythropoietin treatment Hypoglycaemia Hyponatremia
Data presented as number (%) or mean ⫾ SD. NICU, neonatal intensive care unit.
Discussion
management (Van Der Ham et al. 2012). Mercer et al.’s randomised controlled study demonstrated the importance of antibiotic therapy in the event of PPROM occurring up to 32 weeks’ gestation (Mercer et al. 1997). The ACOG recommends conservative management with the administration of glucocorticoids and antibiotics up to 33 weeks’ gestation (ACOG 2007). However, the RCOG states that delivery should be considered at 34 weeks’ gestation, and that women should be informed of the increased risk of chorioamnionitis and the decreased risk of respiratory problems in the neonate (RCOG 2006). An alternative model is to compare the obstetrical and neonatal outcomes of PPROM versus SPTL. Only a few such studies were identified in our literature search. Sims et al. retrospectively compared a PPROM group of 99 neonates and an SPTL group of 267 neonates (at 24–34 weeks’ gestation). Similar to our study findings, women who presented with PPROM and delivered within 24 h were excluded, and steroid and antibiotics were administered to all PPROM patients. Their results showed that neonates in the PPROM group had a lower incidence of RDS (Sims et al. 2002). Sciscione et al. analysed the outcome of neonates with very low birth weight (⬍ 1500 g) who were delivered due to SPTL versus similar infants who were delivered due to PPROM. Their cohort is comparable to the early subgroups in our study. These authors concluded that the neonates who were delivered as a result of PPROM had a higher survival rate than those who were delivered after SPTL (Sciscione et al. 2008).
The results of our analysis demonstrate that expectant management of women presenting with PPROM at 28–31 weeks’ gestation is associated with lower rates of adverse neonatal outcome compared with cases of SPTL at the same gestational age. However, we did not detect any benefit for conservative management in the event of PPROM occurrence at 32–34 weeks’ gestation. The most appropriate model to evaluate the benefit of expectant management of a PPROM event is a prospective clinical trial in which obstetrical and neonatal outcomes of PPROM cases managed expectantly are compared with PPROM cases who were actively delivered. Hartling et al.’s meta-analysis evaluated four randomised controlled trials that were relevant to this issue. These authors concluded that while intentional delivery may be more favourable than expectant management for some maternal outcomes, there is insufficient evidence to suggest that either strategy is beneficial or harmful for the baby (Spinnato et al. 1987; Cox and Leveno 1995; Mercer et al. 1996; Naef et al. 1998; Hartling et al. 2006). Since none of those trials included glucocorticoids or systematic antibiotic treatment as part of the management, their relevance to the contemporary clinical context is called into doubt. Van Der Ham et al. randomised women who presented with PPROM between 340 and 370 weeks’ gestation to either induction of labour or expectant management. Patients in both groups received antibiotics. The authors found that induction of labour did not improve pregnancy outcomes compared with expectant Table IV. Maternal outcome in PPROM and SPTL Groups.
Early gestational age at labour (28–31 weeks)
Outcome
Late gestational age at labour (32–34 weeks)
Early PPROM (n ⫽ 43)
Early SPTL (n ⫽ 37)
p
Late PPROM (n ⫽ 51)
Late PTL (n ⫽ 49)
p
17 (39.5) 15 (34.8) 17.3 ⫾ 5.1 37.3 ⫾ 0.6 3.1 ⫾ 1.2
7 (18.9) 8 (21.6) 14.3 ⫾ 3.8 37.1 ⫾ 0.5 2.5 ⫾ 0.9
0.05 0.19 ⬍ 0.01 0.08 0.049
18 (35.2) 9 (17.6) 16.2 ⫾ 4.2 37.1 ⫾ 0.3 2.9 ⫾ 1.4
4 (8.1) 1 (2) 13.1 ⫾ 3.3 36.8 ⫾ 0.4 2.2 ⫾ 0.5
⬍ 0.01 ⬍ 0.01 0.06 ⬍ 0.01 ⬍ 0.01
Caesarean/instrumental deliveries Chorioamnionitis White blood count max (mm3) Body temperature (Co) LOS postpartum (days) Data presented as number (%) or mean ⫾ SD. LOS, length of stay; N/A, not applicable.
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Conservative management of PPROM We observed that the group of women who presented with PPROM at 32–34 weeks’ gestation (the late subgroup) had a significantly higher rate of chorioamnionitis and operative delivery or caesarean section, as well as prolonged length of post-delivery stay in hospital compared with the late SPTL subgroup. Tanir et al. also observed that histological chorioamnionitis was more common among PPROM cases compared with that among SPTL cases, but they did not stratify the outcome according to gestational week (Tanir et al. 2003). We observed an inverse correlation between gestational age at PPROM and the probability of chorioamnionitis, in accordance with other reports (Ramsey et al. 2005; Aziz et al. 2008; Test et al. 2011). We did not find any link between the length of latency period and the rate of chorioamnionitis in the PPROM group: this is in agreement with Aziz et al., but not with Test et al. and Ramsey et al., who demonstrated opposite correlations (Ramsey et al. 2005; Aziz et al. 2008; Test et al. 2011). We then scrutinised the effect of a latency period on adverse neonatal outcome and found that a prolonged latency period (i.e. ⬎ 7 days) was not associated with improved neonatal outcome. Moreover, neonates of women in the PPROM group who had an extended latency period at 32–34 weeks’ gestation suffered from higher rates of early neonatal sepsis. Our results demonstrate that the most important factor influencing neonatal outcome is gestational age at the time of ROM. In a prospective study of PPROM cases at 24–34 weeks’ gestation, Pasquier et al. did not detect any association between a latency period and neonatal outcomes. Those authors also concluded that the risk of adverse neonatal outcome is inversely related to gestational age at PPROM (Pasquier et al. 2009). Locatelli et al. found that gestational age at PPROM was independently predictive of white matter damage (Locatelli et al. 2005). The practitioner who advocates expectant management needs to find a balance between two opposing processes: as the period of latency is prolonged, the rate of adverse neonatal outcome associated with prematurity decreases, but the risk of chorioamnionitis and related neonatal complications increases. We strived to identify the definitive point at which expectant management might be counterproductive. According to our observations, expectant management of a woman with PPROM at 32–34 weeks’ gestation is not associated with improved neonatal outcome. Furthermore, we witnessed a higher rate of chorioamnionitis and neonatal sepsis in combination with a prolonged latency period among those women. We are aware of several possible limitations of this study. It has been claimed that SPTL and PPROM are associated with different pathophysiological mechanisms, whereupon a comparison of neonatal outcome between these two clinical entities may be open to question. Being limited as we were by the nature of a retrospective design, we thought that a study group comprised of SPTL cases will best reflect an alternative management, i.e. expeditious delivery. An additional weakness of this study is the lack of follow-up, thus precluding knowledge of the long-term outcome of these premature newborns, especially with regard to their neurological development. In summary, our findings demonstrate that expectant management of PPROM cases at 28–31 weeks’ gestation is associated with improved neonatal outcome in comparison to the neonatal outcome of SPTL cases at the same gestational age. This does not hold true at 32–34 weeks’ gestation. We also found higher rates of chorioamnionitis and a higher incidence of neonatal sepsis to be associated with prolonged latency rates at 32–34 weeks’ gestation, indicating that expectant management might be counterproductive and call for judicious decision-making.
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Acknowledgments We thank Esther Eshkol, the institutional medical and scientific copyeditor. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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