A C TA Obstetricia et Gynecologica

AOGS M A I N R E S E A R C H A R T I C L E

Aggressive intervention of previable preterm premature rupture of membranes

KEN MIYAZAKI, MADOKA FURUHASHI, KANA YOSHIDA & KAORU ISHIKAWA
Department of Obstetrics and Gynecology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan

Key words Previable, preterm premature rupture of membranes, amnioinfusion, cervical cerclage, tocolysis Correspondence Madoka Furuhashi, Department of Obstetrics and Gynecology, Japanese Red Cross Nagoya Daiichi Hospital, 3-35 Michishita-cho, Nakamura-ku, Nagoya 453-8511, Japan. E-mail: furuhashi-f@syd.odn.ne.jp

Abstract Objective. To assess the neonatal and maternal outcomes of pregnancy complicated by previable preterm premature rupture of membranes (PPROM). Design. Retrospective study. Setting. Tertiary referral hospital. Sample. Forty-ve women having aggressive intervention with antibiotics, amnioinfusion, cerclage and tocolysis. Methods. The hospital database between July 2001 and December 2009 was reviewed for women with singleton fetuses and PPROM before 23+0 weeks of gestation. We analysed maternal and neonatal characteristics. Main outcome measures. Neonatal survival without major morbidity. Results. Thirty-eight infants were delivered alive and seven were stillborn. Ten infants died in the neonatal intensive care unit and one in the labor ward. Twenty-seven live-born infants survived to discharge from hospital. The survival rate of pregnancies with aggressive management was 60% (27 of 45); that of live-born infants was 71.1% (27 of 38). The median gestational age at PPROM and at delivery were signicantly lower in the non-surviving group than the surviving group. Thirty-seven women (82.2%) had an amniotic neutrophil elastase level >0.15 g/mL. Only four women (8.9%) developed clinical chorioamnionitis. Overall, 90.7% of the women showed histological evidence of chorioamnionitis. Eighty-three per cent of the surviving children had bronchopulmonary dysplasia. Nine infants had serious sequelae at a corrected age of one and a half years. Maternal complications were uncommon. Conclusions. An aggressive treatment protocol for women with previable PPROM resulted in a high neonatal survival rate. Neonatal survival was associated with higher gestational age at delivery and with more frequent use of antenatal corticosteroids. The prognosis is still bad in PPROM before 22+0 weeks of gestation.
Abbreviations: NICU, neonatal intesive care unit; PPROM, preterm premature rupture of membranes.

Conict of interest The authors have stated explicitly that there are no conicts of interest in connection with this article. Please cite this article as: Miyazaki K, Furuhashi M, Yoshida K, Ishikawa K. Aggressive intervention of previable preterm premature rupture of membranes. Acta Obstet Gynecol Scand 2012;91:923929. Received: 26 Jul 2011 Accepted: 13 April 2012 DOI: 10.1111/j.1600-0412.2012.01432.x

Introduction
Premature rupture of membranes is dened as spontaneous membrane rupture that occurs before the onset of labor. When spontaneous membrane rupture occurs before 37 weeks of gestation, it is referred to as preterm premature rupture of membranes (PPROM). As the limit of fetal viability has progressively declined over the past three decades, it is currently more clinically relevant to differentiate PPROM into previable PPROM (<23 weeks), PPROM remote from term (from viability to 32 weeks of gestation) and PPROM near term (3236 weeks of gestation) (1).

Although PPROM occurring before and at the limits of viability complicates less than 1% of all pregnancies, it represents one of the most devastating diagnoses in pregnancy (2). A recent study demonstrated that infants who died as a result of causes classied as attributable to preterm birth were born overwhelmingly at previable and periviable gestational ages (3), suggesting that extreme prematurity is the most worrisome issue for survival. It is well known that, in addition to a high frequency of mortality, midtrimester PPROM is associated with very high rates of perinatal morbidity because of an increased risk for pulmonary hypoplasia, oligohydramnios, chorioamnionitis and abruption (4). It is also related to

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maternal morbidity, such as chorioamnionitis, endometritis and sepsis (4). The optimal management of pregnancies complicated by previable PPROM remains largely undened and is an area of controversy in obstetrics. Owing to the signicant risk of maternal complications, the relatively poor chance of neonatal survival and the high rate of severe long-term neonatal morbidity among surviving infants, decisions are generally left to individual values or religion. It is a choice for women to desire expeditious delivery. If termination of pregnancy is not proposed, modern obstetric and neonatal management usually includes expectant management to prolong pregnancy and reduce the risk of gestational age-dependent morbidity. In fact, many women ultimately deliver after a brief latency period. More than one-half of women with midtrimester PPROM will deliver within one week and about three quarters will deliver within two weeks (5). However, a subset of these women remain pregnant for an extended period of time, allowing the fetus to mature in utero. Families and clinicians require accurate information about important neonatal outcomes to allow appropriate counseling at the time of PPROM. Unfortunately, there are few articles addressing previable PPROM. With advances in obstetric management of PPROM, specically the use of antibiotics and antenatal steroids (1), the prognosis of infants born following previable PPROM might not have a uniformly poor outcome. Also, there have been considerable recent advances in neonatal care, with resultant improved outcomes at earlier gestation (6). These expectations prompted us to review the clinical course and outcomes of pregnancies following previable PPROM. The aims of this study were, rst, to clarify the mortality and morbidity with severe sequelae of infants at a corrected age of one and a half years and, second, to elucidate whether the aggressive management affected maternal infection.

Material and methods

A review of labor and delivery records from July 2001 to December 2009 at Japanese Red Cross Nagoya Daiichi Hospital was conducted. The hospital is a tertiary referral center with about 1400 deliveries per year. Women with PPROM occurring before 23+0 weeks of gestation were identied. This study was approved by the Institutional Ethical Committee of Japanese Red Cross Nagoya Daiichi Hospital. After counseling by a maternalfetal medicine specialist regarding the risks and benets of pregnancy prolongation compared with pregnancy termination, women who elected the former were included. Women who elected delivery, were carrying a fetus with anomalies, were carrying multiple fetuses or had an intrauterine fetal demise at the time of presentation were excluded. Women were also excluded if PPROM occurred after

genetic amniocentesis, because women with amniocentesesrelated rupture have been previously reported to be a discrete group with longer latency periods and better survival rates than the rest of the population (7). Diagnosis of PPROM was based on history and conrmed by the presence of pooled amniotic uid on a sterile speculum, positive results from a nitrazine test, and ultrasonographic evaluation that demonstrated oligohydramnios. Gestational age was conrmed in all cases by ultrasound in early pregnancy. After women were counseled extensively and had given informed consent, a whole set of hospital bed rest, administration of antibiotics and tocolytic drugs, emergency cerclage and amnioinfusion were applied to all the women. Antibiotics were chosen from among cephalosporins, penicillins, macrolides and carbapenems, of which some were administered singly in sequence until delivery. Tocolytic drugs (intravenous or oral ritodrine, magnesium sulfate and/or indomethacin) were administered continuously until delivery to prevent or suppress uterine contractions. Emergency cerclage was performed with the McDonald technique under intravenous or spinal lumbar anesthesia to prevent cervical dilatation. The tape was removed before vaginal delivery or at cesarean section. Serial amnioinfusion (warm saline 5001500 mL/day) was undertaken and was continued until delivery, the purpose of which did not include retention of uid, but rather lavation by perfusion. Under ultrasonographic guidance, a 21-gauge needle was inserted transabdominally into the amniotic cavity. Amniotic uid was aspirated for measurement of neutrophil elastase (8). An indwelling catheter with an outside diameter of 0.8 mm was inserted over a guide wire. Maternal and fetal status were closely monitored for development of chorioamnionitis, labor and/or fetal compromise. Body temperature was measured three times a day. White blood cell count and C-reactive protein were measured twice a week. Fetal well-being and uterine contractions were monitored on a cardiotocogram whenever needed, but at least twice a week. The aggressive management was abandoned and delivery expedited if any of the following criteria were noted: (i) clinical chorioamnionitis, characterized by two or more of the following conditions: temperature elevation to 38 C, white blood cell count 15 000/mm3 (i.e. above levels seen in labor or pregnancy) (9), fetal tachycardia, uterine tenderness or foul-smelling vaginal discharge; (ii) non-reassuring assessment for fetal well-being; (iii) fetal demise; (iv) active labor; or (v) failed tocolysis. A single course of antenatal corticosteroids (betamethasone 12 mg intramuscular, repeated 24 hlater) was administered, if at all possible, before delivery. Mild leukocytosis may be provoked by corticosteroid injection, and can be discriminated from infection by the lack of an increase in immature forms of neutrophils (9). Women were allowed to deliver vaginally unless there were obstetric or maternal indications for cesarean section. Following delivery, the presence
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and severity of histological chorioamnionitis were based on Blancs criteria (10). Resuscitation in the delivery room was performed by experienced neonatal staff. Following resuscitation, all newborns were admitted to the neonatal intensive care unit. Neonatal survival without major morbidity, including periventricular leukomalacia, cerebral palsy, mental retardation, paralysis, and retinopathy of prematurity (stage 3), was the primary outcome measure. Cranial ultrasonography was performed on all infants, and intraventricular hemorrhages were graded IIV. Pulmonary hypoplasia was diagnosed by the attending neonatologist secondary to difcult ventilation, with chest X-ray ndings suggestive of poor aeration (11). Bronchopulmonary dysplasia (12) was diagnosed using the National Institutes of Health Workshop severity-based diagnostic criteria (13). Statistical computations were performed using a commercially available statistical analysis package (StatMate III, Atoms Co., Ltd, Tokyo, Japan). A MannWhitney U -test was used for comparison of continuous variables. Comparisons of proportions were performed with Fishers exact probability test. Statistical tests were considered signicant at a p-value of <0.05 and were two tailed.

In total, 37 (82.2%) women showed an amniotic neutrophil elastase level >0.15 g/mL, suggesting amniotic inammation (8) on admission. The mean level was 5.53 g/mL in the surviving and 8.37 g/mL in the non-surviving groups, but this difference was not signicant (Table 1). Only four (8.9%) women developed clinical chorioamnionitis. Overall, 90.7 and 69.2% of women showed histological evidence of chorioamnionitis and funisitis, respectively. Table 2 summarizes neonatal morbidity. Five infants had pulmonary hypoplasia. More than 80% had long-term sequelae with bronchopulmonary dysplasia. Grade III or IV intraventricular hemorrhage was observed in two infants. Periventricular leukomalacia and retinopathy of prematurity were seen in ve and 11 infants, respectively. The leading cause of neonatal death was pulmonary hypoplasia (n = 5), followed by subgaleal hematoma, intracranial hemorrhage, necrotizing enterocolitis, pulmonary hypertension, sepsis and sudden infant death syndrome (each n = 1). Nine infants had serious sequelae at corrected a age of one and a half years. Maternal complications were uncommon. Four women (8.9%), who were not affected with clinical chorioamnionitis, had puerperal endomyometritis, but responded well to medical treatment. There were no cases of maternal sepsis, venous thrombosis, pulmonary embolism or death.

Results
Figure 1 summarizes the outcomes. Over the study period, 72 women presented with previable PPROM occurring before 23 weeks of gestation. In all, 45 patients elected aggressive management; 27 chose to terminate the pregnancy and were excluded from analysis. Thirty-eight infants were delivered alive and seven were stillborn. Twenty-seven live-born infants survived to discharge from hospital; one died on the labor ward and 10 died prior to discharge from hospital. The survival rate of pregnancies with aggressive management was 60% (27 of 45); that of live-born infants was 71.1% (27 of 38). The most common reason for delivery was spontaneous labor (64.4%), followed by intrauterine fetal demise (15.6%), non-reassuring fetal status (11.1%) and chorioamnionitis (8.9%). There were no cases of acute placental abruption. Table 1 shows the maternal and infant characteristics. Maternal age and parity were similar between the group with neonatal survivors and those with neonatal death prior to discharge. There was no signicant difference in mean birthweight, although it tended towards lower values in the nonsurviving group. A single course of antenatal steroids was completed by 81.5 and 27.3% of women with surviving and non-surviving babies, respectively. The relation between gestational age at PPROM and that at delivery is illustrated in Figure 2. The median gestational ages at PPROM and at delivery were signicantly lower in the non-surviving compared with the surviving group (Table 1).
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Discussion
According to a recent review of PPROM before 25 weeks of gestation, fetal death and survival to discharge were 31.6 and 44.4%, respectively, and a signicant difference in survival was found with PPROM before 22 weeks (14.4%) compared with PPROM occurring at and after 22 weeks (57.7%; 14). Our data are consistent with a bad prognosis before 22+0 weeks, but PPROM after this had an acceptable prognosis (Figure 2). Considering that the present study was limited to PPROM before 23+0 weeks, an overall neonatal survival rate of 60% is noteworthy, with nearly two-thirds of surviving infants not having serious sequelae. There are several possible explanations for these improved outcomes compared with other investigations. First, we started medical treatment without delay after the diagnosis of previable PPROM. In contrast, in most previous reports, women with previable PPROM were observed as outpatients and were not admitted to the hospital for close maternal and fetal management until viability was reached (i.e. approximately 24 weeks). Observation with bed rest at home might have advantages in selecting out women with a much higher chance for subsequent live birth, but might also increase fetal demise or stillbirth. Second, pregnancy prolongation played an important part. According to a large-scale investigation of extremely preterm infants from the NICHD Neonatal Research Network, rates of survival to discharge for infants born alive at 22, 23, 24, 25 and 26 weeks were 6, 26, 55, 72 and 84%,

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Figure 1. Outcome of pregnancies affected by membrane rupture before 23+0 weeks of gestation. Abbreviations: NICU, neonatal intesive care unit; and PPROM, preterm premature rupture of membranes.

respectively (15). These data indicated that each additional week of gestational age at birth conferred a substantial survival advantage; the most marked changes were between 22 and 25 weeks. As the median gestational age at delivery was

25 weeks in our study, delay of delivery is likely to contribute substantially to good neonatal outcomes. Third, neonatologists attended in the delivery room, and intensive care was provided for all very preterm deliveries in our center. The

Table 1. Maternal and infant characteristics after aggressive multimodal treatment of preterm premature rupture of membranes. Alive at discharge from hospital (n = 27) 30.7 5.5 13 (48.1) 22 (1722) 26 (2336) 33 (11103) 12 (44.4) 15 (55.5) 1002 451 11 (40.7) 16 (59.3) 22 (81.5) 5.53 9.50 22 of 25 (88.0) 15 of 23 (65.2) Death during hospital stay (n = 11) 33.5 4.2 5 (45.5) 21 (1522) 23 (2229) 40 (055) 7 (63.6) 4 (36.4) 769 261 7 (63.6) 4 (36.4) 3 (27.3) 8.37 8.68 10 of 11 (90.9) 7 of 10 (70)

Characteristic Maternal age (years)a Nulliparousc Gestational age at PPROM (completed weeks)b Gestational age at delivery (completed weeks)b Latent period (days)b Delivery modec Cesarean Vaginal Birthweight (g)a Sex of fetusc Male Female Antenatal steroidsc Amniotic neutrophil elastase (g/mL)a Histological chorioamnionitisc Histological funisitisc

All infants (n = 45) 31.0 6.1 24 (53.3) 22 (1522) 25 (2236) 24 (0103) 18 (40) 27 (60) 871 412 21 (46.7) 24 (53.3) 27 (60) 6.90 9.86 39 of 43 (90.7) 27 of 37 (69.2)

Alive vs. infant death p-Value 0.066d 0.583e 0.044d 0.029d 0.629d 0.238e

0.097d 0.178e

0.003e 0.064d 0.644e 0.560e

Abbreviation: PPROM, preterm premature rupture of membranes. Values are presented as means SDa , median (range)b or n (%)c . d MannWhitney U-test. e Fishers exact probability test. All cesarean sections were emergent. There was no induction, with the exception of intrauterine fetal demise. Some data are missing.

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Figure 2. Survival by gestational age after premature preterm rupture of membranes and delivery. Open circle, survivors without serious sequelae; crosses, survivors with serious sequelae; lled squares, infants died prior to discharge from hospital; and lled triangles, stillborn infants.

practice of withdrawal of neonatal intensive care is known to vary signicantly among countries and regions (16). Finally, we were highly motivated towards aggressively treating mothers who inevitably were going to deliver in the previable period (before 24 weeks). The multimodal management included tocolysis, antibiotics, amnioinfusion and cerclage in all women with previable PPROM; only antenatal steroids were not used routinely. One of the critical issues of previable PPROM is chorioamniotic infection. The prevalence of clinically overt signs of chorioamnionitis is generally low, and many women can have an intrauterine infection without having clinical symptoms such as fever, uterine tenderness and an elevated white blood cell count (17). The level of amniotic neutrophil elastase has been reported to increase signicantly when chorioamnionitis has advanced; therefore, its measurement is useful to predict subclinical and/or histological chorioamnionitis (8). It was unexpected that more than 80% of the women with
Table 2. Neonatal morbidity among live-born infants (n = 38). Comorbid conditions Neonatal sepsis Necrotizing enterocolitis Pulmonary hypoplasia Bronchopulmonary dysplasia Respiratory distress syndrome Pneumonia Patent ductus arteriosis Joint contractures Intraventricular hemorrhage (grade I/II) Intraventricular hemorrhage (grade III/IV) Periventricular leukomalacia Retinopathy of prematurity

n 3 2 5 25 of 30 13 1 4 0 6 2 5 11

Percentage 7.9 5.3 13.2 83.3 34.2 2.6 10.5 0 15.8 5.3 13.2 28.9

Eight neonates died before 28 days.

previable PPROM on admission demonstrated amniotic inammation based on the level of amniotic neutrophil elastase. Antibiotic therapy for women with PPROM is now our routine practice. Systematic reviews have shown that antibiotic administration is associated with prolongation of the time to delivery and reduces neonatal morbidity (18,19). However, intra-amniotic inammation/infection can be controlled but not eradicated (20,21). This concept is supported by the present observation that around 90 and 70% of cases showed histological chorioamnionitis and funisitis, respectively, although only four women had clinical chorioamnionitis. The use of tocolysis is controversial; there are inadequate data on which to make an evidence-based recommendation for or against its use. The median latency to delivery has been shown to be between 6 and 13 days in women with PPROM before 25 weeks of gestation where antibiotics were administered to the majority of women, but a tocolytic agent was used in only 014.3% (14). Considering the median latency of 24 days in the present study, tocolytic therapy might have briey prolonged pregnancy and thereby allowed more time for antibiotic therapy. An adequate volume of amniotic uid is vital for proper lung development (22). There is insufcient evidence to guide clinical practice concerning the use of amnioinfusion for PPROM (23). However, recent studies seem to support amnioinfusion in the management of PPROM, although the sample sizes have been small (24,25). Our experience has been that the infused uid often leaks out and amniotic uid volume is not restored as expected. Rather, we think the prime signicance is as a form of lavation. Flushing the amniotic cavity with a massive amount of saline leads to elimination of inammatory material and bacteria, inhibition of ascending transcervical infection, and collateral uid accumulation to some degree. Cervical cerclage placement concurrent to attempted membrane sealing has been tried for previable PPROM (26). In our management, emergency cerclage was done to prevent cervical dilatation. This procedure is controversial, because the general approach to manage women with PPROM and a cervical cerclage in situ includes early cerclage removal (1). As tocolysis cannot absolutely suppress uterine contractions, additional emergency cerclage could be necessary to arrest cervical dilatation. It is well established that administration of antenatal corticosteroids to women at high risk of delivering an immature preterm infant is one of the most effective obstetric interventions to reduce perinatal morbidity and mortality. Our study demonstrated that neonatal survival was associated with more frequent use of antenatal corticosteroids. Unfortunately, antenatal corticosteroids were not given to every woman because the labor progressed too precipitously in some cases. The period of optimal treatment effect is seven days, and multiple antenatal corticosteroid courses have not

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been recommended owing to potential adverse effects (27). Therefore, there were also women who delivered while we procrastinated about administration. Optimal timing of antenatal steroid administration and delivery are required to maximize neonatal outcomes. Although it has been hypothesized that intrauterine infection activates the fetal production of pro-inammatory cytokines, which subsequently contribute to perinatal injury, including white matter damage and periventricular leukomalacia (28), our data showed that previable PPROM, even with high levels of amniotic neutrophil elastase, could result in live-born infants without serious sequelae. Furthermore, recent studies demonstrated that delayed delivery after PPROM did not change the prognosis with regard to neurological morbidity (29,30). This could justify aggressive management even in cases with amniotic inammation/infection. Prolongation of pregnancy with clinical chorioamnionitis is a matter that remains to be solved.

Funding
No specic funding. References
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24. Tranquilli AL, Giannubilo SR, Bezzeccheri V, Scagnoli C. Transabdominal amnioinfusion in preterm premature rupture of membranes: a randomized controlled trial. BJOG. 2005;112:75963. 25. Butt FT, Ahmed B. The role of antepartum transabdominal amnioinfusion in the management of oligohydramnios in pregnancy. J Matern Fetal Neonatal Med. 2011;24: 4537. 26. OBrien JM, Barton JR, Milligan DA. An aggressive interventional protocol for early midtrimester premature rupture of the membranes using gelatin sponge for cervical plugging. Am J Obstet Gynecol. 2002;187: 11436. 27. National Institutes of Health Consensus Development Panel. Antenatal corticosteroids revisited: repeat courses National Institutes of Health Consensus Development Conference

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