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Outcomes following prolonged preterm premature rupture of the membranes
  1. N J Everest1,2,3,
  2. S E Jacobs1,2,3,
  3. P G Davis1,2,3,
  4. L Begg1,2,3,
  5. S Rogerson1,2,3
  1. 1
    Department of Neonatal Medicine, Royal Women’s Hospital, Melbourne, Victoria, Australia
  2. 2
    Department of Obstetrics and Gynaecology, Royal Women’s Hospital and University of Melbourne, Melbourne, Victoria, Australia
  3. 3
    Department of Obstetrics and Gynaecology, Royal Women's Hospital, Melbourne, Australia
  1. Dr N J Everest, Department of Neonatal Medicine, Royal Children’s Hospital, Flemington Road, Parkville, Australia 3052; neverest{at}mac.com

Abstract

Objective: Rupture of the membranes in the second trimester is reported to be associated with high rates of pregnancy loss, neonatal mortality and morbidity. This article describes the outcomes of liveborn infants delivered following a prolonged period of membrane rupture occurring before 24 weeks’ gestation.

Patients and setting: Over a 5-year period, consecutive pregnancies complicated by spontaneous rupture of the membranes before 24 weeks’ gestation were identified. Evaluation of short-term outcomes before discharge of liveborn infants delivered, in a tertiary referral centre, following prolonged rupture of membranes of duration greater than 2 weeks.

Results: Of 98 pregnancies identified with rupture of the membranes before 24 weeks’ gestation, 40 (41%) women progressed to deliver a liveborn infant following a latent period of at least 14 days. Although most liveborn infants required neonatal intensive care including mechanical ventilation (n = 38; 78%), the survival rate to hospital discharge was 70% (n = 28). Airleak occurred in 7 (25%) survivors and 8 (67%) deaths. Among the survivors, 12 (43%) required supplemental oxygen at 36 weeks’ postmenstrual age and no infant had grade 3 or 4 intraventricular haemorrhage. One infant had a postmortem diagnosis of pulmonary hypoplasia and nine others had clinical features consistent with this diagnosis. Low liquor volume was not uniformly associated with a poor outcome.

Conclusion: With full contemporary neonatal intensive care, the outcome for liveborn infants in the present cohort delivered following membrane rupture occurring before 24 weeks’ gestation, of at least 14 days duration, was better than previously reported.

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Second trimester preterm premature rupture of the membranes (PPROM) occurring before viability “represents one of the most devastating diagnoses in pregnancy, with high perinatal mortality and morbidity”.1 More than 60% of women who experience rupture of the membranes before 26 weeks deliver within 1 week.2 A longer latent period before delivery is associated with an increased risk of perinatal sepsis, oligohydramnios and pulmonary hypoplasia, often superimposed on the risks of extreme prematurity.

Despite reports of mortality rates ranging from 37% to 100% depending on the gestation at membrane rupture,313 we observed that infants born following membrane rupture occurring before 24 weeks’ gestation, who are offered modern neonatal intensive care, do not have a uniformly poor outcome. Families and clinicians require accurate information about important neonatal outcomes to allow appropriate counselling at the time of rupture of membranes through to the time of delivery. Therefore, we reviewed the clinical course and outcomes of pregnancies following membrane rupture occurring before 24 weeks’ gestation and with a membrane rupture to delivery interval (latent period) of 14 days or more.

METHODS

Design and setting

From the maternity unit database of the Royal Women’s Hospital (RWH), Melbourne, Australia, we identified all pregnancies in the period 1 January 2001 to 31 December 2005 complicated by spontaneous membrane rupture occurring before 24 weeks’ gestation and determined the outcome—that is, spontaneous miscarriage, stillbirth, termination, livebirth and survival to primary hospitalisation discharge. All infants were born at the RWH, a level III perinatal centre with more than 5000 deliveries and 1400 admissions to the intensive and special care nurseries every year.

We reviewed the medical histories of all liveborn infants delivered following spontaneous membrane rupture occurring before 24 weeks’ gestation and with a latent period of at least 14 days. Liveborn infants who did not survive either the delivery room or neonatal unit were identified from the mortuary database. Liveborn infants admitted to the neonatal unit were identified from the neonatal unit database.

Pregnancy management

Women with affected pregnancies had a sterile speculum examination to confirm the diagnosis of membrane rupture. A high vaginal swab taken was taken and prophylactic oral erythromycin was given to women without signs of sepsis. A single course of antenatal steroids was administered by the attending obstetric staff, starting at 23 weeks’ and 6 days’ gestation.

The women had their antenatal ultrasound examinations at either the RWH, a regional hospital or in private radiology practice; only those performed at the RWH were available for the study. The timing of the ultrasound assessment of amniotic fluid index (AFI) was at the discretion of the attending obstetrician. Oligohydramnios was defined as an AFI of <2 cm.14 Fetal lung measurements were not done. Counselling for termination was performed by obstetric and neonatal staff on the basis of the pre-existing literature on the outcomes following membrane rupture before 24 weeks’ gestation.

Main outcome measures

The gestation at membrane rupture was calculated using the date of the last menstrual period, confirmed by mid-trimester antenatal ultrasound. If the gestational assessment differed by more than 10 days using each method, the ultrasound estimated date of delivery was used. The diagnosis of membrane rupture was made by the attending obstetric staff. The latent period was the difference between the gestation at membrane rupture and delivery, in days. Histological evidence of all grades of chorioamnionitis was recorded.

Neonatal outcomes

The primary neonatal outcome was survival to hospital discharge. Secondary outcomes were: air-leak syndrome diagnosed clinically and confirmed by chest radiograph, hyaline membrane disease defined as clinical signs of respiratory distress in the first days of life with confirmatory radiological appearance, chronic lung disease defined as supplemental oxygen requirement beyond 36 weeks’ gestation15 and the administration of postnatal steroids.

All infants with birth weight <1250 g were screened for retinopathy of prematurity by an ophthalmologist using the International Classification of Retinopathy of Prematurity.16 Cranial ultrasound was performed on all infants on day 1–3 of life and again on day 7. Intraventricular haemorrhage was classified using the system of Papile.17 Cranial ultrasounds were performed on a monthly basis thereafter to assess the periventricular white matter and ventricular dimensions.

A diagnosis of pulmonary hypoplasia was made ante mortem by the attending neonatologist on the basis of clinical and radiological findings or post mortem using lung weight to body weight ratio.18

Neonatal management

Resuscitation in the delivery room was performed by experienced neonatal staff in accordance with the guidelines of the International Liaison Committee on Resuscitation.19

Infants requiring ventilation were managed using the assist control mode with volume guarantee on the Dräger Babylog 8000+ ventilator (Dräger, Lubeck, Germany). The tidal volume used with this mode of ventilation ranged between 3.5 ml/kg and 5.5 ml/kg. Surfactant (Survanta, Abbott Laboratories, Chicago, USA) was administered in the neonatal unit if an infant’s FiO2 was ⩾0.3. High-frequency oscillatory ventilation (HFOV) using the Dräger 8000+ and/or SensorMedics 3100A (VIASYS Healthcare, Yorba Linda, USA) ventilator was only used as rescue treatment. Muscle relaxation was administered in conjunction with HFOV. Nitric oxide was started as rescue treatment at the discretion of the attending doctor. In general, nitric oxide was given if oxygen saturation remained below 88% when receiving 100% inspired oxygen, and only in combination with HFOV. Infants were managed with nasal continuous positive airway pressure (CPAP) after extubation.

Infants requiring assisted ventilation had a blood culture, C-reactive protein (CRP) and full blood count on admission, and were treated with benzyl penicillin and gentamicin.

Statistical analysis

Statistical analysis was performed using SPSS version 11.5. Outcomes expressed as proportions were analysed using the χ2 test and outcomes expressed as means were analysed using the Student t test.

RESULTS

Between 1 January 2001 and 31 December 2005, the incidence of premature rupture of the membranes occurring before 24 weeks’ gestation was 0.37% (98/26306 pregnancies). Figure 1 summarises the outcomes of the 98 affected pregnancies. When the latent period exceeded 14 days, 40 morphologically normal infants were delivered alive and 10 were stillborn. Thirty-five of the liveborn infants were singletons, the other five were from dichorionic twin pregnancies—only the twin affected by membrane rupture was included in the study. The remainder of the results pertain to the infants who were liveborn.

Figure 1 Outcomes of pregnancies affected by membrane rupture before 24 weeks’ gestation. *One infant received nitric oxide on days 35 and 36 following reventilation on assist control mode for respiratory failure in association with chronic lung disease. CPAP, continuous positive airway pressure; HFOV, high-frequency oscillatory ventilation; NICU, neonatal intensive care unit.

The trend of AFI measurements were available from 30 pregnancies (fig 2). Oligohydramnios or anhydramnios was found at any time point in 16/24 (67%) surviving infants and 2/6 (33%) infants who died (odds ratio 4, 95% CI 0.6 to 27).

Figure 2 Amniotic fluid index in 30 pregnancies affected by membrane rupture occurring before 24 weeks’ gestation, of ⩾14 days duration.

All 40 liveborn infants with a prolonged latent period were offered full resuscitation. Two infants, neither of whom received surfactant, died in the delivery room at 22 and 23 weeks’ gestation. The remaining 38 infants were admitted to the neonatal unit and 28 survived to discharge (70%). Table 1 shows the maternal and infant demographics. A single course of antenatal steroids was completed by 98% of the women. One woman did not receive antenatal steroids at a regional hospital; they were not administered prior to transfer in labour at 22 weeks’ gestation. The gestation at membrane rupture was similar in survivors and infants who died. Survival was not significantly associated with higher birth weight, gestational age and longer latent period.

Table 1 Maternal and infant demographics

Table 2 shows the infant outcomes. No statistically significant differences were seen for any of the infant outcomes between the infants who survived and those who died. Infants who survived had better Apgar scores and cord pH than those who died. Table 3 gives details of the infants who died in the neonatal unit. Only one infant had a postmortem at which a diagnosis of pulmonary hypoplasia was made. The parents of the other infants who died declined a postmortem examination. Nine other infants were assigned a diagnosis of pulmonary hypoplasia on the basis of clinical and radiological findings, five of whom survived. Two infants admitted to the neonatal unit did not receive surfactant because they died within minutes of admission. No infants had grade 3 or 4 intraventricular haemorrhage or periventricular leukomalacia. None of the infants was discharged on oxygen.

Table 2 Infant outcomes
Table 3 Infants who died in the neonatal unit

Figure 1 summarises the respiratory management and outcomes for all infants admitted to NICU. Nine infants (24% of NICU admissions) were never ventilated via an endotracheal tube during their primary hospitalisation and all survived; five were managed with nasal CPAP and oxygen, three with supplemental oxygen alone and one did not require any respiratory support. Six infants were treated with nitric oxide, three of whom survived. Inhaled nitric oxide (iNO) was used during the first 48 h of life in five infants (two survived to discharge) and on days 35 and 36 in one infant with respiratory failure due to severe chronic lung disease who survived. All infants with a diagnosis of chronic lung disease had received endotracheal ventilation. Three infants with chronic lung disease were treated with postnatal steroids, one of whom survived.

Blood cultures were taken from 35 infants on admission to the nursery. Two were not cultured since the infants died in the delivery room and three were not taken as the infants were well after delivery. Only one blood culture was positive (Escherichia coli); this was concordant with a placental swab. All but one of the NICU admissions had a CRP taken on admission and at 24 h of age if still alive. Nine of the 31 infants alive at 24 h had raised concentrations of CRP (range 12–29 mg/l).

DISCUSSION

What is already known on this topic

  • Rupture of the membranes in the second trimester has been associated with significant neonatal morbidity and poor survival rates.

  • Human and animal studies show that some infants delivered following prolonged membrane rupture, with early severe respiratory failure consistent with pulmonary hypoplasia, may benefit from inhaled nitric oxide.

What this study adds

  • In our cohort of infants delivered following prolonged membrane rupture occurring before 24 weeks, and treated with modern neonatal intensive care including volume-targeted and high-frequency ventilation and nitric oxide, the rate of survival to discharge is 70%.

  • Hospital-specific information on neonatal outcomes for infants delivered following second trimester membrane rupture is desirable for counselling parents who are undecided whether to continue with the pregnancy.

In our cohort, 62% of mothers delivered a liveborn infant following membrane rupture occurring before 24 weeks’ gestation. With modern intensive care, 70% of liveborn infants delivered following a period of prolonged membrane rupture occurring before 24 weeks’ gestation survived to discharge. This contrasts with the findings of previous studies which reported survival rates between 0 and 63% when membranes were ruptured before 24 weeks, depending on the gestation at PPROM.313 Comparisons with previous reports are difficult because of lack of uniformity of definition of duration of membrane rupture and inclusion of infants delivered following membrane rupture after 24 complete weeks’ gestation. We chose to assess outcomes of infants delivered following a longer period than some previous studies to evaluate the prognosis of those infants at highest risk of adverse outcomes, particularly pulmonary hypoplasia. In many previous reports it is unclear whether a similar range of intensive care treatments were used, including surfactant, different modes of ventilation and nitric oxide. Oligohydramnios at the time of membrane rupture is an independent risk factor for the development of pulmonary hypoplasia.20 In our cohort, the AFI did not remain static and the presence of oligohydramnios and anhydramnios, at any point, was not uniformly associated with poor neonatal outcome.

Almost a quarter of the total population in our study did not receive endotracheal intubation despite being at risk of pulmonary hypoplasia. They had better outcomes than those who received mechanical ventilation. Survival was poorer as the need for respiratory treatment increased. Previous reports indicate that infants born following 14 days or more membrane rupture in the early canalicular phase of lung development are more likely to develop pulmonary hypoplasia compared with those delivered following a shorter latent period.313 A mean latent period of 9 days has also been associated with an increased incidence of persistent pulmonary hypertension of the newborn.21 Despite the minimum length of latent period of 14 days for entry into our study we have shown that survival following modern intensive care has improved compared with previous reports.313

PPROM may cause adverse outcomes via oligohydramnios, which in turn leads to pulmonary hypoplasia and pulmonary artery musculature hyperplasia.10 2224 Postnatally this leads to difficulties with ventilation, including air leak, pulmonary hypertension and severe hypoxia. Animal models and human studies have shown that the administration of nitric oxide improves pulmonary blood flow, and hence ventilation–perfusion mismatch, in infants with varying degrees of abnormal pulmonary development due to premature rupture of the membranes.2527 The use of iNO in the setting of PPROM requires further evaluation in a larger population to investigate its short-term efficacy and effect on survival.

Despite the use of modern neonatal treatments, death resulting from abnormal lung development following prolonged amniotic fluid loss may be inevitable in some cases. We found it difficult to predict poor outcome in the first days of birth as many infants with severe respiratory failure and pulmonary hypertension improved and did remarkably well.

Acknowledgments

We would like to thank L Cady and B Piriatinski for assistance in the collection of the data.

REFERENCES

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Footnotes

  • Competing interests: None.

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