Abstract
Objective
It was the aim of our study to evaluate the independent effect of preterm prelabor rupture of membranes (PPROM) as a cause of preterm delivery on mortality during primary hospital stay and significant morbidities in very-low-birth-weight (VLBW) infants < 32 weeks of gestation.
Design
Observational, epidemiological study design.
Setting
Population-based cohort, German Neonatal Network (GNN).
Population
6102 VLBW infants were enrolled in GNN from 2009-2012, n=4120 fulfilled criteria for primary analysis (< 32 gestational weeks, no pre-eclampsia, HELLP (highly elevated liver enzymes and low platelets syndrome) or placental abruption as cause of preterm birth).
Methods
Multivariable logistic regression analyses included PPROM as potential risk factors for adverse outcomes and well established items such as gestational age in weeks, birth weight, antenatal steroids, center, inborn delivery, multiple birth, gender and being small-for-gestational-age.
Results
PPROM as cause of preterm delivery had no independent effect on the risk of early-onset sepsis, clinical sepsis and blood-culture proven sepsis, while gestational age proved to be the most important contributor to sepsis risk. The diagnosis of PPROM was associated with an increased risk for bronchopulmonary dysplasia (BPD; OR: 1.25, 95% CI: 1.02-1.55, p=0.03) but not with other major outcomes.
Conclusions
The diagnosis of PPROM per se is not associated with adverse outcome in VLBW infants < 32 weeks apart from a moderately increased risk for BPD. Randomized controlled trials with primary neonatal outcomes are needed to determine which subgroup of VLBW infants benefit from expectant or intentional management of PPROM.
Introduction
Preterm prelabor rupture of membranes (PPROM) occurs in 2–3% of all pregnancies and contributes to 30–40% of preterm births [1]. PPROM is a multifactorial process including certain risk components such as PPROM in previous pregnancy, smoking, socioeconomic status, infection (bacterial vaginosis), amniocentesis, polyhydramnion, multiple gestation and vaginal bleeding. In many cases the cause of PPROM remains unknown. PPROM is initiated by membrane stretch and involves local inflammation and ascending bacterial colonisation [1–2]Women with PPROM between 16 and 26 weeks of gestation were reported to deliver their infant in 79% within four weeks and in 57% within one week after PPROM diagnosis [3]PPROM is associated with a higher risk of prematurity, anhydramnios, cord compression, amniotic infection syndrome (AIS) and placental abruption. PPROM < 20 weeks of gestation causes limb/face deformities, severe lung hypoplasia (Potter´s sequence) and dry lung syndrome which is associated with high mortality and long-term pulmonary complications [4–7].
The initial approach to manage pregnancies complicated by PPROM is based on several parameters assessed upon presentation [8,9]:gestational age, presence of AIS / preterm labor, fetal condition (exposure to antenatal steroids) and availablity of neonatal intensive care. Pregnancies complicated by PPROM ≥ 34 weeks gestational age often receive labor-inducing medication, however, recent data from a randomized controlled trial indicate that this strategy does not substantially improve pregnancy outcomes compared with expectant management [10].Management of PPROM between 22+0 and 34+0 gestational weeks is still a matter of debate. Based on clinical guidelines, PPROM with AIS should receive antibiotics and prompt to termination of pregnancy. PPROM without AIS is closely observed (expectant management) and treated with antibiotics [reviewed in 11].In particular, the treatment for PPROM in the gestational age of 22+0–23+6 weeks is an important aspect of interdisciplinary discussion and needs informed consent of families [8–11].There is currently no evidence on the beneficial use of transabdominal amnioinfusion in women with an (oligo)-hydramnios secondary to PPROM before 26 weeks [10,12].
To what extent PPROM and AIS contribute to adverse outcome is not yet fully understood. AIS and PPROM may be innocent bystanders, as “mild” perinatal inflammation may enhance the functional maturation of the preterm immune system [13]or, vice versa, supposed to be responsible for adverse outcome [14]. A reliable prognosis for VLBW infants delivered after PPROM is difficult to make before birth and in the first hour of life [15]. As up-to-date estimates derived from large-scale population-based studies are scarce, we aimed to determine the role of PPROM as cause of preterm delivery for infant survival and morbidity in very-low-birth-weight (birth weight < 1500g, VLBW) infants < 32 gestational weeks enrolled in the German Neonatal Network (GNN).
Methods
VLBW cohort
We performed an observational study and enrolled VLBW infants in a multi-center trial involving 46 neonatal intensive care units in Germany (GNN). The data were collected from infants born between 1st of January 2009 until 31st of December 2012. The inclusion criteria were as follows: birth weight < 1500g and gestational age ≥22+0 and <32+0 weeks, exclusion criteria: lethal malformations, e.g. trisomy 13 and trisomy 18, and maternal causes of preterm delivery, e.g. placental abruption, HELLP (highly elevated liver enzymes and low platelets) syndrome and pre-eclampsia. After written informed consent was given by the parents, infants were enrolled in GNN by the attending physicians and a predefined clinical data set of 220 parameters including antenatal/postnatal treatment and outcome data were recorded by according data sheets. After discharge, data sheets were sent to the GNN center in Lübeck. A basic data set of other infants born in GNN centers but not enrolled in GNN including birth weight, gestational age, and major outcomes including cause of death was documented. A physician trained in neonatology evaluated the data quality by annual on site monitoring of data sets.
Definitions
Preterm prelabor rupture of membranes (PPROM) was defined as non-iatrogenic rupture of membranes before the onset of labor effective contractions. Gestational age was calculated from the best obstetric estimate based on early prenatal ultrasound and obstetric examination. Small-for-gestational age (SGA) was defined as a birth weight less than 10th percentile for gestational age according to gender-specific standards for birth weight by gestational age in Germany [16]. Amniotic infection syndrome (AIS) was defined as maternal fever (≥ 38.0°C), increased maternal inflammatory markers without any other cause (CRP > 10 mg/L or elevation of white blood cell count > 16000 / μL), fetal or maternal tachycardia, painful uterus and foul smelling liquor. Clinical sepsis was defined as condition with at least two signs of systemic inflammatory response (temperature > 38°C or < 36.5°C, tachycardia > 200/min, new onset or increased frequency of bradycardias or apneas, hyperglycemia > 140 mg/dl, base excess < -10 mval/l, changed skin color, increased oxygen requirements) and neonatologist´s decision to treat with antibiotics for at least 5 days but no proof of causative agent in blood culture and one laboratory sign [17,18]. Blood culture confirmed sepsis was defined as clinical sepsis with proof of causative agent in the blood culture. If coagulase-negative staphylococci (CoNS) were isolated as single pathogen in one peripheral blood culture, two clinical signs and one laboratory sign (platelet count < 100/nl, C-reactive protein > 20 mg/L, immature/total neutrophil ratio > 0.2, white blood cell count < 5/nl) were required for classification of CoNS sepsis.
Early-onset sepsis (EOS) was defined as blood-culture confirmed sepsis occurring within the first 72 h of life. Late-onset sepsis (LOS) was defined as blood-culture confirmed sepsis occurring ≥72 h of life.
Death was defined as all-cause mortality occurring after admission to NICU before discharge home. BPD was diagnosed when needing oxygen at 36 weeks of post menstrual age [19]. Intracerebral haemorrhage grades I-IV were diagnosed according to the ultrasound criteria of Papile [20]. Periventricular leukomalacia (PVL) was diagnosed by means of head ultrasound and/or MRI and included specific findings such as echodense intraparenchymal lesions, periventricular leukomalacia and porencephalic cysts with or without intraventricular hemorrhage.
Antenatal steroids was defined as maternal treatment with betamethasone or dexamethasone for lung maturity of the fetus irrespective of number of doses. Antenatal antibiotics and tocolytics were defined as maternal treatment with antibiotics or tocolytics within the time frame of ≤ 24h before delivery.
Statistical analysis
Data analysis was performed using the SPSS 20.0 data analysis package (Munich, Germany). Differences between infants born after PPROM and infants without PPROM were evaluated with Chi-square test, Fisher´s exact test and Mann-Whitney U test. A p value < 0.05 was considered as statistically significant for single tests. To determine the independent impact of PPROM on outcomes, we performed multivariable logistic regression analyses including well-established risk factors of adverse short-term outcomes in the whole cohort of infants < 32+0 gestational weeks enrolled in GNN.
Ethics
Written informed consent was obtained from parents on behalf of the infants enrolled in our study. The study parts were approved by the local committee on research in human subjects of the University of Lübeck (08–022; 03.12.2010) and the local ethical committees at the other study centers.
Specifically: Ethical Board of the Medical Chamber of the North Rhine region, Ethical Board of the University of Aachen, Ethical Board of the University of Bonn, Ethical Board of the Medical Chamber of the federal state of Mecklenburg-Vorpommern, Ethical Board of the Medical Chamber of Berlin, Ethical Board of the University of Magdeburg, Ethical Board of the University of Halle, Ethical Board of the University of Tübingen, Ethical Board of the Medical School Hannover, Ethical Board of the University of Cologne, Ethical Board of the University of Essen, Ethical Board of the Medical Chamber of the Westphalia-Lippe region, Ethical Board of the Medical Chamber of Hamburg, Ethical Board of the Medical Chamber of the federal state of Hessen, Ethical Board of the Medical Chamber of the federal state of Baden-Württemberg, Ethical Board of the Medical Chamber of the federal state of Bavaria, Ethical Board of the Saar University.
Results
Clinical characteristics
During the observational study period from January 2009 until December 2012 6102 VLBW infants were enrolled in GNN. 4120 infants fulfilled criteria for primary analysis (< 32 gestational weeks without maternal causes of preterm delivery). As shown in Table 1, infants without PPROM (n = 2559) were more likely to be multiples and SGA while infants born after PPROM (n = 1561) were younger at birth.
Table 1. Clinical characteristics of VLBW cohort categorized according to PPROM.
| Clinical characteristics | No PPROM | PPROM | p-value |
|---|---|---|---|
| No. of infants | 2559 | 1561 | |
| Gestational age (weeks), mean (SD) | 28.1 (2.3) | 27.7 (2.3) | 0.01* |
| Birth weight (g), mean (SD) | 1005 (301) | 1045 (295) | < 0.001* |
| SGA (< 10th percentile, %) | 15.6 | 4.7 | < 0.001 |
| Male gender (%) | 51.7 | 54.3 | 0.11 |
| Multiple birth (%) | 41.2 | 35.1 | <0.001 |
| Inborn (%) | 97.3 | 98.3 | 0.04 |
| Antenatal steroids (%) | 91.2 | 92.9 | 0.05 |
| Spontaneous delivery (%) | 11.0 | 12.4 | 0.22 |
| Elective Caesarean Section (%) | 79.6 | 79.3 | 0.9 |
| Emergency Caesarean Section (%) | 9.3 | 8.2 | 0.2 |
| Umbilical artery pH (median, IQR) | 7.33 (7.28–7.37) | 7.34 (7.30–7.38) | 0.10* |
| Maternal background, German (%) | 75.2 | 72.8 | 0.08 |
p-values are derived from Fisher´s exact test or Mann-Whitney-U-test if indicated (*)
Treatment of infants with PPROM
As demonstrated in Table 2, infants with PPROM had a higher likelihood to be exposed to tocolytics and antenatal antibiotics in the time frame ≤ 24h before delivery. The same holds true for more frequent treatment with postnatal antibiotics and inotropes in the “PPROM-group”. These differences may be a consequence of the increased rate of AIS in the infants born after PPROM. There were no differences with regard to other treatment strategies including transfusions, steroids, diuretics or surfactant.
Table 2. Treatment differences of VLBW cohort categorized according to PPROM.
| Clinical characteristics | No PPROM | PPROM | p-value |
|---|---|---|---|
| No. of infants | 2542 | 1545 | |
| Tocolytic treatment of mother (%) | 51.8 | 68.1 | <0.001 |
| Labour refractory to tocolytics(%) | 40.8 | 46.8 | <0.001 |
| Amniotic infection syndrome (%) | 17.0 | 50.1 | <0.001 |
| Antenatal antibiotics (%) | 46.2 | 81.0 | <0.001 |
| Postnatal antibiotics (%) | 88.7 | 95.9 | <0.001 |
| Inotrope support (%) | 20.2 | 23.1 | 0.03 |
| Minimal MAP first 24h, median (IQR | 27 (23–31) | 26 (22–31) | 0.31* |
| Diuretics (%) | 36.8 | 36.6 | 0.90 |
| Transfusions (%) | 48.1 | 48.7 | 0.89 |
| No. of transfusions, median (IQR) | 0 (0–2) | 0 (0–2) | 0.82 |
| Hydrocortisone (%) | 10.7 | 11.6 | 0.41 |
| Dexamethasone (%) | 5.3 | 6.0 | 0.41 |
| Prednisolone (%) | 3.2 | 3.4 | 0.82 |
| Surfactant received (%) | 65.2 | 65.2 | 0.91 |
| surfactant applications, median (IQR) | 1 (1–2) | 1 (1–2) | 0.92* |
| Endotracheal ventilation (%) | 53.4 | 55.4 | 0.20 |
| Duration ventilation, median (IQR) d | 1 (0–7) | 2 (0–8) | 0.40* |
| Duration oxygen supplement | 17 (3–53) | 22 (3–55) | 0.21* |
p-values are derived from Fisher´s exact test or Mann-Whitney-U-test if indicated (*)
Short-term outcomes in infants with PPROM
No differences were noted with regard to short term outcomes in both groups stratified to PPROM (Table 3). In Table 4 we describe an analysis restricted to infants born after PPROM. Infants born after PPROM with concurrent AIS had a lower gestational age and birth weight compared to those infants born after PPROM without AIS. There were no differences in outcomes apart from a higher risk for clinical sepsis in AIS infants, particularly in the first 72h of life (early onset clinical sepsis, 18.2 vs. 12.9%, p = 0.004), and a longer need for O2 supplement.
Table 3. Short-term outcomes categorized according to PPROM.
| Clinical characteristics | No PPROM | PPROM | p-value |
|---|---|---|---|
| No. of infants | 2526 | 1542 | |
| Intracerebral haemorrhage (%) | 18.5 | 19.1 | 0.64 |
| ICH Grade I (%) | 7.0 | 7.3 | |
| ICH Grade II (%) | 4.6 | 4.6 | |
| ICH Grade III (%) | 3.1 | 3.4 | |
| ICH Grade IV (%) | 3.6 | 3.5 | |
| PVL (%) | 3.1 | 3.2 | 0.80 |
| Early-onset sepsis (%) | 1.9 | 2.6 | 0.11 |
| Pneumonia < 72 h (%) | 0.8 | 0.4 | 0.5 |
| Late-onset Pneumonia (%) | 3.5 | 4.3 | 0.12 |
| Clinical sepsis (%) | 34.0 | 36.1 | 0.18 |
| Blood-culture proven sepsis (%) | 13.4 | 14.2 | 0.46 |
| Late-onset sepsis (%) | 12.6 | 13.0 | 0.75 |
| Pneumothorax (%) | 5.4 | 6.5 | 0.15 |
| O2 supplement, median (IQR) days | 15 (3–50) | 20 (2–51) | 0.23* |
| BPD (%) | 13.6 | 15.0 | 0.94 |
| Death (%) | 4.1 | 4.9 | 0.21 |
p-values are derived from Fisher´s exact test or Mann-Whitney-U-test if indicated (*)
Table 4. Short-term outcome in infants born after PPROM categorized according to diagnosis of amniotic infection syndrome (AIS).
| Clinical characteristics | no AIS | AIS | p-value |
|---|---|---|---|
| No. of infants | 777 | 781 | |
| Gestational age (weeks), mean (SD) | 28.1 (2.3) | 27.4 (2.3) | < 0.001* |
| Birth weight (g), mean (SD) | 1074 (300) | 1017 (294) | < 0.001* |
| Intracerebral haemorrhage (%) | 18.8 | 19.3 | 0.80 |
| ICH Grade I (%) | 7.1 | 7.4 | |
| ICH Grade II (%) | 4.7 | 4.6 | |
| ICH Grade III (%) | 3.8 | 3.1 | |
| ICH Grade IV (%) | 2.8 | 4.1 | |
| PVL (%) | 2.6 | 3.7 | 0.25 |
| Early-onset sepsis (%) | 2.2 | 3.1 | 0.34 |
| Pneumonia < 72 h (%) | 0.4 | 0.4 | 0.9 |
| Late-onset Pneumonia | 3.8 | 4.9 | |
| Clinical sepsis (%) | 33.5 | 38.7 | 0.035 |
| Blood-culture proven sepsis (%) | 13.4 | 14.8 | 0.47 |
| Late-onset sepsis (%) | 12.6 | 13.4 | 0.71 |
| Pneumothorax (%) | 6.6 | 6.4 | 0.84 |
| O2 supplement, median (IQR) days | 17 (3–50) | 27 (3–60) | 0.012* |
| BPD (%) | 14.9 | 15.0 | 0.99 |
| Death (%) | 4.9 | 5.0 | 0.99 |
p-values are derived from Fisher´s exact test or Mann-Whitney-U-test if indicated (*)
To determine whether there is an independent effect of PPROM on the risk of adverse outcomes we tested PPROM along with well-known influencing factors (gestational age in weeks, birth weight, antenatal steroids, inborn delivery, multiple birth, center, gender and SGA). In our analysis, PPROM had no independent effect on the risk of blood-culture confirmed total sepsis incidence and EOS. In addition to that, PPROM had no influence on total clinical sepsis incidence and clinical sepsis < 72 h (555 cases /3350 controls; OR 1.11, 95% CI: 0.92–1.35, p = 0.28). Gestational age proved to be the most important contributor to sepsis risk (Table 5).
Table 5. Logistic regression analysis for sepsis-related outcomes including well known-risk factors.
| Outcomes | Early onset Sepsis | Clinical Sepsis | Blood culture proven Sepsis |
|---|---|---|---|
| No. affected infants / controls | 80/3823 | 1368/2554 | 533/3370 |
| PPROM | OR 1.22 (0.77–1.93) p = 0.39 | OR 1.07 (0.92–1.24) p = 0.41 | OR 0.93 (0.76–1.13) p = 0.46 |
| Gestational age (per week) | OR 0.74 (0.60–0.90) p = 0.003 | OR 0.81 (0.76–0.86) p<0.001 | OR 0.80 (0.73–0.86) p<0.001 |
| Birth weight | OR 1.00 (0.99–1.00) p = 0.66 | OR 0.99 (0.99–0.99) p<0.001 | OR 1.00 (0.99–1.00) p = 0.19 |
| Antenatal steroids | OR 0.51 (0.27–0.97) p = 0.04 | OR 0.63 (0.48–0.82) p = 0.001 | OR 0.90 (0.65–1.26) p = 0.54 |
| Multiple birth | OR 0.57 (0.34–0.97) p = 0.04 | OR 0.85 (0.73–0.99) p = 0.03 | OR 0.96 (0.79–1.17) p = 0.68 |
| Inborn | OR 1.34 (0.30–5.90) p = 0.70 | OR 0.79 (0.49–1.27) p = 0.33 | OR 0.67 (0.38–1.18) p = 0.17 |
| Center | OR 1.03 (1.00–1.05) p = 0.006 | OR 1.01 (0.99–1.01) p = 0.10 | OR 1.00 (0.99–1.01) p = 0.77 |
| Gender | OR 1.13 (0.72–1.78) p = 0.61 | OR 0.83 (0.72–0.96) p = 0.01 | OR 1.06 (0.88–1.29) p = 0.54 |
| SGA | OR 1.28 (0.54–3.08) p = 0.58 | OR 1.12 (0.84–1.50) p = 0.45 | OR 0.98 (0.67–1.41) p = 0.88 |
As outlined in Table 6, we analysed the independent effect of PPROM on other major outcomes of VLBW infants adjusted to significant clinical confounders in multivariable prediction models. The diagnosis of PPROM was associated with an increased risk for BPD. This effect is not seen in the much smaller subgroup of infants < 27 weeks (388 BPD cases/ 910 no BPD infants; OR: 1.14, 95% CI: 0.87–1.49, p = 0.35), while PPROM is predictive for BPD in infants born 27+0–31+6 weeks of gestation (163 BPD cases / 2364 no BPD infants; OR: 1.90, 95% CI:1.29–2.79, p = 0.001)
Table 6. Multivariable logistic regression analysis for mortality and morbidities including well known-risk factors.
| Outcomes | Mortality | IVH | PVL | BPD |
|---|---|---|---|---|
| No. affected infants /controls | 173/3745 | 729/3187 | 133/3774 | 561/ 3554 |
| PPROM | OR 1.31 (0.94–1.83) p = 0.12 | OR 0.93 (0.78–1.11) p = 0.42 | OR 0.80 (0.55–1.16) p = 0.25 | OR 1.25 (1.02–1.55) p = 0.03 |
| Gestational age (per week) | OR 0.82 (0.71–0.94) p = 0.004 | OR 0.70 (0.65–0.75) p<0.001 | OR 0.79 (0.68–0.92) p = 0.003 | OR 0.89 (0.82–0.97) p = 0.006 |
| Birth weight (100g steps) | OR 0.99 (0.99–0.99) p<0.001 | OR 1.00 (1.00–1.01) p = 0.46 | OR 1.00 (0.99–1.00) p = 0.44 | OR 0.99 (0.99–0.99) p<0.001 |
| Antenatal steroids | OR 0.93 (0.54–1.59) p = 0.79 | OR 0.54 (0.41–0.72) p<0.001 | OR 0.59 (0.35–1.00) p = 0.05 | OR 1.07 (0.75–1.54) p = 0.70 |
| Multiple birth | OR 1.63 (1.17–2.27) p = 0.003 | OR 1.33 (1.11–1.58) p = 0.02 | OR 0.94 (0.65–1.36) p = 0.75 | OR 0.96 (0.78–1.18) p = 0.69 |
| Inborn | OR 0.53 (0.22–1.29) p = 0.16 | OR 0.94 (0.55–1.60) p = 0.83 | OR 1.04 (0.36–3.06) p = 0.94 | OR 0.55 (0.30–1.02) p = 0.06 |
| Center | OR 0.99 (0.98–1.01) p = 0.24 | OR 1.00 (1.00–1.01) p = 0.05 | OR 1.02 (1.00–1.04) p = 0.007 | OR 1.02 (1.00–1.03) p<0.001 |
| Female | OR 0.64 (0.46–0.90) p = 0.009 | OR 0.82 (0.69–0.98) p = 0.03 | OR 0.99 (0.69–1.41) p = 0.95 | OR 0.55 (0.45–0.68) p<0.001 |
| SGA | OR 1.40 (0.81–2.42) p = 0.23 | OR 0.75 (0.53–1.08) p = 0.12 | OR 1.13 (0.56–2.29) p = 0.74 | OR 1.13 (0.79–1.61) p = 0.52 |
PPROM had no significant impact on the risk of IVH, PVL and mortality. Major contributors to mortality risk were gestational age, birth weight, gender and multiple birth, while the risk for IVH was associated with multiple birth, gestational age, gender and treatment with antenatal steroids.
Discussion
Main findings
Our study presents observational data of the large-scale multicenter GNN cohort evaluating the effect of PPROM as cause of preterm delivery on morbidity and mortality in very-low-birth-weight infants < 32 weeks. Our data suggest that PPROM per se is not associated with adverse outcome. We determined a moderately increased risk for development of BPD associated with PPROM which is restricted to infants born 27+0–31+6 weeks.
Strengths and limitations
The major strengths of our observation are the large cohort size of a multicenter setting and the accurate phenotypic characterization of infants. This is achieved by regular on-site monitoring of data quality. PPROM management in the most vulnerable gestational age groups is still a matter of debate as conclusive studies are lacking [21–23]. Population-based registry data as presented here cannot overcome this problem but provide important epidemiological information to design a future randomized controlled trial. Thus limitations of our approach need to be thoroughly discussed. In our study, PPROM was defined as non-iatrogenic rupture of membranes before the onset of labor effective contractions. The duration and the cause of PPROM as well as the stratification into anhydramnion or oligohydramnion were not recorded. Therefore the decision to treat PPROM expectantly or intention to treat expectantly cannot be extracted from our main data set. The study findings imply that PPROM itself has no additional impact on adverse outcome adjusted to gestational age and other known risk factors. Previous retrospective single centre cohort studies revealed conflicting results. Some investigators found increased infectious morbidity and mortality in PPROM patients [24,25] while another study noted no adverse outcome in PPROM patients as compared to infants without PPROM [26]. In line with previous observations, gestational age proved to be the most important risk factor for NICU mortality and major neonatal morbidity [27]. The effect of PPROM on BPD risk—independent of gestational age, AIS, antenatal steroids, gender and other contributors—is a major finding of our study, but is only restricted to the smaller subgroup of infants born between 27 and 32 weeks of gestation. This aspect has had a long-standing history of discussion and mainly reflects the presumed association between PPROM, chorioamnionitis and BPD [14]. Notably, a meta-analysis [28]noted significant publication bias and therefore concluded that despite a large body of evidence, “chorioamnionitis cannot be definitively considered a risk factor for BPD”, and the same holds true for PPROM in our perspective.
Currently, the main clinical question whether pregnancies that are aggressively managed differ in infant outcomes than those managed more conservatively still remains unanswered [21, 22]). Ideally, this comparison would take place in the context of a randomized trial. In an observational study, the comparison should be between patients managed expectantly and PPROM patients that might have been managed expectantly, but were not. Our “PPROM” cohort presumably included a mix of patients with a large proportion of infants with surrogate parameters of expectant management (treatment with antenatal steroids: 92.9%, being inborn: 98.3%; elective Caesarean section: 79.3%, no further administration of antenatal antibiotics until < 24h before delivery: 19%) The best observational design would have been to compare outcomes between PPROM managed following different protocols with different thresholds for obstetrical interventions. Our neonatal network lacks these monitored obstetrical data as neonatal but not maternal case record files were the primary data source. For future studies we amended the documentation sheets which will allow to compare outcomes for newborns with different durations of PPROM and thus arguably provide some insight into how to manage PPROM.
Another limitation of our study is potential selection bias which is regarded as major challenge in population-based data. For example, NICU mortality in our study cohort is low and does not fully reflect the mortality rate of infants born in GNN centers. Specifically, the study enrolled 69.5% of infants born in centers of GNN (2355/7702, <32 weeks, 2009–2012). A basic data set including major outcomes (but not cause of preterm delivery) was documented for non-enrolled patients. Notably, the mortality during primary stay in hospital differed remarkably between enrolled patients (4.2%) and non-enrolled infants (25.6%). This is mainly explained by a large proportion of early death in non-enrolled patients due to primary palliative (comfort) care (18.6% of deaths), congenital anomalies (6.2% of deaths) and RDS/early respiratory failure which accounted for 24.6% of NICU deaths. Other less acute causes of death in non-enrolled patients included pulmonary haemorrhage (5.3%), sepsis (15%), NEC/FIP (8.5%), higher grade IVH (10.2%), BPD (2.2%), and others (8.9%).
Another important aspect for future design of randomized trials is the correct diagnosis of AIS following PPROM. Prolongation of pregnancy (to avoid morbidity associated with prematurity) in line with prevention of foetal infection is a major challenge in obstetric management of PPROM. Clinicians are thereby faced with a crucial diagnostic problem of relevant AIS/chorioamnionitis/fetal inflammation, Our analysis revealed that 50% of infants born after PPROM were also exposed to AIS. However, only 2.6% developed EOS while 14% had a clinical sepsis within the first 72 hours of life. Infants with PPROM with or without concurrent AIS did not differ remarkably in outcomes in our setting. Furthermore, AIS was not found to be an independent risk factor for major neonatal complications (data not shown) indicating that current diagnostic criteria of AIS are not specific enough to select the most critical cases. With regard to obstetrical management PPROM infants and infants without PPROM had no differences in rates of spontaneous delivery (12.4 vs. 11.0%), elective C/S (79.3 vs. 79.6%) and emergency caesarean section (8.2 vs. 9.3%). But it has to be considered in future studies that remarkable differences between study centers exist, e.g. the spontaneous delivery rate in PPROM patients differed from 0–47%. In addition to that, the study centers themselves are important covariates in determining neonatal outcomes, i.e. risk for EOS, BPD and PVL.
Besides center-specific variation there might be selection bias of centers with favourable outcomes in GNN which is a well-known limitation of population-based studies [29]. In addition to that, centralization of perinatal services is associated with improved outcome, as it has been well demonstrated by the Swedish EXPRESS study group [30, 31]. This is particularly important for the most vulnerable subgroup of infants < 27 weeks whose mortality and morbidities are largely determined by gestational age at birth [4, 32]. Both medical and logistic aspects have to be considered for the interdisciplinary discussion on how to manage PPROM. In line with that, strategies for better outcome including individualized care and decision making need to be evaluated in a multicenter randomized trial [4, 33, 34].
Conclusion
Despite limitations our large-scale epidemiological data provide a basis for the important interdisciplinary discussion on PPROM-related outcome. The diagnosis of PPROM per se is not associated with adverse outcome in VLBW infants < 32 weeks apart from a moderately increased risk for BPD. Randomized controlled trials with primary neonatal outcomes are needed to determine which subgroup of VLBW infants benefit from expectant or intentional management of PPROM.
Acknowledgments
The authors are indebted to all parents and their infants, to all nurses and doctors and study centers who participated in GNN.
The members of the German Neonatal Network (GNN) are: Stefan Avenarius, Department of Pediatrics, University of Magdeburg; Kai Bockenholt, Children’s Hospital Cologne-Amsterdamer Strasse; Bettina Bohnhorst, Department of Neonatology, Hanover Medical School; Michael Dördelmann, Diakonissenhospital Flensburg; Silke Ehlers, Bürgerhospital Frankfurt; Corinna Gebauer Department of Pediatrics, University of Leipzig; Hubert Gerleve, Children’s Hospital Coesfeld; Ludwig Gortner, Department of Pediatrics, University of Homburg; Peter Groneck, Children’s Hospital Leverkusen; Georg Hillebrand, MD, Children’s Hospital Itzehoe; Thomas Hoehn, Department of Pediatrics, University of Düsseldorf; Mechthild Hubert, Children’s Hospital Siegen; Helmut Hummler, Department of Neonatology, University of Ulm; Andreas Jenke, Children’s Hospital Wuppertal; Reinhard Jensen, Children’s Hospital Heide; Olaf Kannt, Children’s Hospital Schwerin; Helmut Küster, Department of Pediatrics, University of Göttingen; Reinhard Laux, Children’s Hospital Hamburg-Barmbek; Ursula Lieser, Department of Pediatrics, University of Halle; Michael Mögel, Department of Pediatrics, University of Dresden; Jens Möller, Children’s Hospital Saarbrücken; Dirk Müller, Children’s Hospital Kassel; Jochen Reese, Children’s Hospital Eutin; Claudia Roll, Department of Pediatrics, University Witten-Herdecke, Children’s Hospital Datteln; Thomas Schaible, Department of Pediatrics, University of Mannheim; Stefan Seeliger, Children’s Hospital Neuburg/Ingolstadt; Hugo Segerer, Children’s Hospital St. Hedwig, Regensburg; Norbert Teig, Department of Pediatrics, University of Bochum; Ursula Weller, Children’s Hospital Bielefeld; Matthias Vochem, Olgahospital Stuttgart; and Jürgen Wintgens, Children’s Hospital Mönchengladbach.
We thank Anja Kaufmann, Birgit Schröder, Sabine Lorenz and Bea Hatje for data documentation and Michael Preuss and Andreas Ziegler for statistical support.
Data Availability
To ensure patient privacy for ethical and legal reasons, the data are available upon request from the corresponding author.
Funding Statement
This study is supported by a grant of the German government (Bundesministerium für Bildung und Forschung, German Ministry of Education and Research). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
References
- 1. Mercer BM (2003) Preterm premature rupture of the membranes. Obstet Gynecol 101:178–193. [DOI] [PubMed] [Google Scholar]
- 2. Mercer BM (2005) Preterm premature rupture of the membranes: Current approaches to evaluation and management. Obstet Gynecol Clin North Am 32:411–428. [DOI] [PubMed] [Google Scholar]
- 3. Schucker JL, Mercer BM (1996) Midtrimester premature rupture of membranes. Semin Perinatol 20: 389–400. [DOI] [PubMed] [Google Scholar]
- 4. Waters TP, Mercer BM (2009) The management of preterm premature rupture of the membranes near the limit of the fetal viability. Am J Obstet Gynecol 201:230–240. 10.1016/j.ajog.2009.06.049 [DOI] [PubMed] [Google Scholar]
- 5. Blott M, Greenough A (1988) Dry lung syndrome after oligohydramnios. Arch Dis Child. 63: 683–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Verspyck E, Bisson V, Roman H, Marret S (2014) Adverse respiratory outcome after premature rupture of membranes before viability. Acta Paediatr 103: 256–61. 10.1111/apa.12489 [DOI] [PubMed] [Google Scholar]
- 7. Williams O, Hutchings G, Hubinont C, Debauche C, Greenough A (2012) Pulmonary effects of prolonged oligohydramnios following mid-trimester rupture of the membranes—antenatal and postnatal management. Neonatology 101: 83–90. 10.1159/000329445 [DOI] [PubMed] [Google Scholar]
- 8. Medina TM, Hill DA (2006) Preterm premature rupture of membranes: diagnosis and management. Am Fam Physician 73: 659–64. [PubMed] [Google Scholar]
- 9. Van Teeffelen S, Pajkrt E, Willekes C, Van Kuijk SM, Mol BW (2013) Transabdominal amnioinfusion for improving fetal outcomes after oligohydramnios secondary to preterm prelabour rupture of membranes before 26 weeks. Cochrane Database Syst Rev 8: CD009952 10.1002/14651858.CD009952.pub2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. van der Ham DP, Vijgen SM, Nijhuis JG, van Beek JJ, Opmeer BC, Mulder AL, et al. ; PPROMEXIL trial group (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 Med 9: e1001208 10.1371/journal.pmed.1001208 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Schleußner E (2013) The prevention, diagnosis and treatment of premature labor. Dtsch Arztebl Int. 110: 227–35. 10.3238/arztebl.2013.0227 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. van Teeffelen AS, van der Ham DP, Willekes C, Al Nasiry S, Nijhuis JG, van Kuijk S, et al. (2014) Midtrimester preterm prelabour rupture of membranes (PPROM): expectant management or amnioinfusion for improving perinatal outcomes (PPROMEXIL—III trial). BMC Pregnancy Childbirth 14:128 10.1186/1471-2393-14-128 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Strunk T, Doherty D, Jacques A, Simmer K, Richmond P, Kohan R, et al. (2012) Histologic chorioamnionitis is associated with reduced risk of late-onset sepsis in preterm Infants. Pediatrics 129:134–141. [DOI] [PubMed] [Google Scholar]
- 14. Thomas W, Speer CP (2011) Chorioamnionitis: important risk factor or innocent bystander for neonatal outcome. Neonatology 99: 177–187. 10.1159/000320170 [DOI] [PubMed] [Google Scholar]
- 15. Messerschmidt A, Olischar M, Birnbacher R, Sauer A, Weber M, Puschnig D, et al. (2011) Is it possible to make a reliable prognosis within the first hour of life for very low birth weight infants delivered after preterm premature rupture of membranes? Neonatology 99: 146–52. 10.1159/000313969 [DOI] [PubMed] [Google Scholar]
- 16. Voigt M, Rochow N, Straube S, Briese V, Olbertz D, Jorch G (2010) Birth weight percentile charts based on daily measurements for very preterm male and female infants at the age of 154–223 days. J Perinat Med 38: 289–295 10.1515/JPM.2010.031 [DOI] [PubMed] [Google Scholar]
- 17. Schwab F, Geffers C, Barwolff S, Ruden H, Gastmeier P (2007) Reducing neonatal nosocomial bloodstream infections through participation in a national surveillance system. J Hosp Infect 65: 319–325. [DOI] [PubMed] [Google Scholar]
- 18. Geffers C, Baerwolff S, Schwab F, Gastmeier P (2008) Incidence of healthcare-associated infections in high-risk neonates: results from the German surveillance system for very-low-birthweight infants. J Hosp Infect 68: 214–221. 10.1016/j.jhin.2008.01.016 [DOI] [PubMed] [Google Scholar]
- 19. Shennan AT, Dunn MS, Ohlsson A, Lenox K, Hoskins EM (1988) Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirements in the neonatal period. Pediatrics 82:527–532. [PubMed] [Google Scholar]
- 20. Papile LA, Burstein J, Burstein R, Koffler H (1978) Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 92: 529–34. [DOI] [PubMed] [Google Scholar]
- 21. Simhan HN, Canavan TP (2005) Preterm premature rupture of membranes: diagnosis, evaluation and management strategies. BJOG.112 Suppl 1:32–7. [DOI] [PubMed] [Google Scholar]
- 22. Al-Mandeel H, Alhindi MY, Sauve R (2013) Effects of intentional delivery on maternal and neonatal outcomes in pregnancies with preterm prelabour rupture of membranes between 28 and 34 weeks of gestation: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 26: 83–9. 10.3109/14767058.2012.718388 [DOI] [PubMed] [Google Scholar]
- 23. Roberts D, Vause S, Martin W, Green P, Walkinshaw S, Bricker L, et al. (2014) Amnioinfusion in very early preterm premature rupture of membranes—pregnancy, neonatal and maternal outcomes in the AMIPROM randomised controlled pilot study.Ultrasound Obstet Gynecol 43:490–9 10.1002/uog.13258 [DOI] [PubMed] [Google Scholar]
- 24. Furman B, Shoham-Vardi I, Bashiri A, Erez O, Mazor M (2000) Clinical significance and outcome of preterm prelabor rupture of membranes: population-based study. Eur J Obstet Gynecol Reprod Biol 92: 209–16. [DOI] [PubMed] [Google Scholar]
- 25. Newman DE, Paamoni-Keren O, Press F, Wiznitzer A, Mazor M, Sheiner E (2009) Neonatal outcome in preterm deliveries between 23 and 27 weeks' gestation with and without preterm premature rupture of membranes. Arch Gynecol Obstet 280: 7–11. 10.1007/s00404-008-0836-8 [DOI] [PubMed] [Google Scholar]
- 26. Furman B, Shoham-Vardi I, Bashiri A, Erez O, Mazor M (2001) Preterm premature rupture of membranes is not an independent risk factor for neonatal morbidity. J Matern Fetal Med 10: 107–11. [DOI] [PubMed] [Google Scholar]
- 27. Manuck TA, Eller AG, Esplin MS, Stoddard GJ, Varner MW, Silver RM (2009) Outcomes of expectantly mmanaged pretrm premature rupture of membranes occurring before 24 weeks of gestation. Obstet Gynecol 114: 29–37. 10.1097/AOG.0b013e3181ab6fd3 [DOI] [PubMed] [Google Scholar]
- 28. Hartling L, Liang Y, Lacaze-Masmonteil T (2012) Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 97: F8–F17. 10.1136/adc.2010.210187 [DOI] [PubMed] [Google Scholar]
- 29. Evans DJ, Levene MI (2001) Evidence of selection bias in preterm survival studies: a systematic review. Arch Dis Child Fetal Neonatal Ed 84: F79–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Finnström O, Olausson PO, Sedin G, Serenius F, Svenningsen N, Thiringer K, et al. (1997) The Swedish national prospective study on extremely low birthweight (ELBW) infants. Incidence, mortality, morbidity and survival in relation to level of care. Acta Paediatr 86: 503–11. [DOI] [PubMed] [Google Scholar]
- 31. EXPRESS Group, Fellman V, Hellström-Westas L, Norman M, Westgren M, Källén K, Lagercrantz H, et al. (2009) One-year survival of extremely preterm infants after active perinatal care in Sweden. JAMA 301: 2225–33. 10.1001/jama.2009.771 [DOI] [PubMed] [Google Scholar]
- 32. van der Heyden JL, van der Ham DP, van Kuijk S, Notten KJ, Janssen T, Nijhuis JG, et al. (2013) Outcome of pregnancies with preterm prelabor rupture of membranes before 27 weeks gestation: a retrospective cohort study. Eur J Obstet Gynecol Reprod Biol 170:125–130. 10.1016/j.ejogrb.2013.06.012 [DOI] [PubMed] [Google Scholar]
- 33. Tyson JE, Parikh NA, Langer J, Green C, Higgins RD; National Institute of Child Health and Human Development Neonatal Research Network (2008) Intensive care for extreme prematurity—moving beyond gestational age. N Engl J Med 358: 1672–81. 10.1056/NEJMoa073059 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Hartling L, Chari R, Friesen C, Vandermeer B, Lacaze-Masmonteil T (2006) A systemativ review of intentional delivery in women with preterm prelabor rupture of membranes. J Matern Fet Neonat Med 19: 177–187. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
To ensure patient privacy for ethical and legal reasons, the data are available upon request from the corresponding author.