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Original Studies

Risk for Late-onset Blood-culture Proven Sepsis in Very-low-birth Weight Infants Born Small for Gestational Age

A Large Multicenter Study from the German Neonatal Network

Tröger, Birte MD*; Göpel, Wolfgang MD*; Faust, Kirstin MD*; Müller, Thilo*; Jorch, Gerhard MD; Felderhoff-Müser, Ursula MD, PhD; Gortner, Ludwig MD§; Heitmann, Friedhelm MD; Hoehn, Thomas MD, PhD; Kribs, Angela MD**; Laux, Reinhard MD††; Roll, Claudia MD, PhD‡‡; Emeis, Michael MD§§; Mögel, Michael MD¶¶; Siegel, Jens MD‖‖; Vochem, Matthias MD***; von der Wense, Axel MD†††; Wieg, Christian MD‡‡‡; Herting, Egbert MD, PhD*; Härtel, Christoph MD* for the German Neonatal Network

Author Information
The Pediatric Infectious Disease Journal: March 2014 - Volume 33 - Issue 3 - p 238-243
doi: 10.1097/INF.0000000000000031
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Abstract

Sepsis continues to be a major cause of mortality and long-term morbidity in very-low-birth-weight infants (VLBW, birth weight < 1500 g). The individual risk profile is mainly influenced by gestational age, immaturity of host defenses, requirement of invasive treatment modalities and prolonged hospitalization.1–3 Subnormal intrauterine growth is considered to be an additional risk factor for adverse neonatal outcomes in VLBW infants.4 This issue is of utmost importance because identifying the optimal time point of delivery—thereby balancing the risks of unfavorable in-utero environment and iatrogenic prematurity—is still a major clinical challenge.5 Recent studies demonstrated that preterm infants being small for gestational age (SGA, birth weight < 10th percentile) have an increased risk for mortality, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC) when compared with non-SGA preterm infants.4,6–10 Long-term consequences of intrauterine growth restriction include metabolic disorders, endocrinologic and neurological sequelae.4 Less is known, however, to what extent intrauterine growth restriction contributes to susceptibility for sepsis, and the available data are scarce. Small single-center cohort studies postulated an increased risk of sepsis in SGA preterm infants.11,12 In the German national surveillance system for nosocomial infections (NEO-KISS), preterm SGA infants seemed to have a higher likelihood of clinical sepsis (irrespective of microbiological confirmation of bloodstream infection) 13 In contrast, a Norwegian population-based study with extremely low birth weight infants (birth weight < 1000 g) found no robust association between SGA and blood-culture–proven sepsis.6 Large-scale epidemiological data are needed to determine whether SGA infants display a VLBW subgroup that will most likely benefit from prophylactic strategies to prevent sepsis. We therefore analyzed data of the German Neonatal Network, a prospective, population-based study including 46 German neonatal intensive care units. We restricted our analysis to blood-culture–confirmed late-onset sepsis (bloodstream infection occurring ≥ 72 hours of age) and we also introduced a gestational age limit of < 32+0 weeks postmenstrual age.

METHODS

Study Population

The German Neonatal Network (GNN) is a well-established, prospective multicenter collaboration of 46 German NICUs which provides a platform for benchmarking practice, interventional trials and the investigation of genetic and clinical risk profiles of VLBW infants. After informed written parental consent, a predefined clinical data set of 220 parameters is recorded for each patient on clinical record files. Data quality is approved by regular onsite monitoring of participating centers by a physician trained in neonatology including cross-check of local microbiological readouts.

Inclusion Criteria

The inclusion criteria for GNN are: birth weight < 1500 g and gestational age ≤36+6 weeks. To minimize the bias of overrepresentation of SGA infants in older VLBW infants, we introduced gestational age limits from 23+0 weeks to < 32+0 weeks post menstrual age. Furthermore, we restricted the analysis to infants born 2003–2011 with complete data sets on sepsis including information on pathogens of bloodstream infections.

Exclusion Criteria

Infants with lethal abnormalities and exclusively early onset of sepsis (sepsis within the first 72 hours of life) were not considered for this study.

Definitions

SGA was defined as a birth weight less than tenth percentile for post menstrual age according to gender-specific standards for birth weight by post menstrual age in Germany.14 Gestational age was defined according to postmenstrual age (obstetrical dating). Late-onset sepsis was defined as blood-culture–confirmed clinical sepsis (2 clinical signs, according to NEO-KISS criteria and microbiologically confirmed bloodstream infection)15,16 occurring ≥ 72 hours of age. If coagulase-negative staphylococci (CoNS) were isolated as single pathogen in 1 peripheral blood culture, 2 clinical signs (eg lethargy, tachypnea, hypothermia < 36.0°C, prolonged capillary refill time > 2 sec, increased frequency of apneas, bradycardias and desaturations) and 1 laboratory sign (platelet count < 100/nL, C-reactive protein > 20 mg/L, immature/total neutrophil ratio > 0.2, white blood cell count < 5/nL) 15,16 were required for classification of CoNS sepsis.

All-cause mortality was defined as death occurring after admission to neonatal intensive care units before discharge home. BPD was diagnosed when needing oxygen or assisted ventilation evaluated at 36 weeks of post menstrual age. Intraventricular hemorrhage (IVH) grades I-IV was diagnosed according to the ultrasound criteria of Papile.17 Cystic periventricular leukomalacia (PVL) was defined as periventricular lesions. The diagnosis of NEC required surgical intervention.18 Higher stage ROP was noted when treatment was required.19 Data concerning time taken to attain full enteral feedings (150 mL/kg/d) and antenatal steroids were also documented.

Data on causes of preterm delivery included preterm labor, preeclampsia,20 pathological vascular Doppler or pathological c ardiotocography, placental abruption and others.

Data Entry

All data were entered in an Access database by health record administrators at the main GNN office of the University of Lübeck. After discharge, clinical record files of the participating hospitals are sent to the study centre.

Ethical Approval

Ethical approval was given for all study parts by the University of Lübeck Ethical Committee1 and by all local ethical committees at the participating study centers. Informed written consent was given by parents (as legal representatives) on behalf of their infants.

Statistical Analysis

Data analysis was performed using SPSS 20.0 (Munich, Germany). The χ2 test, Fisher´s Exact test and Mann-Whitney U test were used for statistical analysis of differences between groups. To analyze effects of SGA which are independent of gestational age and other confounding factors including gender, antenatal steroids, multiple birth, ethnicity, inborn delivery, Caesarean section, cause of preterm delivery, length of stay, duration of parenteral nutrition, duration of mechanical ventilation and prophylactic treatment of the infant with glycopeptide antibiotics, multivariate logistic regression analysis with stepwise conditional exclusion of nonsignificant parameters were performed. The level of significance was defined as P < 0.05 in single comparisons. The Hosmer-Lemeshow model was used to demonstrate that the model fits the data well. Infants with missing data were excluded from multivariate logistic regression analysis.

RESULTS

Clinical Characteristics of the Cohort

From January 2003 to December 2011, 8504 VLBW infants were eligible for this study. Parents of 1747 infants were not asked for participation in this study. In most of these cases, the attending physicians had not considered participation or forgotten to ask the parents. In addition to that, early death was a major cause of nonparticipation. Furthermore, parents of 90 infants declined participation, and in 44 cases, informed consent was not possible due to substantial communication problems. For 674 infants, the cause for nonparticipation remained unknown. Sixty three infants were enrolled in GNN; however, no information on sepsis/blood culture results was documented. Thus, a total of 5886 (69%) eligible VLBW infants fulfilled inclusion criteria for this study. We compared clinical characteristics of SGA infants (n = 692) and non-SGA infants (n = 5194), as outlined in Table 1. SGA infants had a lower gestational age and less likelihood of multiple births than non-SGA infants. Furthermore, >90% of SGA infants were born by Caesarean section, and 65% of SGA infants were delivered due to pathological Doppler results.

TABLE 1
TABLE 1:
Clinical Characteristics of the VLBW Cohort With Gestational Age 23 + 0 to 31 + 6 Weeks Stratified to Birth Weight Percentile < 10 (n = 5886)

Risk for Late-onset Sepsis

With regard to the incidence of blood-culture proven late-onset sepsis, SGA infants carried a higher risk than non-SGA infants (20.1% vs. 14.3 %, P < 0.001; Fig. 1). This difference was only observed among infants with a gestational age of 29 to < 32 weeks and attributed to sepsis episodes with coagulase-negative staphylococci (12.8 vs. 8.3 %, P < 0.001, Table 2). In line with that, sepsis episodes caused by gram-positive bacteria differed between both groups (16.2 vs. 11.4 %, P < 0.001), while no difference was noted for sepsis with gram-negative bacteria (4.0 vs. 3.7%, P = 0.66).

TABLE 2
TABLE 2:
Pathogenic Spectrum of Late-onset Sepsis Episodes
FIGURE 1
FIGURE 1:
Incidence of Late-onset Sepsis in SGA Infants Compared With Non-SGA Infants Stratified to Gestational Age (Postmenstrual Age in Completed Weeks).

In a subgroup analysis of 5561 VLBW infants with full data sets regarding multiple episodes of sepsis (up to a maximum of 3 episodes), we noted 6/633 (0.9%) SGA infants versus 37/4928 (0.8%) non-SGA infants with a second blood-culture–confirmed sepsis episode and 4/633 (0.4%) SGA infants versus 15/4928 (0.3%) non-SGA infants with a third sepsis episode.

Treatment Modalities

SGA infants may be predisposed for sepsis because of longer durations of hospitalization, mechanical ventilation and parenteral nutrition. In addition to that, SGA infants were more often treated with central venous lines, third-line antibiotics and prophylaxis with fluconazole or vancomycin/teicoplanin prophylaxis (Table 3). In a subgroup analysis of VLBW infants receiving glycopeptide antibiotics for prophylaxis of catheter-related sepsis (n = 523), we noted no difference of late-onset sepsis risk in SGA (17/100, 17.0%) versus non-SGA infants (60/423, 14.2%; P = 0.48).

TABLE 3
TABLE 3:
Treatment Modalities of the VLBW Cohort With Potential Impact on Sepsis Risk

Risk Factors for Late-onset Sepsis in VLBW Infants

We performed a multivariate logistic regression analysis including potential contributing factors to late-onset sepsis risk, that is, gestational age, SGA, gender, antenatal steroids, multiple birth, ethnicity, inborn delivery, Caesarean section, cause of preterm delivery, duration of parenteral nutrition and prophylactic treatment of the infant with glycopeptide antibiotics or fluconazole. This Hosmer-Lemeshow P-value for this test was 0.58. We found that higher gestational age [per week; odds ratio (OR): 0.75, 95% confidence interval (CI): 0.72–0.78, P < 0.0001], treatment with antenatal steroids (OR: 0.7, 95% CI: 0.53–0.92, P = 0.01), German descendance (OR: 0.76, 95% CI: 0.63–0.91, P = 0.003) and treatment with prophylactic glycopeptide antibiotics (OR: 0.64, 95% CI: 0.47–0.87, P = 0.005) were protective factors against late-onset sepsis. In addition to longer duration of parenteral nutrition (per day; OR: 1.016, 95% CI: 1.011–1.021, P < 0.0001), SGA was found to be a risk factor for late-onset sepsis (OR: 1.31, 95% CI: 1.02–1.68, P = 0.03).

Outcome Measures

In the whole cohort, SGA infants had a higher risk for adverse outcomes, that is, mortality, BPD and NEC, patent ductus arteriosus and ROP requiring surgery than non-SGA infants. When we stratified our analysis to gestational age groups, as outlined in Tables 4 and 5, we were able to demonstrate that SGA predisposes to mortality and BPD in all gestational age groups while SGA predisposed to higher stage ROP only in infants < 29 weeks of gestational age. In contrast, non-SGA infants born extremely preterm (< 27 weeks of gestational age) had a higher risk for IVH grade III-IV than SGA infants. Additionally, non-SGA infants from 23+0–24+6 weeks were more likely to develop PVL. Since 2010, attending neonatologists are asked to declare the cause of mortality. In a small subgroup of this study cohort based on 117 nonsurvivors enrolled in GNN in the years 2010 and 2011, we noted that 8/41 SGA infants (19.5%) and 17/76 (22.4%) non-SGA infants died from sepsis. In 14/25 patients with sepsis-associated mortality, a blood-culture proven sepsis was documented.

TABLE 4
TABLE 4:
Outcome Data of Preterm Infants 23 + 0 ≤ 26 + 6 SSW Stratified to SGA
TABLE 5
TABLE 5:
Outcome Data of Preterm Infants 27 + 0 ≤ 31 + 6 SSW Stratified to SGA

DISCUSSION

In this large multicenter study of VLBW infants born at 23 to < 32 weeks post menstrual age, we found that being SGA contributes to susceptibility for late-onset sepsis. The difference between SGA and non-SGA infants is related to sepsis episodes with coagulase-negative staphylococci in the group of infants ≥ 29 weeks of gestation.

In our study, 15% of infants developed a blood-culture proven late-onset sepsis. This is comparable with previous data of the National Institute of Child Health and Human Development (NICHD) network which reported blood-culture–proven late-onset sepsis rates of 21% in VLBW infants.1 With regard to SGA and risk of late-onset sepsis, large-scale data are scarce. The German national surveillance system for nosocomial infections in VLBW infants (NEO-KISS) reported late-onset sepsis rates of 42 % in SGA infants and 31% in non-SGA infants, but restricted their analysis to infants born between 24 and 28 weeks of gestational age. We introduced a gestational age limit from 23 to 32 weeks to minimize the bias of overrepresentation of SGA infants in the VLBW cohort with a gestational age 32 to < 37 weeks. Despite the use of gender- and gestational age-specific birth weight percentiles in our cohort, we noted a slightly higher proportion of SGA infants (11.6%) than the expected 10%. Although we used percentiles that are based on the gender-specific average of the population, there remains a need for a method that distinguishes fetuses that have failed to maintain their growth potential close to preterm delivery and those that are normal or genetically small. In addition to that, SGA infants in our cohort were less likely to be multiples which is in line with previous population-based studies.7,21 To assure data quality and to minimize underreporting bias, we performed onsite monitoring of data in all participating centers. This may explain differences to the data of the NEO-KISS registry. Furthermore, NEO-KISS restricts surveillance up to the weight of 1800 grams and diagnosis of sepsis is made irrespective of microbiological confirmation of bloodstream infection.13 Noteworthy, SGA infants in GNN had a lower gestational age. We therefore performed a regression analysis including gestational age which proved that SGA is an independent risk factor for late-onset sepsis in the whole cohort.

When we stratified sepsis risk according to gestational age groups, we noted no difference between SGA and non-SGA infants in the gestational age groups < 27 weeks. This implies that extremely premature delivery probably outweighs the impact of SGA in these subgroups. In line with that, a population-based study from Norway with extremely low birth weight infants (birth weight < 1000 grams) showed no robust association between SGA and blood-culture proven sepsis.6 In contrast, our data suggest that older SGA infants with 27 to < 32 weeks of gestational age are predisposed for CoNS sepsis. This finding might be explained by different treatment modalities required for SGA infants such as increased rate of central venous catheters, longer time to attain full enteral feedings and frequent use of third-line antibiotics compared with non-SGA infants. We also noted that SGA infants have a higher rate of mechanical ventilation, more ventilator days and a longer stay in hospital. When we included these confounding factors in our multivariate regression analysis, SGA was not found to be an independent risk factor for late-onset sepsis anymore. However, it is important to note that the association between the noted confounders and sepsis incidence is bidirectional. These factors may contribute to the risk of sepsis, but sepsis vice versa also leads to longer duration of mechanical ventilation and hospitalization. Thus clinical risk factors for late-onset sepsis might be well-acknowledged, and the underlying pathophysiology of sepsis predisposition in SGA infants needs to be further investigated to guide individualized preventive measures in this vulnerable subgroup. In line with that, conclusions for clinical practice have to be well balanced. For example, less use of central lines and parenteral nutrition would result in a huge challenge to provide enough nutrition to SGA infants who take a median of 16 days to full enteral feeding in our study. Furthermore, some NICUs prefer to use prophylactic low-dose treatment with vancomycin (continuous infusion or lock principle) or teicoplanin in VLBW infants with peripheral venous catheters or central lines. There is evidence from previous studies that prophylactic glycopeptide antibiotics reduce the incidence of nosocomial sepsis in preterm infants with vascular access.22–25 Methodological limitations of these studies may significantly impact on the data. For example, blood cultures drawn from central lines may have been contaminated with antibiotic remnants in treated groups and thus reveal a lower rate of blood-culture proven sepsis.24 Frequent unprotected manipulations on vascular catheters in the control group (placebo flushes) may in contrast lead to higher rates of bloodstream infection.25 Other drawbacks of its widespread use would be increased levels of resistance (enterococci spp., Staphylococcus aureus), ototoxicity and renal side effects. In our cohort, the lack of a significant difference of the late-onset sepsis risk in the subgroup treated with glycopeptide prophylaxis may well be due to a much lower number of infants and less power to detect a significant difference (17% in SGA infants vs. 14.2% in appropriate for gestational age infants). Whether SGA infants benefit from other potential preventive measures including human milk feeding, lactoferrin and probiotics needs to be subject to further studies. Up to date, a general recommendation for the administration of probiotics to reduce rates of mortality or late-onset sepsis in SGA infants cannot be made.26,27

Less is known to what extent differences in innate and adaptive immune responses in SGA infants contribute to sepsis pathophysiology. Previous reports noted thymic atrophy as well as lymphopenia and deficiencies of humoral responses in SGA infants compared with non-SGA infants.28,29 In a recent study, we demonstrated that SGA infants had remarkably different full blood counts than non-SGA infants, that is diminished numbers of white blood cells on day 1, 3 and 7 of life and a decreased number of platelets on day 1.30 Given the complex view of immunoregulation under chronic hypoxia, SGA infants are less able to mount innate immune responses which may have a role in the complex network of factors leading to adverse outcomes.30 Interestingly, maternal morbidities such as preeclampsia are thought to have an impact on the expression of immunomodulatory molecules such as cryopyrin and toll-like receptors.31 Future studies will have to elucidate whether these immunological changes of the mother also influence the infant´s susceptibility for late-onset infection.

Apart from our findings related to late-onset infection, we confirmed previous reports on higher rates of mortality and BPD in SGA infants.6,7,32 Exposure to intrauterine hypoxia, reduced energy supply of different organs and endocrine changes such as alterations in insulin-like growth factor system are known to have an impact on adverse outcomes in SGA infants, for example, through alterations in surfactant production and impaired extracellular matrix deposition in the lung.33–35 Interestingly, we noted that non-SGA infants <27 weeks were at higher risk for IVH III and IV in our cohort which excluded infants with early onset sepsis. Likewise, non-SGA infants < 25 weeks had an increased susceptibility for PVL. Previous studies reported inconsistent data regarding IVH risk and association with SGA.6,7,36,37 The potential benefit of being SGA may be related to the adaptation of SGA infants to broader autoregulatory changes of the cerebral blood flow or to higher cortisol levels in SGA infants.38,39 On the other hand, the increased risk to IVH and PVL in the non-SGA cohort may be explained by different causes of preterm delivery, especially inflammation at the fetomaternal interface.

In conclusion, our study demonstrated that SGA contributes to the risk of late-onset sepsis. Our data point to the need of further studies to elucidate underlying immunological pathways. Large population-based studies such as GNN may help to identify patients that most likely benefit from individualized treatment strategies. Consequently, it may assist in the design of clinical trials to assess the efficacy of preventive therapies.

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Keywords:

very-low-birth-weight preterm infants; intrauterine growth restriction; nosocomial sepsis; adverse neonatal outcome

© 2014 by Lippincott Williams & Wilkins, Inc.