Keywords

Preterm infant; Late-onset sepsis; Gross motor outcome

Abbreviations

AIMS: Alberta Infant Motor Scale; BPD: Bronchopulmonary Dysplasia; CRP: C-reactive protein; HS-PDA: Hemodynamic Significant Patent Ductus Arteriosus; IVH: Intraventricular Hemorrhage; LOS: Late-onset sepsis; NEC: Necrotizing Enterocolitis; PVL: Periventricular Leukomalacia; RDS: Respiratory Distress Syndrome

Introduction

The incidence of prematurity is approximately 7.7% of all births in the Netherlands. In 1.3% of all births the gestational age is less than 32 weeks [1]. Prematurity is associated with increased mortality and morbidity [2]. This includes somatic problems such as lung disease and retinopathy, but also impaired psychomotor development with associated learning disabilities, which is an important outcome parameter of neonatal intensive care treatment[3].

During admission to the intensive care unit many hazardous episodes will occur, compromising the development of the infant’s brain and thereby the long term psychomotor outcome. One of the associated risk factors for impaired neurodevelopmental outcome is sepsis [4,5]. Preterm and low birth weight infants have a high risk of acquiring nosocomial sepsis up to 33% in preterm infants fewer than 28 weeks gestational age, associated with length of hospital stay and need for invasive devices. Another factor might be an immature immune system [6,7]. Dammann et al. described an association of intraventricular hemorrhage or periventricular white matter lesions and pro-inflammatory cytokines like IL-6 due to intra-uterine infection[8]. White matter injury has a role in disturbance of cerebral networking and control and modulation of the motor system and thus on neurodevelopmental outcome[9].

Long term motor outcome is one of the most important outcome parameters of neonatal intensive care. Mitha et al. reported a higher incidence of cerebral palsy following neonatal sepsis compared to infants without an infectious episode during admittance [10]. Early detection of developmental delay is desirable, to implement early intervention in order to improve long term outcome. Several screening tools are used for the assessment of neurodevelopment at different ages.

One of the screening tools for gross motor development in early infancy is the Alberta Infant Motor Scale (AIMS). The AIMS is designed to measure gross motor skills from term equivalent age including independent walking, sit and stand [11]. Components tested in the AIMS are weight bearing properties, posture and antigravity movements[12]. Though this scale was not designed as a predictive tool, it has moderate to excellent predictive validity. It can be used to classify the infants development as normal or suspicious/abnormal at twelve months corrected age[13].

The aim of this study was to analyze whether early gross motor development is different in preterm infants who experienced lateonset sepsis during their Neonatal Intensive Care hospitalization compared to infants who did not have a sepsis.

Materials and Methods

In this study we prospectively collected preterm infants who were suspected of having a late onset sepsis (LOS). Infants admitted at the level III Neonatal Intensive Care Unit of the VU Medical Center were eligible if gestational age was under 32 weeks and/ or birth weight under 1500 grams and written parental consent was present. Inclusion period was between March 2008 and December 2014. Exclusion criteria were infant’s congenital abnormalities, e.g. syndromal/chromosomal abnormalities or inborn errors of metabolism. The medical ethical committee of the VU University Medical Center approved this study.

LOS has no definition on which international literature reached consensus [14]. We defined suspicion of LOS on clinical symptoms, E.g. temperature (hypo- or hyperthermia or instable temperature), respiratory instability (apnea), circulatory instability (hypotension or tachycardia), gastrointestinal problems (feeding difficulties) or neurological symptoms (apathy, irritability). Cultures were taken from blood and cerebrospinal fluid. Late onset was defined as onset of clinical symptoms occurred after the first 72 hours postnatally. LOS was defined as proven if blood culture turned positive. If blood culture turned positive for coagulase-negative staphylococci elevation of C-reactive protein (CRP) within 2 days after onset of symptoms and blood culture was required for a final diagnosis[15]. LOS was defined probable if blood culture did not turn positive, but antibiotics were continued for seven days based on the clinical symptoms of the infant.

Patient data were collected, e.g. gestational age and birth weight, gender, respiratory and circulatory data (duration of ventilation, hemodynamic significant ductus arteriosus), medication use (steroids), cerebral ultrasound abnormalities (intraventricular haemorrhage according to Papile [16]), necrotizing enterocolitis (NEC) stage 2 or 3 according to Bell [17] and bronchopulmonary dysplasia (BPD) grading according to Jobe [18]. Surgical interventions were defined as abdominal, cardiac and ophthalmological surgery, or surgery for other indications.

At corrected age of six and twelve months surviving patients were invited for follow-up. A neonatologist performed physical examination and motor outcome was assessed according to the Alberta Infant Motor Scale assessed by a pediatric physiotherapist and expressed in Z-scores.

Statistical analysis was performed with SPSS using version 22 (SPSS Inc, Chicago, Illinois, USA). Statistical analyses were performed with Chi-square using Fisher’s exact test as appropriate for dichotomous data and T test for paired data. For independent data the independent T test was used. A probability P value<0.05 was considered statistically significant.

Results

The patient characteristics are stated in Table 1 Due to inclusion criteria of gestational age <32 weeks and/or <1500 gram there is a broad range in these variables. Major co-morbidity is stated in Table 2 for the total study population and separately for the proven and no proven infection groups. Only for head circumference SDS a significant difference was found between the proven versus no proven infection groups. In nine patients the indication for surgery was gastro-intestinal problems, in one for placement of a central venous line. In Table 3 the causal agents in the blood culture are presented. Of the 117 patients, 21 patients had two and one patient had three infectious episodes to be analyzed in this study. If patients had more than one infectious episode the causal agents were stated separately. In 32 of the 117 patients, blood culture revealed no micro-organisms, 3 of these patients had two clinical infectious episodes in which both blood cultures were negative. Of the 117 patients suspected LOS in total 85 were proven with positive blood cultures, of the 32 patients with negative blood cultures 14 were treated with antibiotics for 7 days due to clinical symptoms and in 18 antibiotics were discontinued after 48 hours due to negative blood culture and no clinical suspicion of LOS.

Table 1: Patient characteristics.

Table 2: Major co-morbidity.

Table 3: Causal infectious agents in blood culture.

Cerebral fluid was obtained in 68 patients of whom 61 samples showed no micro-organisms, in 3 coagulase-negative staphylococci were found and in 4 patients Staphylococci aureus were isolated.

Of the cohort 12 patients died during admission, one deceased after discharge due to progressive neuromuscular disease.

Table 4 represents biometric parameters at birth, six and twelve months corrected age showing no differences between the groups with or without proven LOS (resp. n=85 and 32) as the prevalence in chorioamnionitis between both groups (28.6% vs 31.3%, p=0.821).

Table 4: Comparison of birth weight and head circumference at birth, six and twelve months corrected age.

Table 5 presents gross motor development at six and twelve months corrected age. At six months corrected age AIMS Z-score revealed a significant difference in favor of the sepsis group (median Z-score (minimum-maximum) in proven LOS group -0.64 (-2.78 ±0.80) versus -1.14 (-2.29 ± 0.80) in the non-proven LOS group, p=0.050). This difference could not be reproduced at twelve months corrected age (median Z-score in proven LOS group -0.89 (-5.22 ± 0.66) versus -0.69 (-6.336 ± 0.31) in the nonproven LOS group, p=0.378). Differences in AIMS Z-score at six and twelve months corrected age were not significant whether meningitis was present or not (p-value resp. 0.763 and 0.160). Table 6 shows the changes in head circumference and AIMS over time.

Table 5: Comparison of AIMS Z-score at six and twelve months corrected age.

Table 6: Change of head circumference SDS and AIMS between six and twelve months corrected age.

In our cohort 75% of the positive blood cultures revealed presences of coagulase-negative staphylococci. When dividing the LOS group in LOS with other causal agents than coagulasenegative staphylococci versus non-proven LOS no significant difference could be found (six months corrected age p=0.687, twelve months corrected age p=0.083). However, at six months corrected age, the AIMS between the group with infection by coagulase negative staphylococci (n=50) to the group with lateonset sepsis by other causal agents (n=12) is significant different in favor of the CoNS group (p=0.008). This difference could not be demonstrated at twelve months corrected age (p=0.219).

With respect to co-morbidity six month corrected age AIMS Z-scores showed a trend to lower scores in patients with necrotizing enterocolitis (Table 7). In total four patients with NEC did not survive. Surgery was performed in nine patients, in five because of complications of NEC, in four because of solitary perforation without signs of NEC. No differences were found between the groups with or without surgery (p=0.120). Two of the nine patients who had surgery did not survive. In 80% (n=16) of the patients with NEC blood culture was positive: in 11 patient CoNS was found and in five other causal agents (S. aureus, Klebsiella and E. coli).

Table 7: Comorbidity in neonatal period and AIMS at six months corrected age.

Incidence of other co-morbidity did not reveal any differences between the proven and no proven LOS groups.

Discussion

Although in our study the six month corrected age neurodevelopmental outcome as measured by AIMS was in favor of the proven infection group, at twelve months corrected age these infants just deteriorated in neurodevelopmental outcome in comparison to the non-proven infection group.

The initial outcome at six months corrected age in the proven infection group might be explained by the high incidence of coagulase-negative staphylococci, with their relative mild course of disease during hospitalization. However, studies have shown long-term adverse effects of these relative mild infections[10, 19]. In our cohort a high incidence of coagulase-negative staphylococci is present, as shown in 75% of the positive blood cultures. Other studies report incidences of 40 to 60% [7,20]. The course of a coagulase-negative staphylococci sepsis tends to be milder than sepsis by other micro-organisms, which might implicate less detrimental effects of the inflammatory response. However developmental delay following coagulase negative staphylococci has been reported [19].

Therefore we suggest that screening with AIMS for gross motor developmental delay at six months corrected age is too early and might be due to the relatively low sensitivity of the AIMS at six months of age[21].

We did find a trend in lower AIMS scores at six months corrected age in patients with necrotizing enterocolitis, and also lower scores at twelve months corrected age although this difference is less clear then in the proven LOS group. Why the AIMS scores in infants with NEC already deviate at six months corrected age in comparison to the LOS group might be the result of the protracted inflammatory state during the course of the NEC[22], the concomitant prolonged hospital stay and impaired growth. An impaired neurodevelopment after NEC has been described by Rees et al. as well[23]. Another factor might be the effect of anesthesia during additional surgery in case of severe NEC. In general, it is presumed that general anesthesia might have effects on the developing brain. One randomized study comparing local versus general anesthesia showed no differences in neurodevelopmental outcome. However, only half of this cohort was born preterm and surgery was performed elective [24]. In our study 25% of the patients with NEC underwent surgery due to a protracted course to recovery, and therefore was not elective, thus the result of the previous study is hardly applicable to our cohort. Our patients are also in the patient category dependent on central venous catheters for total parenteral nutrition which is an extra risk factor for bloodstream infections.

The patients with no proven LOS had lower birth weight, however not significant, and had a significant smaller head circumference at birth. These differences were not present anymore at six months corrected age, suggesting catch-up of a possible adverse intra-uterine environment. One could speculate, the adverse intra-uterine environment might have effects on later development as well, according to the trend to lower AIMS scores at corrected age of six months in the no proven infection group. Neurodevelopment and head circumference showed a detriment in the proven LOS group during the period of six to twelve months corrected age. In the Netherlands, a specially developed follow up program including physiotherapy is initiated to evaluate neurodevelopment of the NICU population. If a developmental delay is suspected during this follow up period, physiotherapeutic intervention is intensified and if required additional treatment will be commenced. This intensified physiotherapeutic intervention might explain the improvement of neurodevelopment at the corrected age of twelve months.

This study also has several limitations. Several infants experienced two or more infectious episodes and only one episode was included in the study, due to ethical or practical causes (for example parents withdrew informed consent during the second infectious episode or in some cases an arterial catheter could not be inserted for sampling). This implicates the possibility of more damage done by repeatedly exposure to inflammatory agents in the same patient, whereas only one episode has been registered. Also the presence of chorioamnionitis may have an effect on long term outcome, although in this cohort no difference in prevalence between the proven versus non proven infection groups was demonstrated.

Also, AIMS was a secondary outcome measure in this study. Therefore, the study was not powered for his outcome measure including correction for severe comorbidity influencing outcome. Nevertheless, our results show at twelve months corrected age this interesting finding in our cohort.

Conclusion

In this study after late onset sepsis at twelve months corrected age follow up preterm infants revealed aberrant neurodevelopment, indicating that the occurrence of late-onset sepsis may contribute to an impaired development of gross motor function.

Patients with NEC, seem more at risk for a deterioration in development, among others induced by protracted exposure to inflammatory responses and thus might earlier present gross motor developmental delay than LOS alone.

Acknowledgements

We would like to thank Dr. S.A. Prins for critically reviewing this manuscript.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Funding

This study was funded by Fonds Nuts Ohra (grant numbers 0901- 042, 1101-093). The study sponsor had no role in study design, in the collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication.

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