Abstract
Introduction
Due to the nonspecific clinical presentation, clinicians often empirically treat newborns at risk of early-onset sepsis (EOS). Recently, the Canadian Paediatric Society (CPS) published updated recommendations that promote a more judicious approach to EOS management.
Objective
To examine the compliance with the CPS statement at a tertiary perinatal site and characterize the types of deviations.
Methods
A retrospective chart review was conducted for all term and late pre-term newborns at risk for sepsis, between January 1 and June 30, 2018. The prevalence of newborns with EOS risk factors was measured during the first month. Management strategies for eligible newborns during the 6-month period were compared to the CPS recommendations to establish the rate of noncompliance. The type of noncompliance, readmission rate, and rate of culture-positive EOS were examined.
Results
In the first month, 29% (66 of 228) of newborns had EOS risk factors. Among the 100 newborns born in the 6-month period for whom the CPS recommendations apply, 47 (47%) received noncompliant management. Of those, 51% (N=24) had inappropriately initiated investigations, 17% (N=8) had inappropriate antibiotics, and 32% (N=15) had both. The rate of readmission for a septic workup was 1.6% (N= 2). None had culture-positive sepsis while admitted.
Conclusion
A large proportion of term and late preterm newborns (29%) had EOS risk factors, but none had culture-confirmed EOS. The rate of noncompliance with the CPS recommendations was high (47%), mainly due to overzealous management. Future initiatives should aim at increasing compliance, particularly in newborns at lower EOS risk.
Keywords: Antibiotics, Early-onset sepsis, Investigations, Newborn
Early-onset sepsis (EOS) is most commonly defined as a serious systemic infection that manifests within 72 hours of birth (1,2). While EOS is relatively rare with an estimated culture-positive rate of 0.77 to 1 per 1,000 live births (3), it carries a mortality rate of approximately 2 to 3% (4). High risk of death, along with a lack of specific signs and symptoms at presentation, often leads clinicians to having a low threshold for initiating investigations and pre-emptive antibiotic therapy. Studies show that for every newborn that receives antibiotics for EOS, 6 to 16 are treated needlessly (5). Excessive antibiotic use is a well-established cause of antimicrobial resistance (6–8) and may lead to harmful downstream consequences, including necrotizing enterocolitis, late-onset sepsis, and mortality (6,9,10). Similarly, routine investigative tests such as a complete blood count and C-reactive protein may lead to overprescribing and unnecessary invasive procedures, as they may falsely heighten suspicion of EOS (11). Overzealous management can lead to prolonged hospitalizations and separation of the infant and mother (6,12,13). In the current era of antimicrobial stewardship and efforts to improve investigative testing, these factors have led to the recent scrutiny of EOS management and have prompted institutions to evaluate and improve clinical practice in this vulnerable patient population.
In January 2017, the Canadian Paediatric Society (CPS) published an updated statement with new recommendations for the management of newborns at increased risk of EOS (14). Recommendations on investigations and use of antibiotics for EOS were divided into five groups according to the presumed risk (Table 1), which was identified by the newborn’s clinical presentation (unwell- or well-appearing) and the presence of maternal risk factors for EOS (Table 2). Unwell appearing newborns require investigations and antibiotics, while the risk of EOS is insufficient to warrant initiation of a sepsis protocol in asymptomatic newborns with a single maternal risk factor (Group 4). The strengths of the recommendations for Groups 1 through 4 are listed as ‘Strong’ by the CPS. While the statement is primarily intended for term newborns, it may be applied to well-appearing late preterm newborns under certain circumstances, albeit with a ‘Weak’ strength of recommendation. Due to paucity of data to inform the ideal management of asymptomatic newborns born to mothers with multiple risk factors and/or chorioamnionitis (Group 5), the CPS statement recommends an individualized approach, which is also listed as a ‘Weak Recommendation’.
Table 1.
Summary of the 2017 CPS Recommendations (Adapted from Jefferies, 2017 [14])
| Group | Signs suggestive of sepsisa | Number of maternal risk factorsb | Investigations (INV)c,d,e,f | Antibiotics (ABX)e,f |
|---|---|---|---|---|
| 1 | Any (excluding respiratory signs only) | Not relevant | CBC ± CRP Blood culture (BC) | Empiric IV ABX |
| 2 | Respiratory signs only | 1–3 | ||
| 3 | Respiratory signs only | 0 | ||
| 4 | None | 1 | No INV | No ABX |
| 5 | ≥2 and/or chorioamnionitis diagnosis | Individualized approach | Individualized approach |
CBC Complete blood count; CPS Canadian Paediatric Society; CRP C-reactive protein.
aClinical signs suggestive of neonatal sepsis are listed in Table 2.
bMaternal risk factors are listed in Table 2.
cLumbar puncture (LP) investigations were excluded because they are not part of the initial septic workup in our institution. LP is performed when the newborns who are suspected to have sepsis present with seizures.
dWe included CRP as an option, because our current practice at Victoria General Hospital often includes CRP when CBCs are ordered. Also, the CPS statement does not provide definitive arguments for its exclusion.
eFor Group 3 newborns only, investigations and antibiotic treatment may be delayed for up to 6 hours after birth to see if the respiratory signs resolve. We considered investigations or antibiotics to be appropriate as long as they were not ordered with the first/initial admission orders.
fFor Group 4 newborns only, the CPS statement recommends a watchful period of 24 h before discharge. We did not examine the length of stay, and therefore did not evaluate whether newborns were discharged after24 h.
Table 2.
Signs suggestive of EOS (A) and maternal risk factors (B)
| A.Signs Suggestive of EOS (15–19) |
|---|
| Persistent respiratory distress (e.g., grunting, flaring, retracting) for at least 1 h after admission to either NICU or Postpartum unit, which require the following respiratory interventions: • NCPAP/NFNC/mechanical ventilation, or • Supplemental O2 ≥ 2h to maintain O2 saturation >90% |
| Hemodynamic instability requiring vasoactive drugs (e.g., epinephrine, norepinephrine, dopamine, dobutamine) |
| Neonatal encephalopathy/perinatal depression defined as: • Seizures and/or Apgar score <5 @ 5 min |
| Temperature instability (≤36.2°C and >38°C) lasting: • ≥ 4 h; or ≥ 2 h if in combination with either tachycardia (HR ≥ 160), tachypnea (RR ≥ 60), or respiratory distress not requiring supplemental O2 |
| B.Maternal Risk Factors: |
| 1. GBS risk factors, defined as either: • GBS-positive status and inadequate IAP • GBS-unknown status and inadequate IAP • GBS bacteriuria at any time during the current pregnancy and inadequate IAP • A previous infant with invasive GBS disease and inadequate IAP 2. Prolonged rupture of membranes ≥ 18 h 3. Fever (temperature ≥ 38°C) |
APGAR Appearance, Pulse, Grimace, Activity, and Respiration; GBS Group B streptococcus; HR Heart rate; IAP Intrapartum antibiotic prophylaxis; NCPAP Nasal continuous positive airway pressure; NFNC Neonatal high-flow nasal cannula; NICU Neonatal intensive care unit; O2 Oxygen.
Given the overuse of antimicrobials in neonatal units, the recently published CPS recommendations, and our need to align the management of EOS at our site with the best evidence, this study aimed to evaluate the compliance to these recommendations, and describe the management of newborns in whom an individualized approach is recommended (Group 5).
ETHICS APPROVAL
This study was approved by the Health Research Ethics Board (HREB) at Island Health. HREB waived the need for informed consent. The research was conducted in accordance with the ethical standards of the responsible committee (HREB) and with the principles set forth in the Helsinki Declaration.
METHODS
Study design and population
This study was a retrospective chart review conducted at a 22-bed neonatal intensive care unit (NICU) and 28-bed postpartum tertiary perinatal care centre (Victoria General Hospital, Victoria, BC, Canada).
The first part of the study consisted of a retrospective chart review of all consecutive admissions in January 2018 in order to estimate the prevalence of newborns born ≥35 weeks gestation at risk for sepsis and the percentage that fall into each of the Groups 1 through 5 (Table 1). NICU and postpartum unit admission records, electronic health records and paper charts of newborns were screened for exclusion and inclusion criteria. Newborns exhibiting at least one clinical sign suggestive of sepsis (Table 2, A) and/or born to mothers with a minimum of one risk factor for neonatal sepsis (Table 2, B) were considered to be at risk for sepsis. Newborns admitted on postnatal day ≥3, those started on antibiotics for conditions other than sepsis, those with seizure-predisposing conditions, and those with known major congenital abnormalities were excluded.
The second part entailed screening all newborns admitted during a 6-month period (January 1 to June 30, 2018) to select 20 to 30 consecutive newborns fitting the description of each of the five risk groups (Table 1) for detailed analysis. The same inclusion and exclusion criteria were applied. Enrollment for this part of the study was stopped for each group once 30 newborns had been enrolled or the 6-month study period had ended, whichever was first. Once a newborn was deemed eligible, a more detailed chart review was conducted to ascertain which signs of sepsis (Table 2, A), maternal risk factors (Table 2, B), management strategies (investigations and antibiotics), and baseline characteristics (Table 3) were present. EOS signs were predefined by synthesizing parameters from the existing literature and consulting with members of the health care team that routinely manages EOS at our site (15–19). Management strategies were cross-checked with the CPS recommendations to establish the rate of noncompliance for Groups 1 through 4 (Group 5 could not be analyzed as CPS recommendations call for an ‘individualized approach’).
Table 3.
Baseline characteristics of included newborns January 1 to June 30, 2018
| Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Total | |
|---|---|---|---|---|---|---|
| Total N (%) | 20 (16) | 20 (16) | 30 (24) | 30 (24) | 25 (20) | 125 (100) |
| Location | ||||||
| NICU | 19 (95) | 20 (100) | 30 (100) | 6 (20) | 9 (36) | 85 (68) |
| Postpartum Unit | 1 (5) | — | — | 24 (80) | 16 (64) | 40 (32) |
| Gestational Age (weeks) | ||||||
| 35–37 | 0 (0) | 3 (15) | 9 (30) | 6 (20) | 3 (12) | 21 (17) |
| 37–40 | 9 (45) | 11 (55) | 14 (47) | 16 (53) | 9 (36) | 59 (47) |
| >40 | 11 (55) | 6 (30) | 7 (23) | 8 (27) | 13 (52) | 45 (36) |
| Birth Weight (g) | ||||||
| <1,500 | — | — | — | — | — | — |
| 1,500–2,500 | — | — | 2 (7) | 3 (10) | — | 5 (4) |
| >2,500 | 20 (100) | 20 (100) | 28 (93) | 27 (90) | 25 (100) | 120 (96) |
| Gender | ||||||
| Male | 11 (55) | 13 (65) | 19 (63) | 15 (50) | 15 (60) | 73 (58) |
| Female | 9 (45) | 7 (35) | 11 (37) | 15 (50) | 10 (40) | 52 (42) |
| Mode of Delivery | ||||||
| Vaginal | 13 (65) | 15 (75) | 13 (43) | 24 (80) | 17 (68) | 82 (66) |
| Caesarean Section | 7 (35) | 5 (25) | 17 (57) | 6 (20) | 8 (32) | 43 (34) |
Due to the retrospective nature of the study, missing binary newborn or maternal data points were classified as not having occurred (e.g., if there is no documentation of fever, the newborn is deemed to have been afebrile). Missing baseline characteristics data were marked as ‘Other’ in the database. The likelihood of missing newborns who developed sepsis after discharge is low, as that information is available through our electronic health record system which contains data for readmissions throughout Vancouver Island. At our NICU, patients are managed by paediatrics or neonatologists if a newborn requires intensive care (e.g., mechanical ventilation). In the postpartum unit, newborns are monitored by general practitioners and midwives, and consulting paediatrics guide management of EOS when warranted. In addition, a clinical pharmacist provides recommendations on the management of newborns at risk for EOS.
The principle investigator (MS) was involved in the collection and analysis of study data but was not involved in the care of newborns or mothers.
Outcome measures
The primary outcome was the proportion of newborns in Groups 1 through 4 managed with strategies that deviated from the 2017 CPS statement recommendations.
Secondary outcomes included: 1) the prevalence of infants falling into Groups 1 through 5 within the first 30 days of the study; 2) the types of deviations from the CPS recommendations; 3) the proportion of newborns in Group 5 that received investigations or antibiotics within 72 hours of birth; 4) the average duration of antibiotic treatment; 5) the rate of readmission for septic work-up within 7 days of discharge; and 6) the rate of culture-positive EOS.
Statistical analysis
For the primary outcome, we hypothesized that 50% of newborns would receive noncompliant management. A sample size of 97 newborns from Groups 1 through 4 was calculated using a 95% confidence level with a 10% margin of error. The screening period of January 1 to June 30, 2018 was selected by taking into account the newborn admission rate at our site.
The primary and secondary outcomes of this study were expressed using descriptive statistics.
Results
During the 6-month study period, 655 newborns (gestational age ≥35 weeks) were screened. Of the 228 newborns of all gestational ages admitted during January 2018, 66 (29%) were born at 35 weeks or later and fit the criteria to be at risk for sepsis. Group 4 was the most frequently encountered risk group (N=41, 62%). Four (6%) were categorized into Group 1, 5 (8%) into Group 2, 6 (9%) into Group 3, and 10 (15%) into Group 5.
One-hundred and twenty-five newborns (53 females; 72 males) were included in the second part of our study for detailed analysis. The number of newborns in each group and their baseline characteristics are depicted in Table 3. Eighty-three per cent of newborns (N=104) were born at ≥37 weeks of gestational age and almost all (N=120, 96%) had a birth weight of ≥2,500 g. Twenty-five newborns belonged to Group 5, for which the CPS statement does not give specific recommendations (9 [36%] were solely observed, 9 [36%] had investigations on admission, 7 [28%] had investigations after an initial observational period, and 4 [16%] received antibiotics). Therefore, 100 newborns in Groups 1 through 4 were included in the primary outcome analysis.
Of the 100 newborns, 47 were managed with strategies that deviated from the CPS recommendations. Most belonged to Group 3 (N=17; 36%) or Group 4 (N=15; 32%). Of the four newborns in Group 1 with noncompliant management, one (25%) was investigated but not treated, one (25%) received delayed investigations and antibiotics, and two (50%) received neither investigations nor antibiotics. Of the 11 inappropriately managed newborns in Group 2, 1 (9%) received delayed treatment, whereas 10 (91%) did not receive the indicated antibiotics at all. Four of those 10 also received inappropriate investigations which were either delayed (N=3; 27%) or not performed (N=1, 9%). All (N=17, 100%) newborns with noncompliant management in Group 3 received investigations immediately at admission, and seven (64%) of those also received antibiotics without the suggested observational period. Finally, of the 15 well-appearing newborns in Group 4 with noncompliant management, 14 (93%) had unnecessary investigations, and 1 (7%) received both investigations and antibiotics that were not indicated.
Even though 40 (32%) newborns in Groups 1 through 5 received antibiotics (for a mean duration of treatment = 2.85 days) and 91 (73%) underwent investigations, none had culture-positive sepsis during their admission. The rate of readmission for a septic workup within 7 days of discharge was 2 of 125 (1.6%). Both readmitted newborns had received noncompliant management strategies. The initiation of antibiotics and investigations was inappropriately delayed for the newborn in Group 1, whereas the newborns in Group 3 received overzealous investigations which were deemed to not have contributed to the readmission.
Discussion
The overall noncompliance rate of our site to the recommendations of the 2017 CPS position statement was 47%. The most unwell-appearing infants (Group 1) received the lowest rate of noncompliant management (8.5%). We hypothesize that this is because the CPS statement continues to call for immediate investigations and treatment due to the acuity in presentation, a recommendation which appears to be followed by clinicians at our site (14,20). For newborns that presented with respiratory signs only but were born to mothers with EOS risk factors (Group 2), withholding antibiotics when they were indicated was the most common reason for noncompliance. However, deviation from guidelines occurred infrequently, and may have been due to clinically subtle or transient respiratory signs where an observation period in lieu of antibiotics is justified. Conversely, the management strategies of newborns with lower EOS risk (Groups 3 and 4) at our site may require improvement. The suggestions by the CPS for an observational period in Group 3 was not followed in most (N=17) of the newborns in that group and 100% of the noncompliance was as a result of indiscriminate ordering of investigations and/or antibiotics. Likewise in Group 4, 94% of noncompliance was due to unnecessary investigations, despite the recommendation for a watchful period alone prior to discharge. Since Group 4 is the most commonly encountered group at our site, this potentially equates to hundreds of unnecessary investigations along with their downstream consequences that can be avoided annually. A streamlined strategy such as a site-specific protocol that supports and facilitates watchful waiting before interventions and antibiotics could be considered for these newborns at lower risk for EOS.
The management of newborns born to mothers with chorioamnionitis or multiple risk factors (Group 5) is controversial. The most recent American Academy of Pediatrics (AAP) guideline advocates for routine administration of empirical antibiotics for newborns with maternal chorioamnionitis (4), whereas a 2018 study by Joshi et al. provided supporting evidence for an initial monitoring period to evaluate the need for antibiotic treatment (21). This study showed that after implementing a new multidisciplinary approach where well-appearing newborns were observed before investigations or antibiotics were initiated, the rate of antibiotic administration decreased by 55%, without compromising newborn safety. In our cohort, there were no newborns with culture-positive EOS nor readmissions after discharge and a large proportion (9 of 25, 36%) in Group 5 underwent an observational period only. As well, out of those that received investigations, 7 of 16 (44%) were ordered after a watchful waiting period, suggesting a judicious approach.
Our results show that although about one-third of newborns with EOS risk factors received antibiotics and almost three-quarters underwent investigations for sepsis, none had culture-positive EOS. This indicates that our intervention rate well supersedes that of the true EOS rate, suggesting that our management strategies may be unwarranted in this population, especially because asymptomatic newborns (Group 4) are the most frequently encountered group at our site. Previous studies have also shown similar results. In a retrospective study of 2,785 newborns who underwent a septic evaluation, only 22 newborns (0.8%) were found to have culture-proven EOS (22). Similarly, Strunk et al. (2018) showed that only 2 out of 4,234 newborns evaluated for suspected sepsis had confirmed EOS, despite 11.1% of newborns undergoing investigative studies and 7.6% receiving treatment with antibiotic therapy (23), further supporting the idea that investigations and antibiotics are over-used.
One limitation of the study is that the CPS statement did not provide specifics on the signs used to define sepsis, and therefore, we have extrapolated EOS parameters from existing literature (15–19). Another limitation is that maternal data and risk factors were extracted from neonatal charts which might be incomplete. Intrapartum antibiotics can lead to culture-negative EOS; so, it is possible that some newborns in the current study had unrecognized EOS. In addition, we included newborns at gestational age 35 to 37 weeks, which could have led to the inclusion of some who do not have specific recommendations outlined by the CPS statement. Guidelines for the management of EOS in late preterm newborns currently do not exist and primary research is urgently needed to support their optimal treatment. Finally, newborns were not followed up into infancy, and thus, the long-term clinical outcomes or consequences of noncompliant management were not correlated to the results of our study.
CONCLUSION
The diagnosis and management of newborn EOS is challenging and dependent on the clinical presentation of the newborn, as well as a number of maternal risk factors. Although investigations and antibiotics are used liberally in the majority of newborns with EOS risk factors, culture-positive sepsis is rare. Standardizing treatment by protocolizing EOS management may improve compliance with the current recommendations, particularly if emphasis is given to more conservative management in those with lower EOS risk, and thus warrants consideration for further quality improvement initiatives. High-quality primary research to study the optimal management of EOS is needed to support the recommendations based on weak or moderate quality evidence, and to positively impact guideline uptake.
Funding: The authors did not receive financial support for the research, authorship or publication of this manuscript.
Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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