Antibiotics use practices for hospitalized asphyxiated neonates: a cross-sectional survey across selected Nigerian newborn units

Introduction

Perinatal asphyxia significantly contributes to neonatal admissions, especially in low-middle-income countries (LMIC), where the healthcare system is weak and access to obstetric care is sub-optimal (1). Antibiotic use is quite common in the neonatal units and the usage does not often correlate with proven bloodstream infection (2). It is also being used for a prolonged period than required (2,3). Antibiotics have significantly enhanced survival rates in high-risk populations when used for proven infections. However, excessive antibiotic use could disrupt an infant’s bacterial microbiome and has been associated with adverse outcomes such as invasive candidiasis, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity, neurodevelopmental impairment, and mortality (4,5). Furthermore, overuse of antibiotics can lead to multi-drug resistant organisms and increased healthcare costs at both the unit and public health levels (6-8).

Neonates with severe perinatal asphyxia often present with features that are clinically indistinguishable from the features of sepsis, such as respiratory distress, temperature instability, circulatory disturbance, apnea, lethargy, and a poor suck and hence, administered antibiotics empirically (9). In most resource-poor settings, microbiologic testing for a sick newborn is rarely performed, mainly due to limited facilities and affordability of the cost. Consequently, broad-spectrum antibiotics are used, often for longer periods than stipulated for prophylactic treatment (10). This practice has implications for the growing concern of antibiotic resistance and the overall cost of healthcare, especially in these resource-poor settings.

There is currently a dearth of information on the use of antibiotics among asphyxiated neonates in Nigeria, and there is no recommendation on its use in the latest edition of National guidelines for comprehensive newborn care (11). This study determined the antibiotic use practices across newborn units in Nigeria. The findings will provide insight into the use of antibiotics for a newborn with asphyxia and inform the planning of antibiotic stewardship programs across newborn units in typical resource-poor settings. We present this article in accordance with the STROBE reporting checklist (available at https://jxym.amegroups.com/article/view/10.21037/jxym-24-7/rc).

Methods

It was a descriptive cross-sectional study conducted between September 2021 and January 2022. It was conducted across selected neonatal units in the six Nigerian geopolitical zones, with the Neonatologists working in such units as respondents. Given that newborn care, especially for sick neonates such as those with asphyxia, often occurs in Nigeria’s tertiary health facilities (12), the enrollment of respondents was from the tertiary health centres. There are six geopolitical zones in Nigeria [i.e., South-west (SW), South-east (SE), South-south (SS), North-east (NE), North-west (NW), and North-central (NC)], each comprising six states except SE with five states, and NW and NC with seven states each.

According to a previous report, there are about 85 tertiary health facilities in Nigeria (at least two per state), 88% of whom are government-owned (13). The present study considered only the public/government-owned tertiary facilities (75, i.e., 88% of 85 facilities). Thirty percent (30%) of these facilities was estimated as the minimum sample size; hence, respondents from 23 facilities participated in the study. A list of the 75 tertiary health facilities (federal and state-owned) was prepared and grouped by geopolitical zones. There are 12, 12, 15, 9, 11 and 16 public owned tertiary facilities in NC, NE, NW, SE, SS and SW respectively. A random sampling method was used to select participating centers. A table of random numbers was generated for each geopolitical zone using online software (14). Proportionately, 4, 4, 5, 2, 3 and 5 facilities were randomly selected to participate in the survey using the formula for proportionate allocation of sample, i.e., nh=NhN×n (15), where n_{h =} proportionate sample size, Nh = number of health facilities in each zone, N = total number of health facilities (n=75), n = estimated sample size (n=23).

To reach respondents across the selected health facilities in the country, the researchers leveraged the existing network provided by the nationwide maternal and perinatal surveillance program (MPD4QED) and personal contacts.

A self-administered questionnaire was used to collect data via an online survey tool (Google Forms; https://forms.gle/zy3QHsVgsCZYMZCr6). Respondents were contacted [via email, Short Message Service (SMS), or phone call] to detail the essence of the study, and their participation was requested. Each prospective respondent was sent the link to the online questionnaire. The questionnaire has questions on the location of the neonatal units and antibiotic use practices for asphyxiated newborns. The collected data was exported to and analyzed with the SPSS software version 25. Qualitative variables such as reasons for antibiotic use were presented with bar charts and quantitative variables were summarized using frequency distribution tables.

Study outcome

The main outcome of the study is the usage of antibiotics for hospitalized asphyxiated newborns.

Definition of terms (16)

• Directed antibiotic therapy—antibiotic therapy aimed at micro-organisms that have been confirmed as the cause of an infection;
• Empiric therapy—antibiotics therapy in the presence of a clinical syndrome that may be due to infection before confirmatory evidence of the infection or its cause;
• Prophylactic antibiotics therapy—administration of antibiotics to prevent infection in a defined at-risk situation, e.g., prematurity, neonates delivered to mothers with prolonged rupture of membrane or chorioamnionitis.

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Research Ethics Committee of Dalhatu Araf Specialist Hospital, Lafia (No. DASHREC/415). The Google Form contains information about the study and respondents consented by filling out and submitting the questionnaires.

Results

Respondents (neonatologists) from 23 public-owned Nigerian newborn units participated in the survey. Table 1 shows the distribution of the participating units across the six geopolitical zones and their use of antibiotics for newborns with perinatal asphyxia. All the participants indicated the usage of antibiotics for asphyxiated neonates with 16 (69.6%) units using prophylactic antibiotics while the remaining seven (30.4%) centers indicated empiric rather than prophylactic antibiotic use.

In 16 (69.6%) units, perinatal asphyxia was reported to account for at least 30% of all admissions, i.e., it accounted for 30–59% of admissions in 15 (65.2%) of the newborn units and over 60% in one (Table 2). Institutional sepsis surveillance was available in 12 (52.2%) centers. The most common pathogens reported to be associated with newborn sepsis were Staphylococcus aureus 11 (47.8%) and Escherichia coli 8 (34.8%), respectively. However, most respondents [17 (73.9%)] were unaware of any specific pathogen associated with sepsis among asphyxiated neonates (Table 2).

Gentamicin, ceftazidime, ampicillin-sulbactam, and cefuroxime are the most frequently used antibiotics for prophylaxis among asphyxiated neonates (Table 2). Of the 16 centers using prophylactic antibiotics, 14 (87.5%) centers used it for 4–7 days, while two (12.5%) centers used it for 8–14 days. Seven (30.4%) centers that did not commence prophylaxis antibiotics would commence empirical antibiotics in the presence of some factors in the asphyxiated baby. The most common indications for empirical antibiotics use were the presence of risk factors for sepsis 7 (100.0%), fever 5 (71.4%), and respiratory distress 4 (57.1%), respectively (Figure 1). The other reasons proffered by the seven centers for empirical antibiotics and the frequency of use are present in Figure 1.

Figure 1 Bar chart showing the reasons for empirical antibiotic use and the frequency of usage.

Discussion

This study investigated the practice of antibiotics for hospitalized asphyxiated newborn infants across 23 Nigerian neonatal units. All the participants reported either prophylactic or empirical use of antibiotics for asphyxiated neonates. Although the study does not measure actual antibiotic use, the findings could drive policies on rational antibiotic use in the participating centers.

Approximately two-thirds of the units surveyed reported initiating prophylactic antibiotics for asphyxiated neonates, even though most respondents are unaware of the pathogens causing sepsis among these newborns. The high rate of prophylactic antibiotics usage for asphyxiated neonates in the current study suggests that asphyxia is considered a risk factor for bacteria sepsis, consistent with the previous studies (17-20). However, these previous studies suggesting an association between perinatal asphyxia and neonatal sepsis were mostly retrospective or descriptive with unmatched cases and controls. Furthermore, cases were inconsistently defined with Apgar scores less than six or seven at the first or fifth minutes in the different studies. In addition to being retrospective, one of the studies (20) included all newborns with variable exposure risks while in two others (18,19) sepsis was defined clinically without a microbiologic report. Hence, findings may not be free from bias or confounding effects thus affecting their validity.

Furthermore, prospective studies establishing the burden of bacterial infection or the benefits of antibiotic prophylaxis on the outcomes of asphyxiated neonates are scares in Nigeria and other high-burden countries. Studies for developed countries suggest the rates of bacteraemia are low among asphyxiated neonates (21,22). In a large retrospective cohort study of 1,084 neonates with severe perinatal asphyxia in the Netherlands, only 13 neonates (1.2%) had proven bacterial sepsis (21). However, the study reported only the death rate (21.4%) among the septic neonates precluding assessment of the impact of sepsis or antibiotic therapy on survival. In another prospective cohort study of 258 neonates with hypoxic-ischaemic encephalopathy (HIE), only 4 (1.6%) had proven bacterial infections (23,24). The risk of moderate-severe brain injury was also comparable among the neonates with or without sepsis suggesting a lack of effect of sepsis on the severity of neuronal injury.

Birth asphyxia was reported to account for over 30% of the admissions in at least two-thirds of the enrolled sites. This thus highlights the high burden of asphyxia in newborns in Nigeria consistent with the statistics reported from most LMIC (1). This finding buttresses the need to know the impact of antibiotic use in such affected neonates, as mentioned above.

Prophylactic antibiotics use for prolonged periods identified in this study is consistent with earlier reports (3). Evidently, antimicrobial stewardship is poor or non-existent in most of the newborn facilities surveyed. This is because sepsis surveillance is available in only about half of the units and most units are unaware of any specific pathogen causing sepsis among asphyxiated neonates whose symptoms may be clinically indistinguishable from those of sepsis. An effective antimicrobial stewardship program could have directed the discontinuation of antibiotics amongst subjects receiving prophylactic antibiotics after 48–72 hours in the absence of positive culture rather than prolonging the treatment period.

We also noted an increased usage of second and third-generation cephalosporins as prophylaxis, contrary to the use of penicillin and aminoglycoside as recommended in the National guideline on neonatal sepsis treatment (25). While the choice of antibiotics may reflect the local sensitivity pattern to isolates obtained from newborns with culture-proven sepsis, deploying broad-spectrum antibiotics as prophylaxis on asphyxiated neonates may be inaccurate and cost-ineffective, mainly because the associated pathogens are primarily unknown. Thus, this fact brings to the fore the need for accurate data on the burden of sepsis amongst newborns with asphyxia. Such findings will provide valuable information in developing national guidelines and promoting rational antibiotic use.

Limitations

Being a survey, the study does not measure actual antibiotic use. Nevertheless, we believed that the findings could provide insight into the actual use of antibiotics for asphyxiated newborns in Nigeria. Also, this study sampled the opinion of a neonatologist in each of the participating health facilities and such opinions are subject to recall bias. In addition, we acknowledged that more than one neonatologist might be present in a facility and could have varied opinions. Barring the limitations, we anticipate that this study would form a baseline for directly measuring antibiotic use in neonatal units. In addition, we hope that participating centers will be urged by this survey to implement antimicrobial stewardship activities so that antibiotics are administered more judiciously.

Conclusions

This study has shown that most Nigerian newborn units use antibiotics for asphyxiated neonates with about two-thirds reporting prophylactic. However, this high rate of antibiotic use does not reflect the awareness of bacterial aetiology of sepsis among these newborns. Broad-spectrum antibiotic usage was frequent with prolonged prophylaxis duration use, which could increase the risk of the emergence of antibiotic resistance.

Recommendations

We, therefore, recommend:

• Prospective studies to
  • Ascertain the association between asphyxia and neonatal sepsis.
  • Assess the impact of antibiotic use on the outcome of asphyxiated neonates.
• The implementation of an antimicrobial stewardship program across newborn units. This will improve antibiotic prescribing practices in neonatal units.
• The use of biomarkers of infection such as procalcitonin or C-reactive protein to predict the presence of bacteraemia and guide the initiation of antibiotics among asphyxiated neonates.

Acknowledgments

The authors appreciate the participating neonatologists from the Maternal and Perinatal Database for Quality, Equity, and Dignity (MPD 4-QED) Network.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jxym.amegroups.com/article/view/10.21037/jxym-24-7/rc

Peer Review File: Available at https://jxym.amegroups.com/article/view/10.21037/jxym-24-7/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jxym.amegroups.com/article/view/10.21037/jxym-24-7/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Research Ethics Committee of Dalhatu Araf Specialist Hospital, Lafia (No. DASHREC/415). The Google Form contains information about the study and respondents consented by completing and submitting the questionnaires.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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