Risk factors for neonatal sepsis in Sub-Saharan Africa: a systematic review with meta-analysis

Introduction

The Millennium Development Goals from 1990 identified newborn health as a key priority for global development.¹ The global neonatal mortality rate has decreased by 37%, from 33 to 21 deaths per 1000 live births since then.² In 2016, the Sustainable Development Goals (SDGs) were announced.³ SDG goal 3 aims to ensure healthy lives and promote well-being for all at all ages, and includes subtarget 3.2: by 2030, to end preventable deaths of newborns and children under 5 years of age, with all countries aiming to reduce neonatal mortality to at least 12 per 1000 live births and under-5 mortality to at least as low as 25 per 1000 live births.³ However, today a child born in Sub-Saharan Africa is still 10 times more likely to die in the first month compared with a child born in a high-income country.⁴ In 2018, 2.5 million children died within the first 28 days of life globally.⁴ In the same year, countries in Sub-Saharan Africa had the highest mortality, with 28 neonatal deaths per 1000 live births.^{2 4}

The majority of the 2.5 million neonatal deaths in 2018 worldwide can be divided into three main causes, each contributing approximately one-third to neonatal deaths: infections, intrapartum asphyxia and preterm birth complications.^{2 5} However, the causes of neonatal death vary among countries and regions.⁵ In countries with high neonatal mortality, almost 50% of deaths are due to severe infection with sepsis, making sepsis a leading cause of admissions and deaths in neonatal units in low-income and middle-income countries (LMICs).^{5 6} The Sub-Saharan African region includes some of the highest rates of neonatal mortality due to neonatal sepsis, yet prevention strategies are and remain unsatisfactory.⁷ Improved understanding of the underlying causes of neonatal sepsis is necessary to optimise prevention and management guidelines. Evidence from reviews of risk factors has been used globally to guide the development of management guidelines and prevention strategies for neonatal sepsis.⁸ The WHO recommends prophylactic antibiotics to newborns within 48 hours after delivery if membranes ruptured >18 hours before delivery, the mother had fever >38°C before delivery or during labour, or the amniotic fluid was foul-smelling or purulent.⁹ However, there might be discrepancies in the risk factors in different parts of the world. In a paper from 2020 on neonatal mortality, the authors conclude that there is a need to develop clinical guidelines for prevention and management of neonatal sepsis that are specific to the Sub-Saharan African context.¹⁰

Multiple studies aiming to identify the risk factors for neonatal sepsis have been performed in Sub-Saharan Africa during the last 10 years. With this systematic review and meta-analysis, we aim to provide quality evidence to identify the risk factors for neonatal sepsis in Sub-Saharan Africa. To the best of our knowledge, this is the first systematic review and meta-analysis to address neonatal risk factors for sepsis in the Sub-Saharan African context.

Methods and materials

This systematic review with meta-analysis has been reported in accordance with the ‘Preferred Reporting Items for Systematic reviews and Meta-analysis’ guidelines (online supplemental appendix 1).¹¹ A protocol (online supplemental appendix 2) was developed for our review in accordance with the ‘Preferred Reporting Items for Systematic reviews and Meta-analysis protocols’ guidelines.¹² It was registered on 12 July 2020 with the ‘International prospective register of systematic reviews PROSPERO’ (ID: CRD42020191067), which can be accessed on its website (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020191067).

Results

A total of 6168 titles were screened after excluding 2674 duplicate records. Of these, 6083 were excluded based on screening of abstracts. The remaining 85 studies underwent full-text assessment for eligibility. Five of these were only available as an abstract online and we requested full text from the authors but only one author replied. Thirty-six full texts met the inclusion criteria of our review after discussion with senior authors and reaching consensus. Reasons for exclusion of 49 full-text records were other focus of study design (eg, not examining risk factors for sepsis) (n=8), wrong patient population/not neonates/no subgroup analysis (n=15), other outcomes/no risk factors studied (n=16), location not according to the protocol setting (eg, not in Sub-Saharan Africa or not in a hospital) (n=4), no full text (n=5) and duplicate (n=1). All included studies were published in peer-reviewed journals. The study selection process is illustrated in figure 1.

All the 36 included studies were of observational study design. Twenty-eight studies were prospective (five cohort, six case–control, eleven cross-sectional studies and six studies of unclear/mixed unspecified design), seven were retrospective (three case–control studies, three cross-sectional studies and one study of unspecified design) and one was combined prospective and retrospective. The total sample size was 23 605 neonates (range: 100¹⁶–8129^{17 18}), and of these 4014 were diagnosed with sepsis. Ten studies reported the use of clinical guidelines for defining/diagnosing neonatal sepsis, while 26 studies required laboratory testing (eg, positive blood culture or haematological criteria) to establish the diagnosis of neonatal sepsis. All studies were conducted in secondary or tertiary level of care hospitals. The included studies were conducted in 10 different Sub-Saharan African countries, with majority of the studies conducted in Nigeria (n=10) and Ethiopia (n=10) (figure 2). The minimum study duration was 32 days¹⁹ and the maximum was 7 years and 6 months.²⁰

Some of the included studies had a narrowed approach; for example, some studies only examined one or a few risk factors, and some studies only examined a narrowed population (ie, babies born before arrival). There were variations in defining EONS and LONS, with EONS ranging from 48 hours to 7 days. The characteristics of the included studies are provided in table 1.

According to the the NHLBI quality assessment, 6 studies were rated as good, 8 were rated as fair and 22 were rated as poor (online supplemental appendix 4, table 1). No studies were excluded after quality assessment.

Risk factors were classified as neonatal, maternal or sociodemographic factors in our review. A total of 60 risk factors were reported. Twenty-seven studies examined both neonatal and maternal risk factors.

Discussion

It is of importance to prevent neonatal sepsis in order to reduce neonatal mortality to at least as low as 12 per 1000 live births in 2030, as specified by the SDG. One step is to identify the risk factors for neonatal sepsis. In this systematic review and meta-analysis, we found that the significant risk factors for neonatal sepsis in Sub-Saharan Africa were resuscitation at birth, low birth weight (<1.5 kg and 1.5–2.5 kg), low Apgar score at the first and fifth minute, prematurity <37 weeks, no crying right after birth, male sex, prolonged labour, PROM, multiple digital vaginal examinations, meconium-stained amniotic fluid, intrapartum maternal fever, foul-smelling vaginal discharge and low socioeconomic status. Male sex was found to be a significant risk factor in the meta-analysis, even though only 1 of the 23 studies which examined the association found male sex to be a risk factor (table 2).

Our findings are to some extent in line with a literature review from 2009 on the risk factors for maternal sepsis and EONS in Sub-Saharan Africa, where the most common risk factors for EONS were identified as prematurity, PROM, maternal fever, low birth weight and difficulties at delivery (obstructed labour or birth asphyxia).⁷ Our review and meta-analysis furthermore identified resuscitation at birth, low Apgar score at the first and fifth minute, no crying right after birth, male sex, prolonged labour, multiple digital vaginal examinations, meconium-stained amniotic fluid, foul-smelling vaginal discharge and low socioeconomic status as risk factors. However, we did not find birth asphyxia to be a risk factor. The review from 2009 examined the risk factors for EONS only, whereas our review and meta-analysis examined the risk factors for both EONS and LONS. EONS is more likely to reflect vertically acquired infections from the maternal genital tract and consequently has a different aetiology than LONS, different risk factors and potentially different means of prevention.⁷ Not all the included studies in our review and meta-analysis differentiate between EONS and LONS and there is no universal consensus on the definitions.

When comparing our findings with a systematic review and meta-analysis of risk factors for neonatal sepsis in India from 2019, we also find that these are to some extent in line. The review from India found that male gender, outborn admission, need for artificial ventilation, birth weight, delivery <37 weeks of gestation and PROM were risk factors for neonatal sepsis.⁸ Our review and meta-analysis furthermore identified low Apgar score at the first and fifth minute, no crying right after birth, prolonged labour, multiple digital vaginal examinations, meconium-stained amniotic fluid, intrapartum maternal fever, foul-smelling vaginal discharge and low socioeconomic status as risk factors. In our meta-analysis we did not find outborn admission to be a risk factor. The differences between our findings and the findings from India could indicate different risk factors in the two settings, but it could also partly be due to structural differences in the studies included. The Indian review included 13 studies with the diagnosis of neonatal sepsis based on laboratory testing, whereas our review included 36 studies, with 26 studies based on a laboratory-dependent diagnosis of neonatal sepsis and the remaining 10 studies based on clinical diagnosis. Data from studies that used clinical criteria exclusively to diagnose neonatal sepsis were included in our review and meta-analysis due to the fact that not all hospitals in Sub-Saharan Africa have access to validate the sepsis diagnosis with laboratory testing. Furthermore, the studies from the Indian review were solely from hospitals in urban settings, whereas the studies included in this review were conducted at both rural and urban hospitals. Risk factors for neonatal sepsis might be different in urban and rural settings.

Our findings add multiple risk factors to the risk factors identified in the WHO’s universal guidelines. In our meta-analysis we identify resuscitation at birth, low birth weight (<1.5 kg and 1.5–2.5 kg), low Apgar score at the first and fifth minute, prematurity <37 weeks, no crying right after birth, male sex, prolonged labour, multiple digital vaginal examinations, meconium-stained amniotic fluid and low socioeconomic status as significant risk factors for neonatal sepsis, none of which are mentioned in the WHO guidelines. However, further research is needed to confirm our findings and they do not necessarily imply expansion of the WHO criteria for prophylactic antibiotics. That is, in our meta-analysis, male sex is a risk factor, but we do not suggest treating all male children with prophylactic antibiotics. If more risk factors were to be treated with prophylactic antibiotics, the risk of overtreatment should be kept in mind since it could lead to high medical cost and use of resources and increased antibiotic resistance.²³ Alternative preventive strategies, such as in-hospital observation of the newborn and measurement of C-reactive protein (CRP), are used in high-income countries and could be feasible in some LMICs but also challenging, for example, due to lack of resources. Future research should focus on identifying the risk factors qualifying for preventive measures.

This systematic review and meta-analysis has several strengths and limitations. The broad search strategy and the combination of global and regional databases reduced the risk of missing relevant regional studies and ensured that the evidence in this review was derived from different countries and different hospital settings. The relatively high number of included studies is a strength. However, the geographics of the included studies make our findings not necessarily generalisable; Ethiopia and Nigeria together accounted for more than 50% of the included studies and many Sub-Saharan countries are not represented in this review. Furthermore, the countries in Sub-Saharan Africa differ in the level of hospital expertise, hygiene and medical tools, as well as in climate, diseases and bacteria, limiting the generalisability of the review findings. Another limitation is that the studies were heterogeneous; some were based on a clinical diagnosis of sepsis, some laboratory-dependent, some only examined limited populations, some were retrospective and some were prospective. The studies were also heterogeneous in regard to which risk factors to investigate (table 2). This heterogeneity makes them not perfectly comparable and is thus a limitation. The English language restriction is also a possible risk of bias and is a limitation. Africa has 29 francophone countries and it could be presumed that we could have missed relevant studies written in French. However, a quick search in PubMed with language restricted to French showed 105 studies, of which none was relevant to this review based on their English abstracts. The greatest limitation of this systematic review and meta-analysis is the overall poor quality of the included studies. The study designs used for risk factor analysis (eg, cross-sectional studies) differ from experimental designs and are more prone to bias.²⁴ Furthermore, multiple studies found some factors to be significant risk factors for neonatal sepsis, but when looking at the data, we found that the factors were protecting factors. Despite email correspondence with the authors, agreement was not obtained.

This systematic review and meta-analysis found multiple risk factors for neonatal sepsis in Sub-Saharan Africa, many of which are not on the WHO’s recommendations for prophylactic antibiotics. It has previously been emphasised that there is a need to develop clinical guidelines for prevention and treatment of neonatal sepsis that are specific to the Sub-Saharan African context¹⁰ and our review supports this notion. However, even though there are already multiple studies on risk factors for neonatal sepsis in Sub-Saharan Africa, there is a need for research of higher quality in the future as well as research in different settings in order to make presumptions, generalise on the topic or make multinational recommendations for clinical practice. National guidelines for Sub-Saharan African countries might also be beneficial due to differences in risk factors and bacterial agents among the countries. If new guidelines are to be developed, the challenges to implementation and resources should be kept in mind. There are still too many preventable neonatal deaths in LMICs, but with new preventive guidelines it might be possible to save thousands of lives.

Supplementary Material

Data availability statement

No data are available. The only original data published were the protocol of the study, which can be found on the PROSPERO web page (ID: CRD42020191067). The remaining data are published in the articles included in this systematic review and meta-analysis.

Ethics statements