Abstract
Introduction
One in three women carry group B streptococci vaginally, which can infect the amniotic fluid even if the membranes are intact, or can infect the baby during delivery, causing sepsis, pneumonia, or meningitis. Very-low-birthweight infants are at much higher risk of infection or mortality, with up to 3% infected, and mortality rates of up to 30% even with immediate antibiotic treatment. Late-onset group B streptococcal infection begins after 7-9 days, and usually causes fever or meningitis, but is less often fatal compared with early infection.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of prophylactic treatment of asymptomatic neonates less than 7 days old with known risk factors for group B streptococcal infection? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found twelve systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: different antibiotics, monitoring and selective treatment, and routine antibiotic prophylaxis.
Key Points
Early-onset neonatal sepsis, typically caused by group B streptococcal infection, usually begins within 24 hours of birth, affects up to 8 infants per 1000 live births, and leads to death if untreated.
One in three women carry group B streptococci vaginally, which can infect the amniotic fluid even if the membranes are intact, or infect the baby during delivery, causing sepsis, pneumonia, or meningitis.
Very low-birthweight infants are at much higher risk of infection or mortality, with up to 3% infected, and mortality rates of up to 30%, even with immediate antibiotic treatment.
Late-onset group B streptococcal infection begins after 7-9 days and usually causes fever or meningitis, but is less often fatal compared with early infection.
We don't know which antibiotic regimen is most effective at preventing group B streptococcal infection in high-risk neonates.
Routine antibiotic prophylaxis given to low-birthweight babies after birth does not seem to be beneficial in reducing neonatal infection or mortality compared with monitoring and selective antibiotics.
Increasing peripartum antibiotic prophylaxis is associated with a shift in pathogens causing neonatal sepsis, with Escherichia coli becoming a more prevalent cause.
About this condition
Definition
Early-onset neonatal sepsis usually occurs within the first 7 days of life, and is typically caused by infection with group B streptococcus. About 90% of cases present within 24 hours of birth. One in three women carry group B streptococcus, which exists as part of the normal bacterial flora in the vaginal and anal areas. Infection can be transmitted by aspiration of group B streptococcus-positive amniotic fluid by the fetus. Symptoms of early-onset group B streptococcal infection may be non-specific, including temperature instability, poor feeding, excessive crying or irritability, and respiratory distress. Early-onset group B streptococcal infection typically presents with sepsis (69% of cases), leukopenia (31% of cases), pneumonia (26% of cases), respiratory distress (13% of cases), and, rarely, meningitis (11% of cases). Late-onset group B streptococcus infection occurs from 7-9 days of age, through to the end of the second month of life, and differs from early-onset group B streptococcal infection in terms of group B streptococcus serotype, clinical manifestations, and outcome. Late-onset infection typically presents with fever (100% of cases) and meningitis (60% of cases). This review deals with full-term and premature asymptomatic babies born with a known risk factor for group B streptococcal infection, but in whom a specific diagnosis of group B streptococcus (either by blood, urine, or cerebrospinal fluid) has not yet been made. The antenatal or intrapartum treatment of women with known group B streptococcal colonisation or infection is outside the scope of this review.
Incidence/ Prevalence
The overall incidence of neonatal bacterial infections is between one and eight infants per 1000 live births, and between 160 and 300 per 1000 in very low-birthweight infants. Group B streptococcal infection accounts for nearly 50% of serious neonatal bacterial infections. One survey conducted in 2000-2001 estimated that there were 0.72 cases of group B streptococcal infection per 1000 live births in the UK and Ireland and that, of these, 0.48 cases per 1000 live births were early onset, and 0.24 cases per 1000 live births were late-onset infection.Although the estimated incidence of early-onset group B streptococcal infection is 0.5 per 1000 births in the UK overall, incidence varies geographically from 0.21 per 1000 live births in Scotland to 0.73 per 1000 live births in Northern Ireland.Overall, the USA and the UK have relatively similar incidences. One population-based study (427,000 live births) carried out in the USA in 2004 found that the prevalence of early-onset group B streptococcus infections in the USA has decreased from 2.0 per 1000 live births in 1990 to 0.3 per 1000 live births in 2004. This is thought to be a result of the increasing use of maternal intrapartum antibiotic prophylaxis.
Aetiology/ Risk factors
The main risk factor for group B streptococcal infection in the baby is maternal group B streptococcal infection, which is transmitted in utero. Bacteria originating in the maternal genital tract can infect the amniotic fluid via intact or ruptured membranes. Neonatal infection can result from fetal aspiration or ingestion of the infected amniotic fluid. Infection of the neonate can also occur during birth, when the neonate moves through the vagina, with systemic infection occurring via the umbilical cord, respiratory tract, or skin abrasions. Other risk factors for group B streptococcal infection include prematurity, low birthweight, prolonged rupture of membranes, intrapartum fever, chorioamnionitis, maternal ethnicity (black and hispanic mothers are at increased risk compared with white mothers), endometritis, heavy maternal colonisation, and frequent vaginal examinations during labour and delivery. Lower maternal age (less than 20 years) and cigarette smoking have been suggested to be associated with an increased risk of early onset group B streptococcal infection, but these associations have not been proven. Other factors that may increase the risk of group B streptococcal infection include lower socioeconomic status, and maternal urinary tract infection during the third trimester (quantitative estimates of the increase in risk are not available). The role of group B streptococcal colonisation of fathers, siblings, and close household contacts in the development of late-onset group B streptococcal infection is unclear. For further details of risk factors for early-onset group B streptococcal infection, see table 1 . Late-onset group B streptococcus sepsis is predominantly associated with serotype 3, with cases evenly distributed, presenting from 8 to 90 days after birth.
Table 1.
Risk factors for early-onset group B streptococcal infection
| Study type | Risk factor | Risk for group B streptococcus infection |
| Systematic review | Maternal infection (group B streptococcus-positive vaginal culture at delivery) | OR 204, 95% CI 100 to 419 |
| Birthweight 2500 grams or less | OR 7.4, 95% CI 4.5 to 12.1 | |
| Gestation 37 weeks or less | OR 5.8, 95% CI 2.2 to 15.7 | |
| Rupture of membranes more than 18 hours | OR 7.3, 95% CI 4.4 to 12.0 | |
| Intrapartum fever greater than 37.5 °C | OR 4.1, 95% CI 2.2 to 7.6 | |
| Chorioamnionitis | OR 6.4, 95% CI 2.3 to 17.8 | |
| Prospective observational study | Maternal ethnicity: | |
| Black | RR 2.1, 95% 1.3 to 3.4 | |
| Hispanic | RR 2.0, 95% CI 1.1 to 3.6 | |
| Retrospective observational study | Cigarette smoking | OR 1.46, 95% CI 0.52 to 4.11 |
| Maternal age below 20 years | OR 2.57, 95% CI 0.96 to 8.61 | |
| Frequent (more than 6) vaginal examinations during labour and delivery | OR 2.9, 95% CI 1.1 to 8.0 |
Prognosis
Group B streptococcal infection is a frequent cause of neonatal morbidity and mortality. Untreated, mortality from symptomatic early-onset group B streptococcal infection approaches 100%. The combined morbidity and mortality in early-onset group B streptococcal infection exceeds 50%, despite the use of appropriate antibiotics and supportive treatment. In the UK, one study has estimated that early-onset group B streptococcus infection causes more than 40 neonatal deaths and around 25 cases of long-term disability every year, whereas late-onset group B streptococcus infection causes around 16 deaths and 40 cases of long-term disability every year. Even with immediate initiation of antibiotic treatment, mortality with early-onset group B streptococcal infection has been reported to be as high as about 30%. Mortality is particularly high: among babies born prematurely, with low birthweight; after prolonged rupture of membranes; and in babies who develop respiratory distress, sepsis, meningitis, or leukopenia. Even with aggressive interventions, premature infants have a 4-15 times higher risk of mortality compared with term infants with early-onset group B streptococcus disease. One population-based study (427,000 live births) carried out in the USA in 2004 found that the mortality rate for preterm infants with early-onset group B streptococcus infection was 23%. The morbidity rate in late-onset group B streptococcal infection has been estimated at 4-6%. Late-onset group B streptococcus infection typically presents as bacteraemia or meningitis. Less frequently, late-onset group B streptococcus infection may cause septic arthritis, cellulitis, or focal infections such as osteomyelitis.Late-onset group B streptococcal infection tends to have a less fulminant onset and is less often fatal than early-onset infection. One observational study reported a mortality rate of 14% with early-onset group B streptococcal infection compared with 4% with late-onset infection. Infants with a blood pH of below 7.25, birthweight below 2500 grams, absolute neutrophil count of below 1500 cells per mm3, hypotension, apnoea, and pleural effusion may be at higher risk of mortality. Little information is available concerning long-term sequelae for survivors of neonatal group B streptococcal infection.
Aims of intervention
To prevent morbidity, mortality, and complications associated with group B streptococcal infection, with minimal adverse effects of treatment.
Outcomes
Primary outcomes for this review are mortality, development of infection or sepsis, hospital length of stay or rehospitalisation rates, and adverse effects of treatments, such as ototoxicity, renal toxicity, and phototoxicity. Secondary outcomes are sequelae of infection (such as developmental delay or neurological abnormality, seizures, neurological sequelae, renal dysfunction, pulmonary disorders, immune dysfunction, necrotising enterocolitis, and malabsorption).
Methods
BMJ Clinical Evidence search and appraisal March 2007. We have included only studies of the prophylactic treatment of neonates with known risk factors for group B streptococcal infection. For this review, sources used for the identification of studies were: Medline 1966 to March 2007, Embase 1980 to March 2007, and The Cochrane Library 2007, issue 1. Additional searches were carried out on the NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE websites. Abstracts of studies retrieved in the search were assessed independently by two information specialists. Pre-determined criteria were used to identify relevant studies. Study design criteria included: systematic reviews, RCTs. We included single- and double-blinded studies, as well as all studies described as "open", "open label" or non-blinded. The minimum number of individuals in each trial was 20. The minimum length of follow-up was at least 2 weeks, with any proportion of participants lost to follow-up. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table.
GRADE evaluation of interventions for neonatal infections: group B streptococcus
| Important outcomes | Development of infection, mortality, hospitalisation, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of prophylactic treatment of asymptomatic neonates less than 7 days old with known risk factors for early-onset group B streptococcal infection? | |||||||||
| 2 (116) | Infection incidence | Early prophylaxis antibiotics v monitoring/selective antibiotic | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, methodological weaknesses and inclusion of quasi-randomised RCT |
| 2 (116) | Mortality | Early prophylaxis antibiotics v monitoring/selective antibiotic | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, methodological weaknesses and inclusion of quasi-randomised RCT |
| 1 (1184) | Infection incidence | Early prophylaxis antibiotics v monitoring/selective antibiotic (low-birthweight infants) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for lack of blinding |
| 1 (1184) | Mortality | Early prophylaxis antibiotics v monitoring/selective antibiotics (low-birthweight infants) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for lack of blinding |
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
Glossary
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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