Group B streptococcus (GBS) is the most common cause of sepsis and meningitis in infants less than 3 months of age (Heath and Schuchat, 2007; Stoll et al, 2011). Of those babies infected, about 10% die and half of those who suffer from GBS-meningitis have long-term neurodevelopmental problems (Bedford et al, 2001; Stoll et al, 2011; Edmond et al, 2012; Libster et al, 2012). In England and Wales the number of babies affected annually has risen significantly over the past 20 years (Lamagni et al, 2013). The current rates of infection are 62/100 000 live births, corresponding to 445 cases in 2013 in England, Wales and Northern Ireland alone (Public Health England, 2014), and around 40 neonatal deaths, excluding stillbirths, annually (Depani et al, 2011; Public Health England, 2012). Yet public awareness is low, with a recent survey showing that only one third of women of child-bearing age know about GBS (McQuaid et al, 2013). This article aims to discuss the prevention of GBS infection in infants, with a particular focus on the issues surrounding screening.
Group B streptococcus
Group B streptococcus, also known as group B strep or GBS, is a Gram-positive bacterium found in the genital and gastrointestinal tracts of both men and women (Edmond et al, 2012). In adults, carriage of the bacterium is usually asymptomatic but can cause urinary tract infections and may cause more serious infections in the elderly and those with diabetes (Lamagni et al, 2013). It is not a sexually transmitted disease but is spread through close contact and babies are at particular risk around the time of birth. Between 14 and 30% of UK women are estimated to carry GBS and of babies born to these women, approximately half will become colonised and 2–3% of those colonised will develop invasive GBS infection (Jones et al, 2006; Colbourn and Gilbert, 2007; Daniels et al, 2011). Infection may manifest as septicaemia, meningitis, pneumonia or, more rarely, skin infections (Gibbs et al, 2004). About two thirds of cases of GBS infection present within the first 6 days of life, known as early-onset GBS, but babies remain at raised risk until about 3 months of age (late-onset GBS) (Edmond et al, 2012). Presenting symptoms are usually non-specific, ranging from poor feeding, fever or jaundice to rapid collapse and death. GBS infection is treated with intravenous antibiotics, the duration of which varies with the type of infection, and intensive supportive care may be required (National Institute for Health and Care Excellence, 2012).
GBS prevention
Given the serious nature of GBS infection and the rapid onset of potentially overwhelming sepsis, preventing infection is highly desirable. This can be achieved in the majority of early-onset GBS infections if women with risk factors are given intravenous antibiotics, specifically benzylpenicillin, during labour at least 4 hours before birth (Fairlie et al, 2013; Ohlsson and Shah, 2014). Studies have shown that intravenous antibiotics are 91% effective in term babies and 86% in preterms at preventing invasive early-onset GBS infection (Fairlie et al, 2013). However, it is important to note that intrapartum antibiotics do not seem to have an effect on late-onset infection, which is less common (Schrag and Verani, 2013; Ohlsson and Shah, 2014). Clinical risk factors for early-onset GBS infection include intrapartum fever, prematurity, a history of a previous child infected with GBS, prolonged rupture of membranes and maternal GBS urinary tract infection during the current pregnancy (Royal College of Obstetricians and Gynaecologists (RCOG), 2012). One of the most important risk factors for GBS infection in the infant is maternal carriage—a factor which remains unknown for the majority of UK women given the lack of antenatal screening for GBS carriage. Both the UK National Screening Committee (NSC) and the RCOG advise against universal screening of all pregnant women and instead advocate a risk-based approach in which only women with certain clinical risk factors are given intrapartum antibiotics (RCOG, 2012; NSC, 2013). This is an unusual situation when compared to other developed nations—universal screening is the norm in the USA, Canada and much of Australia and Europe (Verani et al, 2010; Di Renzo et al, 2014). Screening usually consists of rectal and vaginal swabs taken around 35–37 weeks' gestation and plated on enriched culture medium (Verani et al, 2010). If a women tests positive for GBS carriage, or if the result is unknown at the time of delivery (including preterm delivery), she is offered intrapartum antibiotics (Verani et al, 2010).
The risk-based approach
The RCOG sets out the UK risk-based approach to try to prevent early-onset infection in the Green top guideline, ‘The Prevention of Early-onset Neonatal Group B streptococcal Disease’ (RCOG, 2012). The indications for intrapartum antibiotics include the incidental finding of GBS on vaginal swabs or GBS bacteriuria during the current pregnancy, suspected chorioamnionitis, maternal fever or those who have had a previous child affected by GBS infection (RCOG, 2012). Routine screening of all pregnant women is not recommended, although this is acknowledged within the guidelines to be based on the lowest evidence level (evidence level 4, expert opinion) (RCOG, 2012). Despite these guidelines, the recently published RCOG GBS audit found that 55.9% of obstetric units are offering testing to some or all pregnant women for GBS carriage, with 76% of these units doing so sometimes, or always, at the mother's request (RCOG, 2015). However, almost two-thirds reported using non-selective media for culture and almost a third reported that the testing method used was unknown (RCOG, 2015). Of note, 3.7% of hospitals reported offering universal antenatal screening for GBS. One such example is the London North West NHS Trust which, since 2014, has screened pregnant women at around 35 weeks' gestation using rectal and vaginal swabs and enriched culture media. The introduction of this programme has been well received by health professionals and pregnant women (McQuaid et al, 2015).
Although national guidelines advocate a risk-based strategy, studies have not shown any impact of this approach on GBS infection and the incidence of early-onset invasive GBS infection in babies in the UK has steadily risen from 0.28/1000 to 0.41/1000 live births during the period 2000 to 2010 (Lamagni et al, 2013). It is also important to bear in mind that both these data, and those available from Public Health England, are based on voluntarily reported positive blood/cerebrospinal fluid samples and exclude both stillbirths and cases of probable GBS infection. Given the challenges of obtaining positive cultures from the 1 ml or less of neonatal blood which is sent for culture, it is perhaps not surprising that simply using positive cultures as a measure may result in at least a 50% underestimation of the true burden of this infection in newborn babies (Luck et al, 2003). Therefore, these ‘hidden’ cases should be considered when analysing the impact of infection and screening. The UK is not the only country using a risk-based approach that has seen a rise in GBS infection. In the Netherlands, Bekker et al (2014) have shown the rate of GBS infection has increased by 60% over a 25-year period despite the introduction of risk-based prevention guidelines in 1999 and the authors are calling for a reassessment of the risk-based prevention strategy.
‘Between 14 and 30% of UK women are estimated to carry GBS and of babies born to these women, approximately half will become colonised and 2–3% of those colonised will develop invasive GBS infection’
One important reason that could partly explain these finding is that a number of babies (33–43% in UK studies) who go on to develop early-onset GBS infection have no identifiable clinical risk factors and the presence, or absence, of risk factors correlates poorly with maternal GBS carriage (Heath et al, 2004; Jones et al, 2006; Vergnano et al, 2010; Daniels et al, 2011). There is also evidence to suggest that the guidelines are not being fully implemented. Vergnano et al (2010) carried out a UK study (conducted after the introduction of the RCOG guidelines in 2003), which showed that many women with known risk factors were not receiving appropriate intrapartum antibiotics: of mothers whose babies went on to develop early-onset GBS infection, only 19% of those with identifiable risk factors had received appropriate intrapartum antibiotics. The study estimated that 23 cases of neonatal GBS infection (47.9% of the total cases) could have been prevented if appropriate antibiotics had been given (Vergnano et al, 2010).
Therefore, the current risk-based approach to prevent early-onset GBS infection in the UK is unsatisfactory with little or no evidence that it is working to reduce infection in neonates. It is therefore useful to consider other strategies, such as that of routine antenatal screening for GBS carriage.
The case for and against universal screening
In 2012, the UK NSC decided not to recommend universal screening of pregnant women for GBS carriage (NSC, 2013). While some of the points against screening remain valid concerns, much of the evidence surrounding GBS screening is open to interpretation.
Both the RCOG guidelines and the NSC refer to a lack of evidence that antenatal screening is effective in reducing GBS infection (RCOG, 2012; NSC, 2013). A Cochrane review found that the use of intrapartum antibiotics did reduce early onset GBS infection but did not find an effect on mortality and commented on the lack of good-quality randomised control and risk of bias (Ohlsson and Shah, 2014). However, this review only included 4 studies, 3 of which were over 24 years old (Ohlsson and Shah, 2014), with a total of only about 500 women. The reviewers also commented that it is unlikely that further large randomised control trials will take place given the widespread introduction of screening outside of the UK. It is therefore important to look what other evidence is available.
Prior to the nation-wide introduction of screening in the US in 2002, either a risk-based approach or screening with intrapartum antibiotics for women found to carry GBS was considered acceptable (Centers for Disease Control and Prevention, 1996). A multi-centre, retrospective, cohort study was conducted which compared 5144 randomly-selected mothers, about half of whom had been screened (Schrag et al, 2002a). It found that the risk of early-onset GBS infection was significantly lower in babies born to women who had been screened, even when correcting for potential confounders such as premature birth (Schrag et al, 2002a). These findings led to the national recommendation in the USA that all women should be screened (Schrag et al, 2002b). Since then, population studies have shown that the incidence of early-onset cases has continued to fall (Jordan et al, 2008) with an estimated 70 000 cases prevented by a combination of national guidelines regarding intrapartum antibiotics and screening (Schrag and Verani, 2013). While it is important to note that the US previously had much higher rates of GBS than the UK, by contrast over this period the UK incidence has steadily increased (Lamagni et al, 2013). Other countries that recommend screening, such as Australia and Spain, have also shown a decrease in rates of early-onset infection (Daley et al, 2004; López Sastre et al, 2005; Angstetra et al, 2007). The NSC and the RCOG warn against extrapolating data from other countries and it is important that these results are interpreted in context; however, there are no UK-based trials and it seems unlikely that there will be any in the future. Therefore, the available data have to be used, and these indicate that screening and intrapartum antibiotics significantly reduce infection rates.
Methods of screening
There are some issues regarding how well culture-based tests on swabs taken at 35–37 weeks gestation predict whether a woman will be carrying GBS at the time of birth, with the sensitivity and specificity ranging from 51–87% and 93.7–97.1%, respectively (Di Renzo et al, 2014). This is an important issue as the screening test may miss those who become colonised late on in their pregnancy and could lead to overtreatment of those who have a positive screening test but would then go on to clear the bacteria themselves before birth. Women who go into premature labour before they have been screened would also be missed, as would women who do not attend antenatal care.
There are alternatives such as rapid polymerase chain reaction (PCR) tests on rectal and vaginal swabs, which can be taken when a women arrives in labour and provide a real-time result. These have proven in the UK setting to be significantly more sensitive and specific than the risk-based approach and are highly acceptable to pregnant women (Daniels et al, 2011). A Swiss study compared the results of both culture-based swab tests and a PCR method that could be used by staff on labour ward and found that the sensitivity of the PCR (compared to culture) was 85.71% and specificity 95.66%. It reported no significant difference in sensitivity or specificity between samples tested by staff in the laboratory and those directly tested on labour ward (Mueller et al, 2014). For the samples tested by labour ward staff, results were ready in a mean time of 165 minutes; however, between 13.4 and 23.5% of the labour ward PCR samples were invalid compared to 8.5% of those tested in the laboratory (Mueller et al, 2014). In addition, these methods are expensive, not as widely available and do not provide antibiotic sensitivity data (important for those who are allergic to penicillin). Even the relatively rapid turn-around of a PCR may not leave enough time for the administration of adequate intrapartum antibiotics, particularly as women in the UK are encouraged to stay at home until labour is established. Therefore, antenatal culture-based screening remains an important tool. A recent European consensus has recommended that universal screening be implemented using a combination of culture-based screening, particularly for women with history of penicillin allergy, and rapid PCR testing for others, with intrapartum antibiotics given to both those testing positive for GBS and those with risk factors such as a previously affected child (Di Renzo et al, 2014). This approach would also cover babies born prematurely who might not yet have reached the gestation for screening but remain at even higher risk of GBS infection.
Other issues surrounding the use of intrapartum antibiotics
As highlighted by the NSC, identifying women who are carriers of GBS is not the only factor to consider; the impact of administering prophylactic antibiotics to potentially up to 30% of pregnant women must also be considered. As discussed above, the majority of babies born to mothers who carry GBS do not suffer any adverse consequences and it is not possible to predict which babies will become unwell. However, women should be given the information in order to make an informed decision whether to accept intrapartum antibiotics or alternative strategies, such as enhanced observation of their newborn. In the years following the introduction of screening in the USA, the proportion of women receiving intrapartum antibiotics only rose from 26.8 to 31.7%, suggesting the impact on day-to-day practice may not be as dramatic as predicted (Van Dyke et al, 2009).
The appropriate use of antibiotics is an important issue which critics of GBS screening have raised; however, the short duration and highly targeted nature of intrapartum benzylpenicillin for GBS prophylaxis could be seen as an example of good antibiotic stewardship. GBS remains exquisitely sensitive to benzylpenicillin with only very rare, isolated reports of resistance in Japan (Castor et al, 2008; Panda et al, 2009; Kimura et al, 2013; Lamagni et al, 2013). Caution must be taken with women who give a history of penicillin allergy as clindamycin, clarithromycin and erythromycin resistance rates are on the increase, emphasising the need for culture-based screening which can also determine antibiotic sensitivities (Public Health England, 2012; Lamagni et al, 2013). Anaphylaxis to antibiotics is also highlighted as a potential concern but this is rare with only four published episodes related to GBS prophylaxis since 1996 in the USA, none of which were fatal (Verani et al, 2010).
The UK NSC also highlights the lack of information of the long-term effects of antibiotics in labour. This is certainly an area that requires further research. The long-term effects of GBS infection are much clearer—10% mortality, and significant neurodevelopment problems for a number of survivors. The mortality and morbidity figures also hide the impact of GBS infection on many babies and families who survive with no obvious long-term consequences. Many of these babies will have required admission to neonatal units, resulting in separation from their mothers and some may have required intensive care involving intubation, multiple intravenous lines, and invasive tests such as lumbar punctures. Fortunately, the majority will survive but the impact of this experience will be long lasting for them and their families.
Cost-effectiveness is another important factor; however, UK-based analyses have concluded that, not only is the current risk-based approach not cost-effective, the preferred option may well be to treat all high risk women, including those giving birth prematurely, and screen the remaining low-risk population of pregnant women (Colbourn et al, 2007; Kaambwa et al, 2010). As mentioned above, some UK hospitals have already decided to fund antenatal GBS screening for pregnant women.
Late-onset GBS infection and GBS vaccination
One limitation of intrapartum antibiotics is the lack of impact on late-onset infection (Jordan et al, 2008), although these account for a significantly lower proportion of cases. The introduction of screening could still help by improving awareness of both GBS and the signs and symptoms, which parents need to be aware of—an important issue given the lack of awareness about GBS in women of child bearing age in the UK (McQuaid et al, 2013). Raising awareness of symptoms of late-onset GBS infection empowers parents and health professionals to seek early treatment, potentially resulting in better outcomes for the babies.
Antenatal vaccination against GBS could provide the answer to many of the problems surrounding screening and intrapartum antibiotics. These would no longer be required as women could be vaccinated around 28–35 weeks and the antibodies produced could protect their babies both during and after birth, thus reducing both early and late-onset infection. A potential vaccine candidate has been tested in over 300 pregnant women in South Africa and large-scale clinical trials are due to start in the next year. However a fully-licensed and available vaccine is at least 5 years away (Madhi et al, 2013; Slobod, 2013).
Conclusions
GBS is a very serious condition and the incidence in this country is on the rise. It is therefore particularly important that midwives in the UK are well equipped to discuss the complex issues surrounding antenatal testing with the women under their care, are vigilant about identifying those whose babies are at higher risk of GBS infection and are able to educate about the signs of GBS infection in the newborn. We do have the means to reduce early-onset infection through the use of intrapartum antibiotics if we can properly identify those who should receive them. It would be naively optimistic to suggest that the introduction of universal screening would mean the end of GBS infection; however, the current risk-based approach used in the UK is not working and we could be doing much more to prevent babies and their families suffering from this potentially devastating infection.