Thursday, March 5, 2015

The Puzzling Case of GBS

1. What is GBS?
2. GBS in the United States
3. GBS and IAP Studies
4. The Source of GBS Rates
5. Examining the GBS Narrative
6. Fluctuating Variables
7. GBS Hospital Surveys
8. GBS by Gestation
9. GBS by Race
10. Late-Onset GBS
11. GBS and the Cesarean Complication
12. GBS False Negatives / Positives
13. GBS and Mortality
14. GBS at the State Level
15. GBS Around the World
16. Risks of IAP
17. Alternatives to IAP
18. GBS Conclusions

Your body is literally teeming with microbes - tiny organisms invisible to the naked eye.  In fact, you actually have more microbes than you do human cells.  Countless species of bacteria live in every nook and cranny you have to offer, from your skin, to your hair, fingernails, mouth, intestines, and colon.  For some, the thought of being covered in bacteria may be disturbing, but the reality is that we need them as much as they need us.  All of the bacteria in our bodies have coevolved with us, such that they perform essential tasks within our physiology and play a vital role in our immunity.1,2  They are quite literally indispensable to our health.

Of course, bacteria also have the propensity to cause illness, but it’s important to understand that there is a difference between being colonized with a bacterium and being infected by it.  Colonization involves a mutually beneficial (or neutral) arrangement, whereby bacteria live inside you without causing sickness.  Your body is a source of food and shelter for your microbes, and it is generally not in their interests to destroy their own habitat - in fact, the native bacteria within you actually protect and defend against invading pathogenic microbes.  Having said that, the microbiome is a dynamic system, in which the right set of conditions can lead to changes in the makeup, distribution, and behavior of our microbes…and thus, within certain contexts, normally harmless microbes can become harmful.1  So we are walking ecosystems, the balance of which directly relates to our well being.

There is a specific bacterium called group beta streptococcus (GBS) that is carried by 10-30% of the female population.3  This bacterium lives in the intestines, rectum, and/or vagina, and its colonization can be transient - that is, a woman may carry it this month, and not the next.4  Most of the time its presence is asymptomatic, but occasionally group-b strep can cause health complications such as urinary tract infection, or in the extreme, serious life-threatening infection in the form of sepsis, pneumonia, or meningitis.3,4  Infection in adults occurs primarily among elderly and those with medical conditions,5 but surprisingly, GBS infection is most common among newborn babies.  The consequences of neonatal infection can be quite grim: from long term neurological damage, to hearing or vision loss, to fatality.6,7  Fortunately such horrific outcomes are only a subset of overall infection cases, but even when no permanent damage is sustained, GBS neonatal infection remains a highly traumatic and disruptive ordeal for families.  

If this all sounds pretty scary, it should.  But don’t climb into your panic room yet - just as the majority of women colonized with GBS do not exhibit any adverse side effects, so too the majority of babies born to GBS colonizers do not develop infection.  In fact, the percentage of babies that develop a GBS infection is remarkably minuscule - between 0.5 and 2% of newborns born to GBS colonized mothers3,8 - in practice, this amounts to less than 2 cases of infection for every 1,000 babies that are born.  While such incidence is rare, given the devastating effects when GBS infection does strike, it certainly makes sense to attempt to reduce or eliminate its occurrence to the greatest degree possible.

There are two categories of infection that occur in newborns, early-onset and late-onset.  Early infection occurs within the first week of life, and late-onset between 7 and 90 days after birth.  Although both involve the GBS bacterium, they are evaluated separately.  Prevention efforts to date have been focused on early-onset infection.  

We know that early-onset infection takes hold in the vicinity of birth, because symptoms typically manifest within the first 24 hours of life.  There are a variety of maternal and labor risk factors that have been associated with it, the presence of which are believed to increase the likelihood of infection occurring, but a sizable portion of infections do not exhibit any clinical risk factors.9-11  GBS infection can manifest in both vaginal and Cesarean delivery, with or without prolonged rupture of membranes, and in both full term and preterm births, all of which leads to the deduction that the bacterium must be capable of traveling vertically up the vaginal canal to the uterus, wherein the baby is presumably swallowing amniotic fluid containing the bacterium.3,4,12

At the end of the day, we simply can’t predict when GBS infection will occur, but it seems self-evident that you cannot have GBS infection without the GBS bacterium being present in the first place.  To that end, GBS colonization is considered to be the most predictive and reliable risk factor, and accordingly the medical community in the United States has adopted a strategy of screening all women for GBS at 35-37 weeks of pregnancy, and then treating those with positive cultures using intravenous antibiotics during labor, commonly referred to as IAP (intrapartum antimicrobial prophylaxis).3

Testing is done at 35-37 weeks because it takes a few days for cultures to be analyzed, and results are required before the onset of labor (the timing of which obviously varies from woman to woman).  Given the transient nature of the GBS bacterium, this methodology allows for the possibility that GBS colonization status will change between the time of the test and the time of delivery.  So utilization of a “rapid test” in which a culture could be quickly analyzed on the spot during labor would be ideal, but such has not yet become available to clinicians.  Nevertheless, it is said that culture results obtained at 35-37 weeks match GBS status during delivery with 87-96% accuracy.3,13   

Now, if the prospect of administering antibiotics to every GBS colonized mother, when only .5-2% of their babies are at risk of developing GBS infection, strikes you as inelegant … that’s because it is inelegant.  However, IAP was not intended to be a perfect or permanent solution; it was intended to provide a temporary fix until a better solution was devised (such as a GBS vaccine)14 - and at the end of the day, it doesn’t need to be elegant, it just needs to work.  To that end, since adopting IAP protocols, the U.S. has observed its lowest incidence of GBS early-onset infection to date.  Success!  Case closed then, right?  Well, this is where things get interesting.

Below is a graph from the CDC3 showing GBS infection rates in the U.S. between 1990 and 2008.

Early-onset rates began to decline in correlation with statements from the gynecological and pediatric community, which outlined practices believed to be effective in reducing GBS infection, followed by definitive prevention recommendations by the CDC in 1996 and 2002.  The initial 1996 recommendations entailed a choice by the healthcare provider to utilize either a risk-based strategy (i.e. presence of risk-factors determine who receives antibiotics) or a universal screening strategy (treating anyone colonized with GBS, regardless of risk factors).  Then in 2002, based on a study comparing the effectiveness of both strategies, the CDC revised their recommendations to adopt universal screening only, which was found to be over 50% more effective.11

The above correlation is consistent with the claim that IAP reduces the incidence of GBS early-onset infection, but in and of itself, it does not constitute actual evidence.  It’s only an observation, and it’s important to understand that correlation is not synonymous with causation.  That is to say, two things can appear to be related to each other without a causal component being involved.  So the question is whether infection rates declined coincidentally with the implementation of IAP, or if they declined specifically because of IAP.  The latter is the belief, and it is certainly a sensible one.  However alternative scenarios could also explain the observation (for example, natural changes in GBS colonization or virulence).  So in order to determine if a correlation entails actual causation, you need to conduct clinical research, the gold standard of which is double blind randomized controlled trials - in the case of GBS, this would entail comparing the effectiveness of IAP to a placebo, such that neither patient nor provider knew what was being administered.

There are only a few randomized controlled trials that have tested the effectiveness of IAP.15-17  The CDC’s recommendations are fundamentally based on a handful of studies from around the late 1980’s, which demonstrated IAP was 80% effective in reducing GBS early-onset infection.18  The problem, however, is that those studies suffer from a wealth of flaws.  A review by the Cochrane Collaboration (a well respected research group) found a high risk of bias in a variety of areas “sufficient to affect the interpretation of the results” and which “seriously weakens confidence in the results.”  Ultimately the findings were held to be too flawed to inform clinical procedure, and the review concluded that “there is a lack of evidence from well designed and conducted trials to recommend IAP.”19  Nonetheless, the studies in question are the only randomized controlled trials that have been published to date on this issue (and of course, they did end up influencing clinical procedure).

Non-randomized and observational studies have been done to assess the impact of IAP.  To that end, many have shown IAP has a statistically significant effect in reducing GBS early-onset.20-24  However, other studies show effects that are not statistically significant,25,26 and some show IAP is of little value in treating low birth weight infants.27,28  There is also a 1993 meta-analysis of IAP research which concluded IAP is effective,29 but this was followed by a 1994 meta-analysis which concluded IAP’s effectiveness is not sufficiently supported by the available evidence.30  Then another study from 1999 concluded that the available IAP research was not suitable for formal meta-analysis, due to a wide variety of factors, limitations, and flaws, but that despite such shortcomings the data was not “compromised beyond utility,” and ultimately concluded that IAP is effective.18  

At the end of the day, double blind randomized controlled trials are the gold standard of research for a reason - namely, because anything short of these rigors has the potential to mislead.  This is why the paucity of clinical trials and the Cochrane analysis is troubling.  That being said, as one professional mentioned to me in conversation, there are practical and financial limitations to conducting randomized controlled trials for every single aspect of healthcare, and if such was a requirement for making policy decisions, nothing would ever get done.  This person illustrated the point with a colorful example, “would you advent a randomized controlled trial to evaluate the merits of a parachute?”  I would not.  However, the comparison is faulty, and regardless, GBS prevention was obviously an area in which such clinical research was deemed to be necessary, since a few trials were conducted.  So given the discrepancies in the research mentioned above, I’m left unsettled.

Now, if the quality of existing IAP research does not meet our highest standards, then why not simply conduct new clinical trials in the modern era to sort this out?  Well, from what I’ve gathered, it would be considered unethical to conduct such a study, because we can’t deny pregnant women with GBS access to effective treatment.  Of course, this is comical given the effectiveness of treatment is exactly what we’re looking to establish.  And moreover, is it not unethical to administer antibiotics to laboring women in the absence of reliable clinical evidence?

So we find ourselves back at square one.  The problem posed by this information gap is more than simply academic, in light of the fact that IAP is not without associated risks.  In weighing the costs of these risks against the benefits of preventing infections, naturally it’s important to know that IAP really is reducing GBS early-onset rates.  So before we explore the risks involved with treatment, we must utilize other means of analysis to further investigate the merits of IAP.

In the United States, GBS infections are tracked through the Active Bacterial Core surveillance network (ABCs), which monitors the presence of six different invasive pathogens in the general public.  It is a coordinated effort between the CDC, state health departments, and universities.  The network was officially established in four states in 1995, after which a series of expansions ensued and by 2004 it grew to comprise 10 states, where it remains today.31,32

Prior to ABCs, the CDC had established precursor sites that conducted population-based surveillance of GBS between 1988 and 1994 - these were subsets of what eventually became the ABCs.33,34  Before 1988, there is no population-based surveillance data for GBS.

The expansion of ABCs coincides with the observed decline in early-onset rates.  So we have to ask whether this expansion could be skewing our perceptions of GBS incidence over time.  To that end, because the rate of late-onset infection has been stable throughout the expansion, it is believed that the decline in early-onset is a genuine decline and not a surveillance artifact.35  In addition, disease trends within consistent surveillance areas have been reported to closely match trends when all 10 surveillance areas are combined.36

One other thing to note is that the current GBS surveillance network covers about 10% of the U.S. population.9  So there is a general question as to how reliable national projections based on 10% of the population are, and the CDC is aware that ABCs data may not be generalizable to the entire U.S.38  Nevertheless, by tracking the rate of infection within ABCs over time, we can observe disease trends within the surveillance population and glean useful information.  Having said that, it’s important to remember that ABCs can’t tell us why disease trends change or explain their behavior - it can only report the trend in and of itself.39  

Let’s take another look at the graph from earlier, showing GBS infection rates between 1990 and 2008.  

From 1993 onwards, the amount of hospitals implementing IAP began increasing, as well as the degree of compliance with national guidelines among hospitals (e.g. using appropriate media when culturing for GBS, taking both vaginal and rectal specimens when screening, etc).40-42  All of this correlates with the decline in GBS early-onset, although it is not clear how much credit can be given to IAP between the years 1990 and 1996 - while IAP had begun to be implemented in limited fashion during this period, the degree of compliance therein was far from optimal, yet rates were declining substantially nonetheless.10

The above graph begins at 1990, however a previous graph published by the CDC included data for the year 1989.43  Early-onset was listed somewhere between 1.4 and 1.5, with late-onset at 0.4.  I’m not sure why the 1989 figure was subsequently omitted.  

Also, the early-onset rate for 1990 is listed at around 1.8.  However, a population-based study published in 1992 reports an early-onset rate of 1.4 in 1990.44  There is a similar discrepancy between the rates of late-onset infection as well, cited at 0.3 in the study but listed higher by the CDC.  It seems that the CDC’s graph is adapted from a 2008 study36 in which GBS rates for 1990 were calculated from a surveillance population that did not include a region from the 1992 study’s surveillance population - the entire state of Oklahoma - and this could explain the discrepancy between the reported rates for 1990.  While small differences of this kind may seem trivial at face value, they can be crucial when assessing the effectiveness of a protocol that treats an inherently rare phenomenon.  Tiny alterations matter.

As to why researchers in the 2008 study would exclude Oklahoma from their 1990 calculation, this was not explicitly addressed, so one can only speculate.  Perhaps they felt its exclusion yielded a more consistent surveillance population (since Oklahoma did not end up becoming part of the ABCs network), and thus a more reliable comparison of GBS incidence over time.  However, the more data available, the more accurate the portrayal of disease burden will be, and since ABCs network expanded over the years anyway, I fail to see why the inclusion of Oklahoma in the 1990 calculation would be any more subversive than the addition of new states after 1995.  So I am uncomfortable excluding relevant data in this way.

Now, obviously GBS infections didn’t appear out of nowhere in 1989.  GBS as an infectious agent is said to have “emerged” in the 1970’s, for reasons unknown.4,37,45,46  There are isolated reports, prior to the establishment of surveillance networks, that cite early-onset infection rates of 2-3 per 1,000.4,9  However, these are based on single hospital studies and/or small geographic areas, which may or may not be accurately representative of overall disease incidence.14,34,44  Nevertheless, that’s all we have to go by.  

So let’s take a look at a new graph that I have assembled (click to enlarge), inclusive of all of the above information, along with additional surveillance data for 2009-2012.

An alternative narrative has now become visible.  If GBS infection rates were as high as reported in the 70’s and 80’s, then the obvious question is why did they decline of their own accord by 1990?  Going from 2-3 cases to 1.5 cases per 1,000 births is a rather significant change to have transpired without any IAP contribution.  If early-onset rates were already declining prior to the implementation of IAP, this would cast doubt on IAP’s causal role in their continued decline.  Of course, it’s possible that the estimated incidence of 2-3 per 1,000 in the 70’s and 80’s is not accurate - maybe it was actually lower or higher.  If lower (and there are reported estimates of 1.3 and 1.09 per 1,000),47,48 with rates stable or increasing leading into 1990, then this would be consistent with IAP’s efficacy.  But if higher (and there are reports of 5.1, 5.4, and even 10 per 1,000),11,48,49 then this would cast even greater doubt on IAP’s efficacy.

GBS wasn’t always a major cause of neonatal infection, and whatever factors led to the emergence of GBS, presumably changes in those factors would lead to changes in GBS incidence.  But since we don’t know the conditions that led to the emergence of GBS disease in the first place, we’re not in a position to identify if / when those conditions change.  Moreover, since we don’t have sustained reliable surveillance prior to IAP efforts (e.g. population-based surveillance for a 10 year period with no intervention efforts), we can’t presume to know what degree of fluctuation naturally occurs (if any), in order to compare against trends during the intervention era - by the time reliable surveillance began in the ABCs precursor sites, GBS was already on the radar of the medical community and it was not long before IAP began to be implemented in limited fashion.

In examining GBS disease trends, an important variable is colonization rates.  GBS colonization is not continuously tracked, so we extrapolate general colonization rates from various studies that have been done over the years.  The trouble is that there are a wide range of reported rates,22,49-57 so it’s no surprise that the CDC estimates between 10 and 30 percent of women are colonized…apparently colonization fluctuates.4   However, 10-30% is a rather large window, and it’s important to note that changes in overall colonization can have consequences to the overall incidence of GBS infection.

For the sake of discussion, let’s assume that 1% of colonized mothers have babies that develop infection.  At 4 million births in a year, an overall colonization rate of 10% would result in 4,000 infections, whereas a colonization rate of 30% would result in 12,000 infections.  That’s quite a difference!  So if colonization rates change from one period to the next, so too would the amount of infections automatically.  But of course, the percentage of babies that develop infection isn’t precisely 1%…it’s reportedly between .5 and 2%.3,8  Now we have another fluctuating variable.  Assuming a colonization rate of 20% among 4 million births, an infection rate of .5% would yield 4,000 infections - but an infection rate of 2% would yield 16,000 infections!  So the interaction of both of these variables can lead to increases or decreases, having nothing to do with intervention efforts.

Ideally, culture screening results should be part of the data regularly collected and tracked by ABCs, as this is the only way to factor colonization rates into an analysis of infection rates.  But alas, this is not the case.88  Nevertheless, it is important to realize that an incidence of 1.5 per 1,000 births within the context of a 30% colonization and 2% infection rate, means something very different than 1.5 per 1,000 births within the context of 10% colonization and .5% infection rate.  Without being able to track these variables, we cannot accurately interpret observed disease trends.  As one editorial stated: “We should keep in mind that colonization and infection rates due to GBS change over time, and the results we have seen following…guidelines may be only temporary associations without causal relationships.”58

Perhaps in an effort to get around these limitations, various hospital surveys have been conducted over the years, in order to calculate the proportion of hospitals implementing IAP and compare the infection rates between hospitals with and without IAP protocols.  

A survey of births from 1994 found that hospitals with a screening policy of any kind had fewer early-onset infections than hospitals without a screening policy.40  Another survey of births from 1996-1997 found hospitals that established or revised their IAP policies in 1996 had a significantly lower average amount of early-onset infections in 1997.59  Interestingly, there was also a lower average of early-onset infections among hospitals that did not have prevention policies from 1996-1997, however researchers assessed this decrease as not being statistically significant.  

Take a look at this graph from the CDC,41 illustrating the number of hospitals that established GBS prevention policies each year between 1989 and 1997.

The number of hospitals implementing prevention policies began slowly rising, and then skyrocketed in 1996.  The curious thing to me is that we don’t see a corresponding skyrocketing decline in GBS rates during this time.  Now, after a policy was established, it was presumably carried forward, adding to the total amount of policies overall.  So I have assembled a new graph, reformulating the same data to show the total additive amount of hospitals with prevention policies created since 1989 (i.e. every year includes previous years’ values) in conjunction with GBS early-onset rates.

Look at the rate of change between 1993 and 1999.  There is a steady decrease in early-onset infection (the blue line) during this period.  However, note that the rate of increase in hospitals with GBS disease prevention policies (the green bar) is not linear - it’s exponential.  After the 1996 consensus guidelines were issued, there were substantially more hospitals with prevention policies, and yet this exponential growth was not mirrored by exponential decline in infection rates.  Put differently, the rate of decline in GBS early-onset infection is not proportional to the rate of increase in IAP measures, even though the latter is said to have caused the former.

This discrepancy is all the more curious, given that there was also substantially greater compliance with prevention guidelines in hospitals after 1996.40-42,59  So not only were a significant amount of IAP protocols newly established in 1996, but all of the hospital protocols that were already previously in place had supposedly become more effective.  

To illustrate the importance of this, consider that the use of selective broth media when culturing for GBS is 50% more effective than alternative media in identifying GBS41,60,61 - the proportion of hospitals using this recommended media increased from 6% in 1994 to 47% in 1997.41  Similarly, universal screening is said to be over 50% more effective than a risk-based strategy11 - the proportion of hospitals that screened all women rose from 26% in 1994 to 52% in 1997.41  Screening at 35-37 weeks of pregnancy yields a colonization status more likely to match that at the time of delivery, compared with screening earlier in pregnancy - the proportion of hospitals that were screening at the recommended time increased from 22% to 65% between 1994 and 1997.41  And finally, a combined vaginal and rectal culture is 40% more accurate in identifying GBS than vaginal culture alone60,62 - the proportion of hospitals complying with this recommendation rose from 31% in 1994 to 75% in 1997.41

So I am left confused.  On the one hand, we have survey data showing hospitals with IAP policies have lower incidence of GBS.  On the other hand, there is a mismatch between the linear decline of GBS rates, and the exponential uptake of IAP policies and improved methodology.

This brings us to a 3rd possible narrative.  Namely, that IAP reduces early-onset infections and that early-onset rates are naturally declining on their own - in other words, that IAP is not 100% responsible for the observed decline of early-onset rates, but rather, is enhancing a pre-existing decline.   This scenario would mean that current assessments of IAP’s impact are an overestimation, and notably, it could account for the discrepancy between hospital survey data and GBS rates outlined above.  Of course, the only way to precisely ascertain the degree of IAP's effectiveness is through randomized controlled trials.

Preterm infants have a considerably higher rate of early-onset infection, compared with full term infants.9  Although IAP is said to be 78% effective in preventing early-onset infection in preterm infants,3 a substantial portion of preterm deliveries among GBS colonized mothers occur without IAP, because colonization status is often unknown at the time of delivery (as a result of not having had the standard 35-37 week culture), and despite CDC recommendations, not all practitioners administer IAP in preterm labors where colonization status is unknown.3  So it can be helpful to analyze GBS trends among full term and preterm infants, separately.  

To that end, early-onset incidence among full term infants has declined, in correlation with IAP.  I do not have gestational data prior to 1996, so an assessment of pre-prevention disease trends among full term infants is not possible.  There is an interesting spike in the incidence of preterm infants between 2003 and 2007, however no real conclusions can be drawn from this, due to the above referenced challenges of preterm screening.

There is a disparity in the rates of early-onset infection among whites and blacks, the latter being significantly higher.9,48  The degree of this disparity has diminished since the advent of IAP,64 however it continues to persist nonetheless.  

A similar disparity exists with respect to late-onset infection rates as well.36,63  There are multiple reasons believed to possibly account, or partly account, for this.  One is that in the areas under surveillance, blacks have a higher proportion of preterm births than whites.39,64  Since preterm birth carries a higher risk of GBS infection,3,36 a higher rate of preterm birth would naturally result in a higher rate of overall infection.  However, even when we factor preterm births into the analysis, infection rates for full term black infants remain higher than whites.9,36

Another factor is that black women are believed to have higher general rates of colonization.39,55,64-66  If so, higher colonization rates would be expected to naturally yield more overall infections.  In addition, some speculate that disparities in access to prenatal care could account for the racial discrepancy in GBS incidence.36  However, one study found that even when controlling for these variables, black race remained an independent risk factor for disease.48 

Now, it is interesting to note that incidence among black infants actually increased 70% between 2003 and 2005,39 during a time when universal screening was in full force, despite comparable screening rates and IAP administration for both black and white mothers.63  This increase persists even when we factor gestational age into the analysis.  To that end, both early and late-onset infection among black full term infants rose between 2003 and 2006.9,36  This increase should give us pause, as it flies in the face of IAP’s presumed efficacy - and even though the increase was only temporary, it speaks to the notion that there are other factors at work influencing GBS incidence.

While there have also been significant increases in the rates among black and white preterm infants at various points, as mentioned in the previous section, there are too many variables involved with preterm incidence to draw reliable conclusions.

While the incidence of GBS early-onset infection has decreased dramatically since 1990, rates of late-onset infection (those occurring 7-90 days of life) have remained stable.9  This is to say, IAP (giving antibiotics to laboring women colonized with GBS) has had no appreciable effect on the incidence of late-onset infections as reported from ABCs,3,36 and there are currently no prevention strategies in place to address it.3,4,32  This is partly because the GBS bacterium can be acquired post-delivery (e.g. from caregivers), but half of late-onset infections are believed to have a maternal origin at birth,36,37,53 which begs the question, why would IAP not have had some impact on late-onset rates?

Interestingly, a recent study of 322 NICUs between 1997 and 2010 found that rates of GBS late-onset actually increased.67  This increase correlated with the implementation of universal screening, which taken at face value, appears to suggest that IAP is “shifting” some of the burden of neonatal infections into later periods.  However, the researchers noted that a portion of the observed increase in late-onset infections may be attributable to the study having included more very low birth weight (VLBW) infants over time.  Such infants are more susceptible to infection (having less developed immune systems), and since NICUs in general treat more preterm and VLBW infants compared with other facilities, this could be introducing a bias that is not present within the ABCs dataset.  

That being said, a separate controlled study of full term infants found an association between IAP and late-onset infections.68  And an analysis of late-onset incidence within ABCs found about half of case-infants between 2003 and 2005 were exposed to antibiotics during labor.36  These associations may or may not be indicative of anything, but we have to consider whether it’s possible that ostensibly stable rates of GBS late-onset within ABCs would have been different in the absence of IAP (i.e. that late-onset rates would have declined, but now appear stable as a result of being offset by an increase from IAP, thus masking IAP’s effect).

Another thing worth noting is that the study of 322 NICUs included urine cultures in their analysis, an important source of neonatal infection in their estimation.67  In contrast, the study of late-onset within ABCs excluded GBS urine cultures from their analysis.36  So this may also play a role in the discrepancy between the datasets.

Regardless, reported increases in late-onset infection are outweighed by the decreases in GBS early-onset infection.  But if IAP is causing an increase in late-onset infections, then obviously this would change the cost-benefit ratio of IAP overall.

Cesarean birth does not reduce the risk of GBS infection in newborns.3  However, if a Cesarean is performed before the onset of labor, with intact amniotic membranes, then the risk of neonatal GBS infection becomes negligible and IAP is not recommended.3,4  This would likely apply to virtually all of the following situations:  1) Cesareans scheduled in advance by maternal request  2) Cesareans scheduled in advance because of maternal or fetal health concerns  3) Cesareans scheduled in advance by doctor request, in the absence of health concerns  4) repeat Cesareans scheduled in advance because no VBAC (vaginal birth after Cesarean) will be attempted.  It’s worth noting that the medical community does not advise electing Cesarean as a means of GBS prevention, because Cesarean birth introduces new health risks that outweigh the initial risk of GBS infection.69

Now, GBS rates from ABCs are calculated using the total number of live births that occur in the surveillance area.  “Live birth” refers to birth of a living newborn via vaginal or Cesarean delivery.  But if scheduled Cesareans entail practically no risk of GBS infection, and are not treated within IAP protocols, then we should exclude such births from our calculations of GBS incidence.  If we fail to do this, we will end up padding the numbers by including births outside the scope of GBS among the total births from which GBS rates are derived, and this will decrease the resulting rate of infection that gets calculated.  So we need to examine how many Cesareans are performed before the onset of labor with intact membranes, how that statistic has changed over time, and whether the resulting figures could potentially distort our evaluation of IAP.

This is easier said than done, because no one actually knows the percentage of Cesareans that fall into this category.  Only information included on birth certificates can be tracked at large by health institutions, and birth certificates do not include whether a Cesarean was scheduled or emergency,70 and ABCs does not collect such information either.  So any conclusions to this end are going to be educated estimates, rather than precise figures.  Nevertheless, it is worth attempting to sort this out.  

The Cesarean birth rate overall has dramatically increased since the early 1990’s, rising about 60% between 1996 and 2009.71  There is much debate as to why this rate has risen so drastically, but the relevancy to this discussion is that if the subset of Cesareans that are scheduled was the same or larger over time, then this would result in more padding each successive year during this period (all the more so given the number of total births within the surveillance population also increased each year until 200872).

There are varying estimates on the percentage of Cesareans by maternal request and the percentage of primary Cesareans (women undergoing Cesarean for the first time) without any indicated medical risk.73-76  Some of these estimates conflict, and some are from differing years.  But a study of California births in 1995 found that 4.25% of deliveries were attributable to primary Cesareans in the absence of labor.77  With respect to repeat Cesareans, it is not unreasonable to assume a substantial portion are scheduled, given the prevailing “once a Cesarean, always a Cesarean” mentality in the U.S.

When you factor everything together, I believe it is fair to estimate the percentage of Cesareans without labor or ruptured membranes as accounting for 5% of total births (or 25% of Cesarean births) in the mid 1990s, as some have done.10  It is believed that the proportion of scheduled primary Cesareans has been increasing since 199675 - and the proportion of scheduled repeat Cesareans undoubtedly increased between 1996 and 2004 (as the rate of VBACs declined significantly).75,78  So, it’s plausible that by 2009 (the year in which the U.S Cesarean rate peaked) 50% of Cesareans may have been scheduled in advance, which would be 16.5% of all births.  Of course, we’re not factoring in those women that go into labor prior to their scheduled Cesarean date, but these scenarios are probably rare enough as to be negligible for our purposes.

If we proceed using these estimates, we can re-calculate GBS infection rates for 1997-2009 while excluding scheduled Cesarean births from the analysis, and therein get a sense for how this variable might potentially alter our perceptions of GBS incidence over time.

While these graphs begin at 1997, obviously somewhere between the 1970’s and 1990’s the percentage of scheduled Cesareans was zero, at which point the two lines would overlap.  So the effect of including scheduled Cesareans within an analysis of GBS incidence is that the degree of decline in early-onset rates becomes exaggerated.  Of course, if the assumptions incorporated into these calculations are underestimations, then the discrepancy observed above would be greater, and vice versa.  In addition, a proper analysis would take into account state-specific Cesarean rates and live birth data for each area within ABCs network independently; but my use of national data is sufficient to illustrate the point.

Although the exaggeration depicted here is not significant enough to fundamentally alter overall trends, it’s certainly a variable that should be taken into account, and one that could become more subversive in combination with other potential fluctuating variables and/or in the event that the proportion of scheduled Cesareans continued to increase.

Even with perfect implementation, IAP is not expected to be 100% effective, due to some amount of antibiotic failures and changes in colonization status between the time of screening and delivery.4,10,14,79  However, there are reports of unexpectedly large portions of GBS infection occurring in infants whose mothers tested negative for GBS (i.e. false negatives).  In a study of early-onset infections from 1997-2003 at a Boston hospital, 82% of the mothers of term infants that acquired infection had negative screening test results.80  Another study of a Tennessee birth cohort found 52.5% of early-onset infections resulted from mothers who screened negative.81  Then in a study analyzing GBS incidence in ABCs 10-state network during 2003-2004, 61.4% of the GBS infections that occurred in full term infants were among mothers who screened negative for GBS.49

Now, universal screening at 35-37 weeks of pregnancy is said to have a negative predictive value of 96%3,13 - that is, 96% of the time if you’re not colonized with GBS at the time of screening, you won’t be during delivery.  So the question is if the 4% of negative screening results that we know will be inaccurate accounts for the amount of false negative infections seen in the studies mentioned above.   

To that end, the researchers of the ABCs study calculated the number of infections that would be expected to occur from false negatives - they took 4% of the women who tested negative for GBS, and then applied a rate of infection assumed to transpire in the absence of antibiotic treatment (remember, false negatives do not receive IAP).  Accordingly, they expected to see between 44 and 86 cases of infection.  The number of such infections that actually occurred was 116 cases.  It’s important to note, however, that the researchers assumed a GBS incidence of between 5.1 and 10 cases per 1,000 births in their calculations.  As previously discussed, such incidence was the highest among the ranges reported from the 70’s and 80’s.  If we instead use lower reports for the calculation, or if we use the 1990 overall incidence of 1.8 per 1,000 (since that rate was before IAP guidelines), then the discrepancy between the expected number of infections resulting from false negative cultures and those that actually occurred would be significantly greater than what was concluded in the study.

As to why this discrepancy exists, the researchers speculate it may be the result of a combination of factors such as screening more than 5 weeks before delivery (which decreases the accuracy of screening results), or inferior specimen collection, culture processing, and/or errors in the recording of screening results.  Regardless, if the assumed negative predictive value of screening is underperforming in practice, it stands to reason that the assumed positive predictive value of screening might also be underperforming in practice.  We can’t deduce false positives in the way that we can with false negatives, because false positives only result in unnecessary antibiotics - not infection.  

The positive predictive value (PPV) of universal screening is said to be 87%, which is the figure cited by the CDC and based on a study from 1996.3,13  However, a study from 2002 concluded that the positive predictive value of GBS screening is lower than that previously suspected - their results showed a PPV of 67%.82  This finding was supported by another study from 2010 also showing a PPV of 67%,83 while a study from 2006 showed a PPV of 52%.84  A systematic review of nine separate studies found an average PPV of 69%.85  These lower PPV’s are perhaps in keeping with a study that showed significant changes in GBS colonization occurred in just a 24 hour period, thus casting doubt on the predictive reliability of 35-37 week screening tests in general.86

Of course, rapid testing for GBS administered during actual labor would eliminate all of this ambiguity.  But the current confusion is relevant because IAP’s perceived success is built around the assumption that the mothers receiving antibiotics are the ones actually colonized with GBS - so if the accuracy of our determinations to that end are in doubt, with evidence showing prior assumptions of positive / negative predictive values to be inflated, then it means there are more colonized women not receiving antibiotics than we thought, and more non-colonized women who are receiving antibiotics than we thought - and this would necessarily change our evaluation of IAP’s performance to date.

In full term infants, GBS infection is said to be fatal in 2-3% of cases.3  To be clear, that refers to 2-3% of the 0.5-2% of infants that develop infection from the 10-30% of mothers that are colonized with GBS.  Suffice it to say this is a very tiny amount of overall births.  In preterm infants, the percentage of fatalities from GBS infection is higher, at 20-30%.3

Reports from the 1970’s cited fatality ratios as high as 50%,9,44,48,61 however by 1990 (prior to the IAP era) this amount had drastically declined to 5.8%44 - this reduction is credited to advancements in the quality of neonatal care.14,44,61  From 1990 to 2013, there are many gaps in the mortality data that has been published.  I could not find year-specific rates for early-onset mortality between 1991 and 1996.  ABCs surveillance reports from 1997 onwards list the number of deaths that occur per year in children less than 1 year of age, but they do not differentiate between early and late-onset, nor between full term and preterm.  This makes it difficult to perform a thorough analysis of GBS mortality over time, but the available information is worth examining.

Given the decline in the amount of early-onset infections in the U.S., logically there should be reductions in the number of deaths resulting from GBS each year (since less overall infections means less potential fatalities).  However, since ABCs network expanded between 1990 and 2004 (along with the population in general), this will mean a larger number of births get factored into mortality calculations over time (and more births means more potential infections), which could end up counterbalancing expected declines in the amount of deaths that occur each year.  So if we want to properly assess GBS mortality, we’ll need to look at the percentage of GBS infections that result in fatality (i.e. the case-fatality ratio), rather than the absolute number of deaths.

Here is a graph showing GBS case-fatality ratios, derived from ABCs surveillance reports between 1997 and 2013:

As you can see, case-fatality has increased since 1997, and has remained mostly stable since the advent of universal screening in 2002.  The question is, should this be the case?

If advances in neonatal care were single-handedly responsible for reducing mortality from 50% to 5.8% by 1990, then presumably any additional improvements to the neonatal care system after 1990 would also result in further declines.  Of course, while it seems reasonable to assume that some amount of neonatal care improvement took place during the 23 years between 1990 and 2013, there is no way to objectively confirm this or precisely measure the degree.

The next thing to consider is, how would we expect mortality rates to behave in the absence of IAP?  I would expect that the percentage of babies that die from GBS infection would remain the same without any IAP intervention (assuming equivalent neonatal care)…colonization rates and GBS incidence might fluctuate from year to year, but any acquired infection would presumably entail the same level of severity.

However, if early-onset rates declined because of IAP, then it seems reasonable to expect that case-fatality would also decline (with or without advances in neonatal care).  After all, IAP is eliminating or reducing the population of GBS microbes in the mother, thus preventing the baby from becoming colonized with GBS or otherwise colonized with a lower proportion of the bacterium.  So of the babies that still end up developing infection, the level of GBS in their system is less than it would have been in the absence of IAP, and as a result, this would presumably decrease the likelihood that infection would end in fatality.  It’s impossible to say how much decline we would expect, but we could reasonably expect some decline to occur.

Nonetheless, the case-fatality ratio in 2013 was the same as it was in 1990, and this doesn’t seem to comport with expectations from IAP or improvements in neonatal care.  This raises an interesting question - is it possible that IAP is increasing the severity of infection?  This could potentially occur if the GBS bacteria that survive the onslaught of IAP go on to create a more antibiotic resistant colony in the newborn.  Such would account for the discrepancy between expected declines resulting from neonatal care advancements and IAP, and observed case-fatality rates.  It could also account for why GBS case-fatality appears to have declined between 1990 and 1997 (reaching a low of 2.6%),35,44,72 before steadily climbing back up between 1997 and 2002 (the period of transition to widespread adoption and implementation of IAP36,).

It must be noted that this analysis is limited by a variety of information gaps.  The case-fatality trends in the above graph combine early and late-onset, and they do not assess the proportion of preterm births for each year - if there were increases in the proportion of preterm births within the surveillance population over time, this could inflate overall mortality figures (since preterm births are more prone to GBS fatality4,36).  In addition, there could be cases of infection / fatality between 90 days and 1 year embedded in the ABCs data used to calculate the above figures (although any amounts therein would very likely be negligible).  At the same time, we don’t know if 100% of the cases reported by ABCs for the years above had complete data (sometimes outcomes, gestational age, etc are not known for all reported cases of infection), so these calculations constitute a minimum estimation.

However, there is a population-based study of the ABCs network between 1990 and 2005, which found that late-onset mortality was lower in the era of universal screening (after 2002) than before the advent of IAP (prior to 1996).36  But note from the graph above that overall case-fatality temporarily decreased between 2002 and 2005, before significantly increasing in the years afterward - so it’s possible the findings of this study reflect a temporary association that was about to change.  Regardless, if the case-fatality ratio of late-onset within ABCs decreased after 2002, while the overall case-fatality remained stable on average, then by deduction case-fatality for early-onset would had to have increased.  This is in fact apparent in data from population surveillance for the specific years 1990 and 2004,32,44 data which is robust enough to offer a thorough comparison between the pre-prevention era and the IAP era.  Take a look at the following chart:

The overall case-fatality was higher in 2004 (when universal screening was in full effect) compared to 1990.  Early-onset case-fatality was higher in 2004 than 1990.  When we look at preterm births, case-fatality in 2004 was almost 3 times higher than in 1990.  Late-onset mortality was lower in 2004 than 1990 (outweighed by the aforementioned increases).  We still need to consider the possibility that 2004 had a higher proportion of preterm infections, which could have inflated it’s overall mortality - to that end, the percentage of deaths that were preterm was 80% in both years, and of the total GBS infections in each year (with complete data), 1990 had a higher proportion occur in infants less than 37 weeks gestation…and yet, 1990 still has a lower overall case-fatality compared with 2004.  I find this remarkable.

All together, it appears to suggest that while IAP may be decreasing the amount of GBS early-onset infections, it may be increasing the severity of the remaining infections that occur.

Interestingly, the study of 322 NICUs between 1997 and 2010 mentioned earlier in this article found increases in the mortality rate associated with both GBS and E. coli late-onset infection after universal screening was implemented in 2002 (increases of close to 50%), with stable mortality rates for early-onset.67  The researches speculate that improved survival of VLBW (very low birth weight) and preterm infants over time may be making them more susceptible to infection in the late-onset period.  However, while this may explain increased incidence of infection among VLBW and preterm infants, it’s unclear whether it would explain the increased percentage of fatalities resulting from those infections.  As I see it, if better neonatal care is allowing more VLBW and preterm infants to survive, then we should expect those same improvements in neonatal care to contribute to saving more of those babies that acquire infection (which would reduce the case-fatality ratio).  The fact that we don’t see this confuses me, and again speaks to the possibility of some kind of biologic or selective pressure at work, which is perhaps increasing the virulence of surviving microbes.  

Lastly, it’s also worth mentioning a study which found that when antibiotics were universally administered to neonates at birth (as an alternative strategy to IAP), overall neonatal mortality increased by 40% despite a 68% reduction in the rate of infection.79  Newborns are obviously exposed to IAP through placental transfer, so perhaps the mortality increases discussed in this section are in keeping with this study’s findings.  

In the end, everything we’ve examined here seems to point toward a net increase in case-fatality rates of one kind or another, and so I am left with the impression that IAP reduces the quantity of infections at the expense of increasing infection severity.

The GBS infection rates we have examined so far are representative of the entire ABCs network.  However, in combining data from multiple sources, there is the risk that averaging overall incidence can mask anomalous findings within isolated sites.  So it seems wise that we also examine state-specific GBS infection rates.  Of course, incidence within an isolated area is not a reliable predictor of national trends, but that is not the goal - we’re interested in assessing the effectiveness of IAP in the absence of reliable clinical research.  To that end, if antibiotics effectively reduce early-onset GBS infection, they should do so regardless of the location in which they are administered.  So the ABCs network can be viewed as a collection of separate regions testing the protocol independently, and we should see early-onset rates declining within each respective region in correlation with IAP.

There are two obstacles to this plan.  1)  Only a few of the 10 states that comprise ABCs network were tracking GBS prior to 1995.  However, seven states were tracking GBS from 1996 onwards, which may be of use in assessing the impact of universal screening guidelines.  2) There is no published study that comprehensively examines GBS incidence within each ABCs area for the entire respective history of surveillance - there are only a handful of studies that list state-specific rates, from which such an analysis can be conducted solely with respect to early-onset incidence between 1998 and 2005.32,35,39,64,87

Some states have published GBS data online, however much of the information is limited.  I inquired with the CDC as to how to obtain comprehensive state-specific rates, and they said I would need to contact each state’s health department or Emerging Infections branch.88  Accordingly, I have been in communication with 7 of the states with limited information, but my efforts have been met with very little success - this is mostly due to the fact that these offices are immersed in important workloads and busy schedules, and simply can’t spare the time to facilitate my request…of course, conducting this inquiry as a regular citizen unaffiliated with any institution doesn’t exactly help matters.

In my conversations with a few ABCs coordinators, I was surprised to learn that not all states are in possession of their own data.  I took it for granted that each ABCs state already had comprehensive GBS data specific to their region, and that it was just a matter of getting them to supply me with this information.  However, as it turns out, this is not the case - such information would need to be manually calculated for the first time, requiring the devotion of staff and resources.  It is baffling to me that any agency involved in tracking a disease would not by default have comprehensive internal records of that which they are tracking, but it seems that such information is simply sent to the CDC for integration.  Even still, one would think the CDC would possess compartmentalized records of each surveillance area’s findings, but apparently they either don’t, or otherwise did not wish to share such information with me.

I also got the sense that state-specific trends are generally viewed as unimportant, because the sites are collectively held to be representative of the country, and since assessing national incidence is the main goal of the CDC, isolated trends are essentially irrelevant.  However, this is extremely shortsighted in my opinion, because if you don’t look at state-specific trends, then you can’t ascertain whether a single site (or subset of sites) is disproportionately influencing the overall trend, nor can you ascertain whether all sites are conforming to national expectations.  Of course, even if a site did depart from national trends, there could be a variety of reasons accounting for why that is - but it seems obvious that we should be in a position to know if / when such departures occur, in order to be able to investigate them further.

So with all of that being said, let’s examine some limited state data I have been able to assemble.  Minnesota and Colorado both seem to comport with national trends.

On the other hand, in Connecticut it appears that universal screening has had no impact on early-onset infections.  There was a temporary dip in 2004, but by 2007 rates had increased higher than they were in 2001.

The impact of universal screening in Oregon is ambiguous, with no sustained effect apparent: 

With respect to the remaining states, the available information regarding early and late-onset infection is too limited to be useful, in my opinion.  

Now, it’s possible that the speed and degree of compliance with national guidelines might have varied in each state, and that this might explain the apparent lack of impact of universal screening on early-onset rates within Connecticut and Oregon.  However, based on a CDC analysis of per-state compliance before and after their 2002 guidelines, it is evident that this cannot account for the discrepancy observed, because adoption and implementation of universal screening within CT and OR was optimal.3

There is some additional per-state hospital data that is intriguing.  Take a look at this graph published by the CDC,41 comparing the relationship between the proportion of hospitals with GBS prevention policies and corresponding infection rates, per state.

What is immediately apparent is that the state with the most prevention polices (CT) has the lowest rate, and the state with the least prevention policies (TN) has the highest rate.  But now take a closer look at the middle section of the graph, and notice that Georgia and Minnesota have equivalent prevention polices, yet drastically different infection rates.  Also note that Oregon has a higher amount of prevention polices than Minnesota, yet also has a higher rate of infection.  And finally, note that Minnesota and Maryland have fewer prevention polices than California and Connecticut, yet comparable incidence.

So within the limited data we have examined, not everything is adding up.

There is one more item which I should mention, as it’s quite peculiar.  Georgia’s health department has published data on GBS in which early-onset rates are listed between 1994 and 2007.89  What’s curious, however, is that none of the rates match the figures separately listed by the CDC in connection with Georgia, despite the fact that the source for both is supposedly ABCs.  What makes this all the more curious is that Georgia’s self-published graph shows early-onset rates were increasing from 1995 to 1999, as well as between 2003 and 2007.

This increase is not mirrored in the limited data published by the CDC.32,35,39,64,87  I do not know what to make of this, as I find it hard to believe that either party could be in error.  

Nonetheless, Georgia’s publication explicitly states that the reduced incidence of early-onset observed in U.S. national data is not apparent within their state.  The publication speculates that the state’s increase could be a result of improved case-ascertainment stemming from expanded state-wide surveillance (which began in 2004) and audited surveillance (which also began in 2004 according to this document).  

However, if the expansion of Georgia’s surveillance network resulted in better detection and thus, higher reported incidence, then we would expect to see the same phenomenon occur within ABC’s network overall…which of course, we don’t.  Plus, the rising rates within Georgia’s publication occur within consistent surveillance periods (as opposed to rates jumping up only when the surveillance area expands).   In addition, while Georgia states that audited surveillance (which is said to improve the accuracy and yield of infection cases) began in 2004, it has been reported elsewhere that audited surveillance in Georgia was occurring as early as 1990,44 and ABCs claims to regularly audit surveillance in all of their territories.64,72

So I am quite confused.  I planned on getting to the bottom of this by contacting Georgia’s Emerging Infections branch to submit a data request for GBS rates and/or speak with the ABCs or GBS coordinator.  However, it turned out this was easier said than done.  After days of getting bounced around from place to place, I was unsuccessful in finding the appropriate office, and bizarrely, no one in the health department knew who oversaw this issue.  Eventually, a data coordinator at the health department contacted the State Epidemiologist for guidance on my inquiry, and many weeks later I am still standing by.  So for now, make of this what you will.

Exposure to GBS is said to be similar throughout the world among pregnant women, in developed and developing countries.12  Colonization runs the gamut, with reported rates between 1.6% and 36% depending on the region and year.4,19,90  In general, GBS incidence is said to be lower in countries and hospitals that implement some form of IAP protocols, compared to those that do not.91,92  Early-onset infection rates have declined, in correlation with IAP, in Canada,93,94 Spain,95 France,96 and Australia,97-99 which have adopted prevention strategies similar to the U.S.9  Needless to say, when the same exact correlation pops up independently in separate countries, a causal relationship becomes more compelling.

But as with the United States, things are not so straightforward.  There is limited GBS data available in Europe,100 and it appears many countries were not actively tracking GBS until around the time IAP began to be administered or guidelines were issued,101,102 thus preventing a comprehensive analysis of disease trends starting before IAP.  Furthermore, many international studies of GBS incidence stem from single hospital reports,103-106 and may not be adequately representative.  Amusingly, researchers concluded in one Australian study that IAP was the likely cause of GBS declines because early-onset infections from non-GBS pathogens also declined97 - by this logic, IAP would not be responsible for GBS declines in other countries (such as the U.S.3) where no such decline in non-GBS incidence occurred.  

With respect to Spain, an interesting curiosity was brought to light in a study of hospitals, which analyzed GBS incidence after prevention guidelines were established.101  Hospitals were grouped according to the year in which prevention guidelines were adopted: on or before 1998, and 1999.  Rates decreased in both groups after prevention guidelines were implemented, consistent with IAP’s effectiveness.  However, each group had differing degrees of decrease - rates declined 65% in the 1998 group, and 36% in the 1999 group.  Also interesting is that incidence of E. coli decreased in the first group (the group with greater GBS decline), but increased in the second group.  Lastly, sepsis mortality rates significantly decreased in the first group, but not for the second group.  This suggests to me that other important and relevant factors are at work, potentially skewing our evaluation of IAP.

In the U.K. and Republic of Ireland, where systematic screening is not practiced and IAP rarely administered,107 GBS early-onset infection rates have been .5 per 1,000 live births.19,107,108  This is markedly lower than what we would expect based on U.S. assumptions, and is comparable to the incidence among countries that implement universal screening.94  Some suspect the U.K. rate is a result of underreporting and/or differences in colonization rates,107 but there is no sufficient data to support or refute such assertions.  Interestingly though, the incidence of late-onset infections in the U.K. and Ireland between 1996 and 200412 was basically equivalent to the rate of incidence reported in the U.S. during the same period36…if differences in colonization between the U.S. and U.K. were responsible for the differences in early-onset rates, then presumably one would expect to see differences in the rates of late-onset as well.  

Some assert that incidence in England, Wales, and Northern Ireland has been rising since 2003 and that therefore universal screening should be adopted in the U.K.,109 however such claims are based on the total number of case reports per year, and thus misrepresent the true disease burden by not accounting for fluctuations in the birth population.  When analyzing rates per 1,000 live births, incidence of early-onset infection in these regions was identical in 2003 and 2013 (.37 and .38 respectively).110,111  On the other hand, rates of late-onset did increase during this period (from .18 to .23),112 but since no IAP protocol has ever been associated with decreased late-onset infection, it is reasonable to ask whether IAP is having unintended consequences in the late-onset period.

In Finland, overall neonatal GBS incidence (early and late-onset combined) declined from 3 per 1,000 to .76 per 1,000 live births between 1976 and 1994, in the absence of a universal screening policy or national guidelines.113-115  From 1995-2000, during which IAP was not routinely administered, early-onset was .6 per 1,000 live births,103 comparable to the U.K.

Norway adopted a risk-based prevention strategy in 1998, after rates had been climbing from 1985 throughout the 1990’s.117,118  The impact of their prevention guidelines is somewhat unclear, but it seems that early-onset rates were stable overall before and after their implementation (with late-onset increasing in 2005 and 2006).116,119  Curiously, the country experienced an unexpected and quite significant spike in GBS mortality in 2006, for reasons unknown.116,220  

The Netherlands also established risk-based guidelines in 1999, but although rates initially decreased after it’s implementation,121 a subsequent national surveillance study conducted to assess the impact of prevention protocols found that they did not lead to decreased incidence among newborns.  Rates were analyzed over a 25 year period between 1987 and 2011, and incidence was higher in the period after protocols were implemented.122

Then there’s Israel, India, and Greece, three countries in which incidence is remarkably low in the absence of prevention guidelines, with reported rates between .1 and .3 per 1,000 births.123-126  Overall incidence in the region of Southeast Asia has been reported as low as .02 per 1,000 births.91  A study of women in Zimbabwe actually found that colonization was not even associated with adverse outcomes (i.e. infection).125  And incidence within developing countries is generally lower than developed countries,12,92 though there are some exceptions.91  

Reasons speculated for the aforementioned discrepancies include differences in maternal colonization rates, differences in the virulence of GBS strains and serotype distribution, and differences in clinical diagnosis, however all of these speculations can be refuted by the available evidence.128  Other potential reasons include differences in the quality of surveillance, genetic differences among populations, and differences in the levels of maternal protective antibodies acquired by newborns.12  A compelling case has been made that factors relating to inherent immunity among mother and fetus play a crucial role in explaining why such a small percentage of newborns are susceptible to GBS infection in the first place, why it’s higher in preterm infants, and why some regions have lower incidence despite relatively high rates of colonization.129

All of the confusion outlined in this article makes it impossible to definitively ascertain IAP’s effectiveness and overall worth.  IAP might work as claimed…or it might not.  Of course, most practitioners in the U.S. undoubtedly believe that IAP is effective, but such assurance appears to be based on habit alone.  The dilemma becomes all the more pressing in light of the fact that the use of antibiotics is not completely risk free.

The most extreme risk of IAP is that of maternal anaphylactic shock, which has been documented in response to penicillin (the primary antibiotic used during IAP)4,130-132 and cefazolin (a secondary alternative).133  Women with an allergy to penicillin are obviously given alternative antibiotics, however, one documented case of maternal anaphylaxis (which led to fetal demise) occurred despite the absence of such an allergy.134  However, it must be stressed that anaphylaxis is extremely rare.1,4  According to the CDC, about 1 in 10,000 mothers will experience severe allergic reaction.135  Fatal anaphylaxis has been estimated at 1-4 per 100,0004,136,137 (although some feel this estimate is grossly inflated107).  Regardless, the incidence of maternal anaphylaxis is significantly more rare compared to the incidence of GBS infection, and thus IAP’s reduction of the latter is considered to outweigh the occurrence of the former.3 

IAP also has been associated with increased incidence of maternal and neonatal yeast infection.128  Yeast infection of the breast can dissuade some mothers from breastfeeding their infants.139  Other milder reactions to antibiotics include rash, which occurs in 0.7-4% of penicillin treatments.3

Increasing resistance of bacteria to antibiotics is a major concern in the health community, and this concern extends to IAP protocols.  GBS resistance to erythromycin, clindamycin, and ampicillin following the implementation of IAP have been documented,36,68,90,140,141 as well as E. coli resistance to ampicillin,142-146 however no resistance has yet been observed in penicillin.4,14,36,68,90  That being said, there has been increased penicillin resistance among non-GBS pathogens throughout the world,1 so perhaps it is simply a matter of time before we see the same with GBS, and to that end there are limited initial reports of reduced GBS susceptibility to penicillin in Hong Kong and Japan.147,148  

There is also concern that while IAP may be decreasing the rate of GBS infection, it may be increasing the rate of infection from non-GBS pathogens.  Some studies have demonstrated this with respect to E-coli (particularly among very low birth weight infants)67,140,146,149-152 and late-onset infection from gram-negative pathogens other than E. coli,145 however other research disputes this.9,14,98,153

In general, IAP reflects a philosophy of care that has become standard, in which antibiotics are overprescribed and widely administered as a preventative measure.  Such practices are a primary factor in increasing antibiotic resistance among microbes.154  When an antibiotic is administered, it doesn’t target one specific bacterium, nor does it affect one isolated location.  Rather, there are a variety of bacteria that are susceptible, over and above the “bad” bacteria for which the antibiotic has been prescribed, and after an antibiotic enters the bloodstream it gets circulated throughout the entire body, eliminating susceptible bacteria everywhere (both “good” and “bad”).1  So antibiotics aren’t snipers; they’re bombers.  

This must be appreciated because the more we use antibiotics, the more we select for resistance in the overall bacterial population; i.e. those bacteria with resistant genes that survive an antibiotic onslaught go on to reproduce, which leads to more bacteria with such resistance.1,154  As this compounds, antibiotic resistance increases, which makes them less and less effective.  The more bacteria susceptible to a given antibiotic, the greater the selection for resistance will be.1  Thus, we want to be diligent about our use of antibiotics (particularly broad spectrum antibiotics) and guard against their excessive use so that we don’t facilitate, expedite, and/or exacerbate the creation of “superbugs”, which puts everyone at greater risk of acquiring life-threatening antibiotic-resistant infections.  Additionally, we want to limit the likelihood that small and rare colonies of bacteria (what Dr Martin Blaser refers to as “contingency species” in his book Missing Microbes) will become permanently wiped out from any given antibiotic exposure, as the absence of such species decreases our microbial diversity, which ultimately makes us more vulnerable to future potential pathogens.1

Given the low incidence of GBS infection and the uncertainty regarding when infection will occur, the current IAP strategy necessitates treating a great many so as to save a tiny few, which results in multitudes of women receiving antibiotics who don’t actually need them.  And while penicillin G (the preferred choice for IAP) is narrower in scope compared to alternative options,3 it nevertheless kills a variety of bacteria over and above GBS.156  So about a million mothers will receive antibiotics each year, in our attempts to prevent roughly 6 thousand babies from acquiring infection.37  But of course, antibiotics administered to laboring women also engage their babies via placental transfer, which means about a million newborns are exposed to antibiotics each year through IAP as well.  Of course, 6 thousand neonatal infections is something to take seriously, but so is 2 million exposures to antibiotics.

This becomes particularly relevant in the context of a newborn baby’s microbiome, which begins forming during birth.  Prior to labor, the baby is essentially a blank slate, bacteriologically speaking.2  As the baby moves through the vagina during birth, fundamental microbes are picked up.  Additional microbes are then picked up from the mother’s skin, rectum, and the surrounding birth environment.  Then more through the breast milk, the initial feeding of which typically takes place within the first hour after delivery.  All of this colonization is essential to a healthy infant,1,155 and importantly, the species of bacteria picked up by newborns are not random, but the result of coordinated changes in the microbiomes of mothers that occur throughout pregnancy.1

There is thus concern that IAP may undermine the acquisition of this founding wave of microbes.  The antibiotic, which is administered at regular intervals every four hours, kills both GBS and non-GBS bacteria in the mother.1,156  So the question is what are the consequences of this?  Unfortunately the data is scant.  There have been some studies showing IAP altered the gut microbes of infants when penicillin, ampicillin, and gentamicin were utilized,157,158 and the same has been found with respect to general antibiotic exposure in the first days of life,159 but no studies have investigated the longterm implications of this159 (if indeed there are any).  There has, however, been some such research with respect to Cesarean births, and since Cesarean delivery bypasses the biologically designed processes of newborn colonization (through both surgical delivery and antibiotic administration), it very well may be a useful guide with respect to IAP.  

To that end, it has been shown that the gut microbes of babies born via Cesarean section lack species normally acquired during vaginal birth,1,160 and have differing distributions of colonized bacteria,155,159,161 and this alteration has been associated with an increased risk of certain health conditions such as asthma, obesity, celiac disease, and allergies.1,2,162,163  To be clear, Cesarean delivery in no way guarantees that infants will acquire such maladies, but the point is that this increased risk is a direct result of alterations to the microbiome.  Although the microbiomes of Cesarean and vaginally born babies do begin to converge over time,1 these initial alterations can impact the future health of individuals by modulating the distribution of microbes moving forward, as one study found a significant difference in the gut microbes of 7 year old children born vaginally and via Cesarean.164

It’s reasonable to question whether IAP may have similar effects.  In general, research shows that antibiotic exposure at young ages increases the propensity to become obese and develop asthma,1 and antibiotic exposure in utero has been linked to asthma, eczema, and hay fever.165  The use of penicillin in labor has also been associated with a 2.6-fold increase in respiratory distress among GBS colonized newborns.166  While the microbiome in some babies may end up compensating or making up the gap eventually, this may not be the case for other babies, and even if IAP alterations are only temporary, they nevertheless are occurring during a critical window in newborn development,155 the consequences of which need to be thoroughly evaluated.

What we can say for certain is that the microbiome matters, that birth is the genesis of it, and that IAP has some effect on its formation.  This is an area where research is ongoing, but one that must be factored into any cost-benefit analysis of current GBS protocols.

Ultimately, if we’re going to expose families and society to the risks of antibiotics, whatever they may be, then we better make sure the treatment actually does what we think it does.  Only then can one make the value judgement that the rare amount of newborn GBS infections avoided through treatment outweigh the rarer amount of maternal anaphylaxis resulting from treatment, that the benefits of reducing GBS incidence are worth the risks of fostering antibiotic resistance, and that altering the microbiome of a million babies is acceptable in order to prevent GBS infection in a few thousand babies.  Of course, for those prepared to make the aforementioned value judgements, the limitations of IAP research would appear to make it difficult to do so with confidence.

The most discussed alternative to IAP would be a GBS vaccine, the need and usefulness of which has been cited many times throughout GBS literature.  Research and development has been underway for many years and clinical trials are ongoing.9,12  In comparison to IAP, there are many benefits to a GBS vaccine, along with some drawbacks.9  Regardless, it is not yet available as an option.

Another alternative strategy implemented by some practitioners is the use of probiotics.  The intent here is to effect a microbiome in which GBS is decreased and/or replaced by alternative bacteria, thus circumventing the entire GBS dilemma.  Scientific research on probiotics is generally limited,1,159 but there is a clinical trial currently underway researching its application to GBS,167 so the jury is out.   Still, given the general lack of harm involved with probiotics,1 some find it prudent to take them despite the lack of clinical data.  If they are effective, it would make sense to take them early in pregnancy regardless of GBS status, so as to allow maximum time for the probiotic to build up in the system by 37 weeks.

From my perspective, looking in from outside the medical community, there appears to be a double standard in the way that GBS research gets interpreted and discussed.  Declining incidence among countries with prevention strategies is assumed to be attributable to IAP, while increasing incidence among such countries is assumed to be attributable to compliance failures.  Low incidence in countries with universal screening is assumed to reflect the efficacy of IAP, while low incidence in countries without universal screening or without routine IAP is assumed to reflect underreporting and/or differences in colonization or virulence.  Fundamental assumptions are rarely (if ever) questioned, and contradictory findings typically go without mention.  In bizarre fashion, the clinical trials that spearheaded the IAP era, the quality and reliability of which were harshly criticized by the Cochrane Collaboration, routinely get cited as if beyond reproach.

I am troubled by the general lack of concern that I have encountered over the issues discussed in this article.  Many are dismissive of the Cochrane analysis, and many feel the observed correlation between IAP and GBS rates in the U.S. is sufficient evidence by itself.  But we cannot rely on correlation alone just because it tells us what we want to hear, and the discrepancies outlined above warrant careful consideration.

Although the likelihood of modern trials appears to be nonexistent, it might be within the realm of possibility among countries without IAP protocols, or those without universal screening guidelines.  There could also potentially be useful information gleaned from a study of GBS among homebirths or birthing centers - such families may be more likely to decline antibiotics than families planning to birth in a hospital, which might yield sizable treatment vs no-treatment comparison groups.  To that end, the Midwives Alliance of North America (MANA) compiles and maintains a statistics registry of health data in which a retrospective analysis of this nature would be possible.168-171

In the meantime, families contending with GBS find themselves in a difficult position.  Assessing the risk of developing GBS infection against the pros / cons of IAP is not a straightforward evaluation, and comes down to one’s personal perspective.  Some are uncomfortable with the idea of receiving antibiotics during labor, but the pressure to acquiesce to prevention protocols can be extreme.  Of course, when doctors strongly recommend treatment with unwavering conviction for the safety of the child, it is not surprising that most women agree to receive them.  This is unfortunate, as health recommendations and decisions should be informed by science, and not based in assumptions, intimidation, and/or exaggerated fear.  Equally unfortunate is the vitriol encountered by families that choose to decline antibiotics - it is quite remarkable how such families can be vilified, despite the uncertainties in the research.

In the end, if the medical community is going to continue recommending that laboring women receive antibiotics as a routine preventative measure, then I would argue they have a moral obligation to acquire reliable clinical evidence of its efficacy.  And if / when we subsequently confirm IAP is as effective as currently believed, such will not end the conversation or debate as to whether IAP strategies are ultimately in the best interests of society…but at least we would have a valid discourse to that end, based on known effectiveness and not presumed effectiveness.

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