Consequences of intrapartum antibiotic prophylaxis.
The last month’s entry focused on the risk of culture proven early-onset Group B Streptococcal (EOGBS) infection in term babies born to GBS positive people. Typically, if a pregnant person tests positive for GBS, the obstetric provider (obstetrician or midwife) will make antibiotic administration during labor sound like something that does not warrant much of a discussion. The parents are usually told that the GBS organism can cause serious infection and death in the newborn. However, the provider may not discuss the probability of infection and the likelihood of mortality related to GBS in a term baby; instead, most providers and sources conflate the findings for term babies with preterm babies, if statistics are presented. Additionally, providers tend to avoid discussing the negative effects of antibiotics. Adequate informed consent should include statistics that are relevant to a particular patient and effects of the treatment should embody information on both benefits and risks, as well as alternatives.
Term babies have less than 0.25% chance of developing culture proven EOGBS infection if they were born to GBS positive people who did not receive intrapartum antibiotic prophylaxis, IAP (see last month’s blog). Term babies who develop EOGBS infection have the following prognosis: 2% mortality (Stoll, 2011); 5% develop meningitis (Schrag, 2016), with 32% of those with meningitis sustaining neurological impairment (Kohli-Lynch, 2017); 25% will be stable enough to be cared for in a regular nursery (Stoll, 2011); and the vast majority will be discharged from the hospital without any problems after treatment (Schrag, 2016).
There are indications that arise during pregnancy, birth, or after birth, that warrant NICU admission for newborns to receive to receive a higher level of assessment, and treatment if needed. Assessing for possible GBS infection is one reason why a baby may be admitted to NICU. E. coli can cause newborn infection, and it has been theorized that the reason for the increase in E. coli and other Gram-negative neonatal infections may be related to prophylactic use of antibiotics for GBS (Simonsen, 2014). Additionally, reasons for NICU admission can be unrelated to infection, such as suspicion of injury related to a difficult shoulder dystocia, hypoxic injury related to impaired fetal oxygenation, etc. Still, term babies born to GBS positive people who did not receive antibiotics during labor are roughly 2 to 3 times more likely to be admitted to the NICU than babies born to GBS negative people (Brigtsen, 2015; Burman, 1992). Subsequently, about 4% to 5% of term babies born in the absence of IAP are admitted to the NICU for a variety of reasons (Brigtsen, 2015; Burman, 1992). Those babies who are suspected of having an infection will receive blood tests, chest X-ray, and possibly other tests depending on findings, to rule out infection. Many will receive empiric antibiotics until infection can be ruled out. Most of these babies will have good results and will be discharged from the NICU shortly. Some of the babies who remain in the NICU will have culture confirmed EOGBS infection, while others will have inconclusive results that indicate a probable infection.
Babies who are diagnosed with probable infection have a very different prognosis than babies with culture confirmed EOGBS infection. The prognosis for term babies with probable infection is: mortality less than 0.4%, pneumonia is common, but no cases of meningitis (Hakansson, 2006). The risk of a term baby developing some type of infection (either confirmed or probable) is 1.2% to 1.4% if IAP is not implemented (Brigtsen, 2015; Burman, 1992). Obviously, since the culture confirmed infection (associated with more serious outcomes) is less than 0.25%, then most babies being treated for infection as a result of GBS, have probable infection; therefore, a milder course of illness, a much lower mortality rate, and do not develop meningitis.
Hence, if we consider the more generous estimate of term newborns who get diagnosed with either confirmed or probable infection, we can say that some of that 1.4% of babies born to GBS positive people would benefit from IAP. Though we do not have quality evidence that antibiotic administration during labor reduces the chance of EOGBS infection (Ohlsson, 2014), there is a large body of observational evidence that suggests antibiotics, administered during labor to people who test positive for GBS, reduce the risk of infection by 80% (Russell, 2017). However, the focus on the babies who could benefit from antibiotics during labor ignores the 98.6% of babies who receive unnecessary antibiotics. This is an important consideration as those 98.6% of are exposed to the negative effects of antibiotics without any benefit. The rest of this article will review the risks of IAP.
Antibiotic resistance is on the rise; consequently, more antibiotics are becoming obsolete due to the fact that bacteria are becoming resistant, and novel antibiotics are added to the arsenal at slower and slower pace (Langdon, 2016). Additionally, when antibiotics are used without forethought, problems are created (Kolter, 2017). For example, there is evidence that the over-use of tetracycline starting in the 1940’s provided the opportunity for GBS to become the dominant organism leading to neonatal infections by the 1960’s; hence, due to an enthusiastic introduction of the antibiotic tetracycline, GBS effectively replaced GAS and Streptococcus pneumoniae as the most likely cause of EOGBS and late-onset GBS (LOGBS) infections (Da Cunha 2015; Kolter, 2017).
An unsettling thought is that even one course of antibiotic treatment can result in the development of antibiotic resistant genes amid the organisms that remain colonizing the person after treatment (Raymond, 2016; Seedat, 2017). Essentially, because the active properties of antibiotics are derived from molecules in nature, genetic evolution naturally allows for development of resistance. Moreover, the commensal microbes (the common, peaceful residents within us) can retain genes for antibiotic resistance after antibiotic exposure and share those genes through conjugation, transduction, and transformation with pathogenic bacteria (Raymond, 2016). Hence, the baby can be placed at higher risk of developing antibiotic resistant infections down the line. In fact, some research suggests that the use of IAP to reduce EOGBS infections results in an increase of LOGBS infections (Glasgow, 2005).
Another unfortunate effect of IAP, is the disruption of the microbiota (Seedat, 2017) or the bacterial ecosystems that inhabit our bodies. We are just starting to appreciate how vital these intricate and interdependent microbial ecosystems are to our health. Research consistently points to a greater likelihood of arthritis, inflammatory bowel disease, type 1 diabetes, obesity, allergies, and asthma related to impaired microbiota (Amenyogbe, 2017; Keeney, 2014). There is still so much we do not know about the effects of disturbing these bacterial ecosystems. We do have evidence that the impact of microbiota on future health starts very early in life; moreover, even transient disruptions of the microbiota have lasting consequences (Amenyogbe, 2017; Dzidic, 2018). The microbiota composition undergoes very rapid changes in the newborn and has the power to affect gene expression and the development of the immune system (Amenyogbe, 2017; Dzidic, 2018). What this means is that even temporary effects of antibiotics on the composition of microbiota, negatively impact immune development in such a way that it cannot be undone by restoring the microbiota at a later point. For example, babies who displayed certain microbial composition alterations at one week of age or at one month of age, had a greater tendency to exhibit allergies, eczema, and asthma later in childhood (Amenyogbe, 2017). Animal studies suggest that there are critical periods in the early development of the immune system, where a defect caused by an imbalance in the microbiota, cannot be fixed by eventually correcting the imbalance (Amenyogbe, 2017). The earlier in the infant’s life that the imbalance occurs, the more profound the impact (Amenyogbe, 2017). According to research, microbiota composition at 3 months of age was a better predictor of allergic reactions at 1 year than the microbiota composition at 1 year (Amenyogbe, 2017). Also, composition of the microbiota at 3 months was a better predictor of milk tolerance at 8 years old than microbiota from 6-12 months (Amenyogbe, 2017). In addition to possibly inducing long-term immune system problems, antibiotic administration also seems to have an effect on cognitive and neurological development via microbiota disruption (Dzidic, 2018; Leclercq, 2017).
There is a growing body of evidence to support that the use of IAP interferes with the newborn’s microbiota development (Azad, 2016; Nogacka, 2017; Stearns, 2017). In Azad 2016, healthy term babies had their stools sampled at 3 months and 12 months of age. Gene sequencing technology with PCR amplification was used to determine the operational taxonomic units. Microbiota diversity was calculated by Chao1 estimator of species richness and the Shannon diversity index. When the 113 IAP exposed babies delivered via the birth canal were compared to 42 babies delivered via the birth canal who did receive IAP, there was a moderate effect size from IAP on microbiota community structure at 3 months, but not at 12 months.
Nogacka 2017 trial evaluated the microbiota composition of babies born at term via the birth canal. There were 18 babies who were exposed to IAP for GBS and 22 babies who did not receive IAP. No antibiotics were used during pregnancy (aside from IAP) and for one month after the birth. Samples were collected at 2, 10, 30, and 90 days. Gene sequencing and amplification using primers was performed on the samples. Operational taxonomic units were determined and Chao1, Shannon, and observed number of OTU indices were calculated. Varying levels of dysbiosis (microbiota that had shifted from its normal state) were associated with IAP at each collection interval.
In Stearns 2017, term babies delivered via the birth canal were examined. Fourteen people received IAP for GBS while 53 did not. Analysis of the microbiota was performed via gene sequencing with PCR amplification. Sequences were clustered in operational taxonomic units and taxonomic assignments. The findings show an effect of IAP on the microbiota at 10 days and 6 weeks. Additionally, babies whose gestational parent received IAP for longer periods, had microbiota that showed perturbations at 12 weeks, indicating that longer treatment intervals have a longer influence on the composition of the microbiota.
There is evidence that the mircobiota of people who have GBS in their genital tract, may exhibit some deviations from microbiota composition of those without GBS (Bayo, 2002; Kubota, 2002; Rosen, 2017). Cassidy-Bushrow, 2016 investigated the likelihood that the presence of GBS has an effect on infant microbiome development even if IAP is not implemented. A total of 80 babies born to people with GBS were compared to 182 babies born to GBS negative people. Seventeen babies born to GBS positive people did not receive IAP. All babies had their stools analyzed at 1 month and at 6 months by gene sequencing, with compositional variation assessed by UniFrac, Canberra, and Alpha diversity indices. The findings suggest that GBS positive status partially contributes to the variation in microbiota composition of the infants at 6 months, but not a 1 month.
Aside from the impact on the microbiota and antibiotic resistant infections, the more obvious consequence of IAP, is an allergic reaction. In the general population, the incidence of an extreme life-threatening allergic reaction called anaphylaxis, in response to antibiotics, is 0.01% to 0.05% (Berenguer, 2013; Bhattacharya, 2010). Less severe reactions to antibiotics such as vomiting, inflammation of the colon, fever, swelling of the eyelids, and dermatitis occur in about 1% of people (Bhattacharya, 2010). The more common reactions like rash, neurotoxicity, yeast infections, and diarrhea occur in a higher proportion of people (Berenguer, 2013; Bhattacharya, 2010). An allergic reaction in the birthing person may have a devastating effect on the baby even if the adult recovers well. This is because a anaphylaxis compromises blood flow to the fetus, reduces oxygen delivery, and introduces risk of neurological damage in the baby (Berenguer, 2013). In an article Berenguer 2013, 10 cases of term pregnancies complicated by anaphylaxis triggered by antibiotics in the Penicillin family were reviewed. The results indicate good recovery in the adult in all cases. The findings among the babies are varied, 4 out 10 had good recovery, 4 had neurological damage, and 2 died. In a study (McCall, 2018) that described anaphylactic reaction to various medications among pregnant people, 41% of babies born to people with anaphylaxis were admitted to the NICU, but none died, and 38% of adults with anaphylaxis were admitted to the ICU, and 5% died.
In summation, the vast majority of babies exposed to prophylactic antibiotics for GBS experience no benefit from the treatment (Brigtsen, 2015; Burman, 1992); however, they do incur risks of altered microbiota development (Azad, 2016; Nogacka, 2017; Stearns, 2017). These consequences are chronic diseases, obesity, metabolic disorders, atopic disorders, and alterations in neurocognitive development (Amenyogbe, 2017; Dzidic, 2018; Keeney, 2014; Leclercq, 2017; Walter, 2011). The probability, timing, and severity of these conditions due to IAP cannot be determined at this time (Amenyogbe, 2017; Dzidic, 2018; Keeney, 2014; Leclercq, 2017; Walter, 2011). Additionally, babies exposed to IAP may incur the risk of antibiotic resistant infections at a later point (Glasgow, 2005; Langdon, 2016; Raymond, 2016; Seedat, 2017). Lastly, there is a rare chance that they and the birther may experience dangerous effects of an anaphylactic reaction to the antibiotic used for IAP (Berenguer, 2013; Bhattacharya, 2010; McCall, 2018).