4. Datos y metodología
5.2 Modelos de regresion logísticos
5.2.4 Presencia de algún problema en general
This is the first attempt to systematically review whether bacterial load or bacterial molecular markers are associated with GBS transmission from maternal colonisation, or progression from neonatal colonisation to EOGBS. I applied an extensive search with no date limit to capture as much data as possible. I included microbiology, infectious disease and obstetrician and gynaecology expert input to review the methodology and the findings to ensure that the review made clinical sense. I also involved methodologists and meta-analysts to ensure the systematic review and meta-analysis processes were performed correctly according to best practice. Furthermore, I enlisted second reviewers to duplicate study selection and quality assessment as well as cross-check data extractions, in order to maximise the quality of the review and minimise any errors.210
However, there are some limitations that must be noted. I excluded studies in languages besides English, therefore, there is a possibility that I may have missed prognostic studies in non-English speaking countries. Examining the studies included in this review highlights that the majority of the studies were from the US followed by Europe. Only one study was from the Middle East and one was from Africa. Many countries were not represented and it is not clear whether such studies exist in these countries. This could increase selection bias and question the external validity of the findings. Similarly, as I did not contact the authors directly, I may have missed some information where it was missing or unclear in the study report. Doing so could have clarified the data and the study could have added more value to the review.
As part of the exclusion criteria, I removed studies where participants were given IAP or studies conducted in the context of IAP. This decision was to reduce the bias from IAP interfering with the natural history of GBS transmission or progression to EOGBS. An unintended trade-off might have been that more recent studies were excluded as a result. As IAP is the recommended prevention for GBS, it may now be less feasible to study untreated women only. In the full-text sift, however, there were only four such studies. As there was a sufficient amount of data, I also excluded case-series and case-reports. Again, this could have increased the amount of data included from the literature as there are laboratory studies on small numbers of EOGBS cases. However, these studies have few conclusive implications for clinical practice as the exposed groups with disease cannot be compared with controls.272
6.6.4 Research and policy implications
The stubbornness of EOGBS combined with the harms from IAP underscore the need for more effective screening and/or prevention. With a large number of women who would be over-treated with IAP (due to the poor accuracy of antenatal culture) in addition to the growing list of potential harms associated with IAP, a more refined approach might be required. Antibiotic resistance, in particular, is a major international threat and, while GBS remains almost universally susceptible to penicillin,86 0.2% of GBS isolates had reached the upper
level of susceptibility for beta-lactams in the US in 2005,182, 18 and 5% to 15% of GBS isolates
were described to have reduced penicillin susceptibility in Japan.183 Clindamycin and
erythromycin resistance has also been increasing in the last 20 years.14, 18, 297 Bacterial factors
such as bacterial load, serotype, sequence type and the more precise isolate characterisation through genome sequencing, could provide innovative opportunities to target patients with
only the hypervirulent strains of GBS, limiting the risk of harmful outcomes from widespread IAP and potentially reducing under-treatment . Bacterial load is the most promising of the factors as, despite the dissimilar measurements, it was consistently associated with GBS transmission and EOGBS. However, the current evidence has important drawbacks as discussed in Section 6.6.1.
To better understand the mechanisms of GBS and confirm that heavier bacterial load or GBS serotype III is determinant of EOGBS, larger and better-controlled studies are required. The identified factors could be studied separately and, in combination through risk factor models (possibly along with other clinical and demographic risk factors), in order to more accurately predict the mothers that will transmit GBS and have a neonate with EOGBS. Such a study may be challenging as IAP is the recommended treatment, however it may be possible that these risk factor associations and models could be investigated in prospective cohort or case- control studies in contexts where IAP prevention is not adopted, for example, in Africa or Asia. It may also be possible to conduct retrospective studies on databases from countries that already have a GBS screening policy for pregnant women at 35 to 37 weeks. Analyses could be performed on women who were screen-positive but not treated. This may be a small proportion of all screen-positive women (treated mothers would have to be excluded) but combining data across years and across countries could potentially provide a large enough database for the statistical power required. It might also be worth systematically reviewing whether serotype, bacterial load and other factors are associated with the risk of GBS transmission and EOGBS in the presence of IAP.
Although the findings from this review, particularly on heavy bacterial load but also on serotype III, could possibly be involved in guiding future prevention interventions, they cannot be currently used for clinical practice. Due to the uncertainties in the evidence, the factors identified can only be used as a starting point to guide future research on the mechanisms predictive of GBS vertical transmission and EOGBS. For now, it is still not known why some women transmit GBS to their neonates and why some neonates develop EOGBS, while others do not. Consequently, the screening criterion on the understanding of a condition’s natural history, which needs to be fulfilled for the introduction of GBS screening, remains unmet.
6.7
Conclusions for this chapter
Findings from this chapter have highlighted that serotype III and heavy bacterial load may be important factors associated with GBS transmission and EOGBS. However, most of this evidence is at high risk of bias, therefore, confounding variables might be distorting these associations.
Furthermore, most of the evidence has been published before the year 2000 and it is not clear whether findings are as applicable today as they were around 20 years ago.
More effective prevention and therapy are needed to combat the persistence of EOGBS and the harms from IAP treatment. Future prevention interventions could target particular serotypes or sequence types and high bacterial load.
In particular, there is good evidence to investigate the association of the bacterial load as it was strongly and consistently associated with GBS vertical transmission and EOGBS.
Beyond these bacterial factors, wider research on the mechanisms that underlie the natural history of GBS vertical transmission and EOGBS is essential for the development of new interventions. The factors identified here, in addition to other pathogenic, clinical and demographic risk factors (individually and in risk models) could be studied in large and robust cohort and case-control studies.
In the meantime, the screening requirement that the natural history of a condition should be known before a screening programme is introduced is not currently met, limiting the ability to find a more efficient screening programme.
7.
ADVERSE EVENTS IN WOMEN AND CHILDREN
WHO RECEIVE INTRAPARTUM ANTIBIOTIC
PROPHYLAXIS TREATMENT
7.1
Context of this chapter
Similar to Chapter 6, this chapter presents another part of the 2016 NSC evidence review that I led to assess the harms from IAP treatment.24 My contribution, along with the contribution
of the NSC and the other team members was the same as Chapter 6. While the overarching objectives of the 2016 review were set by the NSC, I led the design of the specific research questions and development of the research protocol outlining the methodology for the systematic review reported in this chapter. I also conducted the searches, study selection, data extraction and report writing. My supervisors and other team members contributed their technical expertise as required and conducted the second-reviewing of the systematic review processes.
7.2
Introduction
As discussed in Chapter 2, IAP is the internationally recommended treatment of EOGBS prevention. The current recommendation for IAP is intravenous penicillin (or ampicillin in the US) given as soon as possible after the onset of labour and then every four hours until delivery.13, 14 Second-line treatment for mothers allergic to penicillin varies across countries.13, 14 In the UK, until September 2017, intravenous clindamycin was recommended.13 However,
in the latest guideline published in September 2017, the recommendations have been modified due to the evidence of increasing clindamycin resistance.15 If a woman has a history of allergy
to beta-lactams that is not severe, i.e. does not have a history of anaphylaxis, angioedema, respiratory distress or urticaria, a cephalosporin is recommended. If a woman has a history of severe allergy to beta-lactams, vancomycin is recommended instead. Similarly, in the US since 2010, intravenous Cefazolin is the first alternative, followed by clindamycin if there is a history of anaphylaxis, respiratory distress, urticaria or angioedema after penicillin or cephalosporin.14
A Cochrane review summarised that the clinical practice of IAP treatment is not supported by valid evidence, due to the high risk of bias in small RCTs more than 20 years ago. While the
use of IAP did reduce the incidence of culture-proven EOGBS (RR 0.17 95% CI 0.04 to 0.74) and probable EOGBS (RR 0.17 95% CI 0.03 to 0.91) compared with no treatment, it did not reduce the incidence of all-cause mortality, mortality from GBS or mortality from other infections.10 On the other hand, the evidence on the adverse events from IAP has not been
previously reviewed. As discussed in Chapter 2, a range of harms have been suggested,23, 13, 32
including maternal anaphylaxis, which although very rare, can be fatal for mother and neonate,14 neonatal infections caused by gram-negative bacteria,298, 19, 32 antibiotic
resistance,299, 298, 86 neonatal microbiota changes that could lead to short and long-term health
problems,191, 32, 192 Clostridium difficile infection in mothers,21 anxiety for the mother, family
and medical staff and the medicalisation of labour.32, 13
The harms from IAP treatment have been poorly documented and understood. This evidence is crucial to decide whether, or not, to recommend a screening programme, as it informs whether the programme does more good than harm. As indicated in Chapters 3 and 4, the 2012 NSC GBS report concluded that, as this evidence has never been reviewed, this major screening criterion was not met. As stated in Chapter 2, in the case of GBS, IAP would be given to over 150,000 pregnant women and their babies every year, of whom over 99% will be over-treated, making the harms from treatment even more important in the context of GBS screening. Therefore, in this chapter, I will explore the evidence about the adverse events to mothers and their children after IAP treatment, in order to identify the implications this may have for a GBS screening programme in the UK (objective 3).
I will first present the aim and specific objectives of the review, followed by the methods used to search, appraise and analyse the data and then report the results. Finally, I will discuss the principal findings compared with previous literature, the strengths and limitations of the review and the research and policy implications.
7.3
Aims and objectives
The aim of this chapter is to identify, appraise and meta-analyse the evidence on the adverse events experienced by women or children after intrapartum antibiotic prophylaxis treatment. I took a broad definition of adverse events to mean any adverse or harmful event experienced after IAP treatment. This included the impact on the microbiome as well as clinical outcomes.
The research objectives are to:
a) Quantify the incidence of each reported adverse event in women who received intrapartum antibiotic prophylaxis compared with women who did not receive it; b) Quantify the incidence of each reported adverse event in neonates whose mothers
received intrapartum antibiotic prophylaxis compared with neonates whose mothers did not receive it;
c) Quantify the overall incidence of any reported adverse events in women who received intrapartum antibiotic prophylaxis compared with women who did not receive it; d) Quantify the overall incidence of any reported adverse events in neonates whose
mothers received intrapartum antibiotic prophylaxis compared with neonates whose mothers did not receive it; and
e) Identify any important gaps in the evidence on adverse events after intrapartum antibiotic prophylaxis.
7.4
Methods
As discussed in Chapter 4, I applied systematic review methodology to address the objectives of this chapter. Evidence on the harms of IAP treatment had not been previously synthesised. It was important to understand the status of the evidence, identify research gaps and determine the direction required for future research to avoid replication and wasting of resources. Furthermore, the harms from IAP could be experienced long-term and a primary study to investigate this was beyond the scope of my thesis. To ensure high standards were maintained, I reported this systematic review according to recommendations from the PRISMA-P 2015 statement.210 The protocol is registered at PROSPERO: CRD42016037195.
7.4.1 Search strategy
I conducted comprehensive electronic literature searches in well-known and recommended databases: MEDLINE (Ovid), MEDLINE In-Process & Other Non-Indexed Citations (Ovid), EMBASE (Ovid), Cochrane Library: Cochrane Database of Systematic Reviews, CENTRAL, DARE and HTA databases (Wiley) and Science Citation Index Expanded (Web of Science) from inception to 16th October 2016. I initially piloted scoping searches and then iteratively
adapted them with input from the team and recommended search filters to inform the development of the final search strategy.300, 301 In the final strategy, I combined three sets of
search terms using both text words and MeSH terms through Boolean operators OR within each set and then AND to combine the sets. The first set was made up of search terms for antibiotic prophylaxis, the second set was made up of search terms for labour and the third set was made up of search terms for adverse events. I limited the search to antibiotics for prophylactic purposes during labour. In preliminary searches, I discovered that some relevant articles did not include terms for adverse events. Therefore, I included terms for known adverse events from IAP such as antibiotic resistance or maternal anaphylaxis. To do this systematically, I used adverse events that are known from the literature,32, 28, 13, 23 and I enlisted
subject area experts as suggested by the UK NSC for further terms. I applied an extensive search strategy with no date limit to capture as much data as possible, but I limited the strategy to humans as this was the population of interest, and to the English language, as I did not have the time or resources to translate studies in other languages (see Appendix 8 for search strategies). Although excluding non-English studies could introduce selection bias,258-260the
impact of this is not clear in the literature, with some reviews showing that it does not affect results.261, 262 Furthermore, methodologists have suggested that the impact of language bias
has reduced recently as a result of the move towards publishing in English.263
I also searched grey literature to reduce reporting bias. Along with a second reviewer, we hand-searched reference lists of all included studies and relevant systematic reviews that were identified from the electronic searches. In addition, subject area experts cross-checked the included studies to identify any further references not captured by the search. The team members of this project also cross-checked the included studies.
7.4.2 Study eligibility criteria Study inclusion criteria
I included studies that satisfied the following criteria:
Study design: prospective or retrospective cohort studies, case-control studies and randomised controlled trials. If the search resulted in an insufficient number of these studies, I included case series with ≥50 patients. If the search still resulted in an insufficient number of studies, I included case series with ≥10 patients. I avoided case series as far as possible, as results from such studies do not have control groups for comparison, making it difficult to interpret whether an adverse event is actually more common in those who have undergone treatment.
Participants: intrapartum women and their children.
Intervention: intrapartum antibiotics given to asymptomatic women for a prophylactic purpose only. The antibiotics could be for any prophylactic purpose and not GBS prevention alone, however, it had to be administered in labour. I also included studies in which women received antibiotics in labour, and then continued to receive antibiotics after labour for prophylactic purposes, so long as women remained asymptomatic.
Comparator: placebo, no treatment or an alternative treatment for prophylactic purposes (comparison of one treatment to another). No comparator for case-series.
Outcome: any adverse outcomes experienced by the mother or child. The criteria for outcomes was intentionally wide to capture as many outcomes as possible.
Type and Language of publication: full-text primary studies published in the English language in medical and healthcare journals or in grey literature, such as organisational websites.
Study exclusion criteria
I excluded studies that fulfilled the following criteria:
Study design: ecological studies, cross-sectional studies, case reports, before and after studies across different participants (e.g. population-level resistance studies). I excluded before and after studies as control participants are not contemporaneous, therefore, adverse outcomes could be a result of other factors other than IAP treatment.
Participants: I excluded the following participants as they were not considered clinically similar enough to the population of women and children who would be receiving IAP for GBS prevention: a) pregnant women given antibiotics before labour; b) neonates given antibiotics after birth; c) pregnant women undergoing elective or emergency caesarean sections; and d) women with symptoms of infection such as intrapartum fever or prolonged rupture of membranes before IAP administration. I excluded women with symptoms of infections as this would contaminate the findings, making it unclear whether the adverse events are a result of the treatment or the infection. I included studies where some participants met the inclusion criteria, and some met the exclusion criteria, if participants meeting the inclusion criteria could be separated or participants that met the exclusion criteria were fewer than 10% of the study
Intervention: antibiotics given for any other purpose than prophylaxis. I excluded prophylaxis for caesarean sections as women and their children who have undergone caesarean sections may also contaminate the findings making it unclear whether the adverse events were a result of the caesarean section or the antibiotics.
Outcomes: Studies reporting only economic evaluation and/or cost-effectiveness outcomes. Type and Language of publication: abstracts, reviews (systematic or non-systematic), editorials, letters, books, consensus statements and opinions. I excluded reviews as sources of primary data but used them to identify the original studies contributing the evidence. I excluded all publications in any language other than English.
7.4.3 Study selection and data management