Infection and antibiotics in the aetiology, prediction and prevention of preterm birth

Oliver, Reeba; Lamont, Ronald F.

doi:10.3109/01443615.2013.842963

Cited by 30 publications

(25 citation statements)

References 107 publications

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“…The failure of antibiotics to help can be ascribed to their difficulty of penetrating to the trophoblasts and placental regions. Unfortunately, no proteomic biomarkers have yet been observed as predictive of PTB (411, 412). In a similar vein, and if we are talking about a time of parturition that is very much more “preterm,” we are in the realm of miscarriages and spontaneous abortions and stillbirths, where infection again remains a major cause (413–416).…”

Section: Direct Evidence For a Role Of Infectious Agents In Pementioning

confidence: 99%

A Dormant Microbial Component in the Development of Preeclampsia

Kell

Kenny

2016

Front. Med.

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Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “preeclampsia” that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.

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Section: Direct Evidence For a Role Of Infectious Agents In Pementioning

confidence: 99%

A Dormant Microbial Component in the Development of Preeclampsia

Kell

Kenny

2016

Front. Med.

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“…The failure of antibiotics to help can be ascribed to their difficulty of penetrating to thetrophoblasts and placental regions. Unfortunately no proteomic biomarkers have yet been observed as predictive of PTB [403; 404]. In a similar vein, and if we are talking about a time of parturition that is very much more ‘preterm’, we are in the realm of miscarriages and spontaneous abortions and stillbirths, where infection again remains a major cause [405–408].…”

Section: Direct Evidence For a Role Of Infectious Agents In Pementioning

confidence: 99%

A Dormant Microbial Component in the Development of Pre-Eclampsia¹

Kell

Kenny

2016

Preprint

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Pre-eclampsia (PE) is a complex, multi-system disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE, and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused.We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is in fact microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of “pre-eclampsia” that we assessed has in fact also been shown to be raised in response to infection. An infectious component to PE fulfils the Bradford Hill criteria for ascribing a disease to an environmental cause, and suggests a number of treatments, some of which have in fact been shown to be successful.PE was classically referred to as endotoxaemia or toxaemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the aetiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.Insight, innovation, integrationMany descriptors of pre-eclampsia are widely accepted (e.g. abnormal trophoblast invasion, oxidative stress, inflammation and altered immune response, and anti-angiogenic responses). However, without knowing what causes them, they do not explain the syndrome. The Biological Insight of this manuscript is that there is considerable evidence to the effect that each of these phenomena (hence PE) are caused by the resuscitation of dormant bacteria that shed (known and potent) inflammagens such as LPS, often as a consequence of iron availability. PE is thus seen as a milder form of sepsis. The Technological Innovations come from the use of molecular markers (of microbes and omics more generally, as well as novel markers of coagulopathies) to measure this. The Benefit of Integration comes from bringing together a huge number of disparate observations into a unifying theme.

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“…As an example, most studies assessing the benefit of screening for BV and subsequent treatment with the objective of preventing preterm birth have been negative [29,32,33,34]. Some authors considered that this lack of effect was due to treatment being initiated too late and with the wrong antibiotic (metronidazole instead of clindamycin) [23,35]. However, a very recent French study including women in early pregnancy treated with clindamycin during 4 days and repeated 1 week later did not show any benefit either [36].…”

Section: Obstetrical Antibiotic Indications During Pregnancymentioning

confidence: 99%

Antibiotic Use and Misuse during Pregnancy and Delivery: Benefits and Risks

Tejada

2014

IJERPH

101

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Although pregnancy is considered as a physiological state, most pregnant women in developed countries receive multiple medications to prevent maternal or neonatal complications, with antibiotics among the most frequently prescribed. During pregnancy, antibiotics are often prescribed in the context of preterm labor, intrapartum fever, prevention of neonatal Group B Streptococcus fever, and cesarean section. Outside this period, they are commonly prescribed in the community setting for respiratory, urinary, and ear, nose and throat infection symptoms. Whereas some of the current indications have insightful reasons to justify their use, potential risks related to overuse and misuse may surpass the benefits. Of note, the recent 2014 World Health Assembly expressed serious concern regarding antibiotic resistance due to antibiotic overuse and misuse and urged immediate action to combat antibiotic resistance on a global scale. Most studies in the obstetrics field have focused on the benefits of antibiotics for short-term maternal and neonatal complications, but with very little (if any) interest in long-term consequences.

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Infection and antibiotics in the aetiology, prediction and prevention of preterm birth

Cited by 30 publications

References 107 publications

A Dormant Microbial Component in the Development of Preeclampsia

A Dormant Microbial Component in the Development of Preeclampsia

A Dormant Microbial Component in the Development of Pre-Eclampsia¹

Antibiotic Use and Misuse during Pregnancy and Delivery: Benefits and Risks

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Infection and antibiotics in the aetiology, prediction and prevention of preterm birth

Cited by 30 publications

References 107 publications

A Dormant Microbial Component in the Development of Preeclampsia

A Dormant Microbial Component in the Development of Preeclampsia

A Dormant Microbial Component in the Development of Pre-Eclampsia1

Antibiotic Use and Misuse during Pregnancy and Delivery: Benefits and Risks

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A Dormant Microbial Component in the Development of Pre-Eclampsia¹