Australian and New Zealand Journal of Obstetrics and Gynaecology 2015; 55: 201–209
DOI: 10.1111/ajo.12303
Review Article
Probiotics in obstetrics and gynaecology Christopher GRIFFIN* School of Women’s and Infants’ Health, The University of Western Australia and King Edward Memorial Hospital, Subiaco, WA, Australia
Despite the great advances in modern medicine, our understanding of the most basic function of our complete genetic makeup is extremely poor. Our complete genetic make up is complemented by 100 trillion cells living within or on our body and is called the microbiome. Manipulation of the microbiome is in the embryological stages of investigation but promises great hope in targeting both pregnancy specific and general medical / gynaecological conditions. This review presents an undertanding of the microbiome manipulation with probiotics in women's health in 2015. Key words: probiotics, obstetrics, gynaecology, gestational diabetes, vaginal discharge, group B streptococcus, pregnancy, constipation, pre-eclampsia, preterm birth.
Introduction ‘If a man will begin with certainties, he shall end in doubts; but if he will be content to begin with doubts he shall end in certainties’. Sir Francis Bacon, 17th Century Philosopher1 In 1878, Joseph Lister produced the first pure culture of lactic acid bacteria (LAB), Lactobacillus lactis.2 In the early 1900s, Henry Tissier, a French paediatrician, isolated Bifidobacteria and used the bacillus to treat infant diarrhoea.3 In the same period, Elie Metchnikoff, a Nobel Peace Prize winner, observed the longevity of life associated with drinking fermented milk products.4 Later, Alfred Nissle isolated a strain of Escherichia coli from a noninfected soldier during an outbreak of shigellosis and used this to treat and prevent shigellosis with some success.5 These ‘live micro-organisms when exogenously administered in adequate amounts to confer a health benefit on the host’ are known as probiotics.6 However, the advent of antibiotics more or less stopped any scientific interest in using microbiological manipulation for the treatment of infectious diseases. Today, we live in an era of potentially cataclysmic microbiological resistance to antibiotics.7 With our progressively greater understanding of the influence of
Correspondence: Dr Christopher Griffin, Consultant in Maternal and Fetal Medicine, School of Women’s and Infants’ Health, The University of Western Australia and King Edward Memorial Hospital, Subiaco, WA, Australia. Email: christopher.griffi[email protected] Received 15 July 2014; accepted 22 November 2014.
probiotics upon inflammation and the immune system, we have entered an era where an ideal climate prevails for the clinical extrapolation of in vitro experimentation to in vivo trials and treatments.8 This review will endeavour to cover the use of probiotics in both infectious and noninfectious diseases in relation to women’s health. The content of this review was obtained using the search terms probtiotic(s), pregnancy, women’s health and gynaecology within the PubMed, MEDLINE, EMBASE and Cochrane databases.
Microbiome isolation In 2010, the presence of maternally derived bacterial DNA was isolated in the fetal gut and placenta.9,10 In 2012, maternally ingested probiotics were shown to modulate the toll-like receptor (TLR)-related gene expression in the fetal intestine.11 In 2014, the placenta was shown to harbour a unique microbiome that was influenced by maternal systemic infections during pregnancy.12 This rapid accumulation of facts was not possible using traditional culture-based technologies. Instead, researchers relied on the relatively stable 16s ribosomal RNA (16s rRNA) portion of the bacteria.13 However, in the past 2 years, the 16s rRNA method for identification has been paralleled and in some eyes surpassed by shotgun metabolomic sequencing (SMS).13 SMS uses the induced fragmented DNA from bacteria rather than the RNA for identification purposes. SMS has the advantage of bypassing the potential errors of culture techniques prior to analysis as well as most importantly to exhibit smaller frequency cell lines. Currently, the understanding of influences of the human microbiome and
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Table 1 Common Mechanisms and Actions of Lactobailli Action
Mechanism
Direct bactericidal activity17
Lactic acid production Bacteriocins Hydrogen peroxide production Glucose metabolism Short-chain fatty acid synthesis Inhibition of EC apoptosis Attenuation of chemically induced EC damage Maintenance of EC intercellular tight junctions Reduction of toxins from pathogenic bacteria to the EC Production of oligosaccharides to prevent attachment of Gram-negative bacilli to EC Increased Goblet cell mucus production Direct reduction in pathogenic bacteria load Direct contact with sub epithelial immune cells via toll-like receptors Activation of Peyer’s patches to secrete IgA Changes to toll-like receptor expression in maternal and fetal tissue to support down regulation of inflammatory processes Decrease in TGF-beta2 in breast milk
Reduction of energy substrate availability in the gut17 Protection of (EC) barrier18–20
Alteration of the host inflammatory response21,22
EC = epithelial cell barrier; TGF-beta 2 = Transforming growth factor-beta 2.
in particular the vaginal microbiome upon pregnancy is still in its embryological stage.14,15
Actions of probiotics The main actions of live whole probiotics are summarised in Table 1. Within the gut mucosa, pathogenic bacteria induce an inflammatory response, whilst commensal bacteria cohabit without inducing an inflammatory response. A balancing act needs to be achieved between over and under stimulation of the inflammatory response. Interestingly, one of the probiotic bactericidal mechanisms via high hydrogen peroxide levels is also self-inhibitory upon the growth of lactobacilli.16 The activation of Peyer’s patches to secrete IgA has been shown to occur in a dose-dependent manner and promotes the clearance of pathogenic bacteria at the luminal surface of the gut epithelium.17 However, probiotics do not have to be alive and whole to exert influences upon the host. Fragments of bacterial DNA, oligonucleotides, are capable of eliciting a host immune reaction.18 Dead, whole or fragmented bacteria act through the same presumed mechanisms as that of live bacteria. This latter effect is at a much lower level than that seen for live bacteria.18,19 Furthermore, it is hypothesised that nondistinct pathways of communication between the gut may exist to effect changes in end organ function and also the end organs microbiological content – brain, heart and breast.20–22
Inflammation, Infection and Pregnancy From implantation to delivery, pregnancy imposes marked inflammatory and immune changes upon the host23,24
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This burden, when exaggerated, that is pro-inflammatory or depressed host anti-inflammatory reaction, is hypothesised to be linked with pre-eclampsia, preterm birth and gestational diabetes.25–27 This link can be further extrapolated to broader adult diseases, that is the fetal origins of adult disease. An attractive in vitro derived hypothesis of interaction between the body’s metabolic function and microbiome is well described showing a complex interplay between dietary fatty acids increasing toll-like receptors to facilitate bacterial lipopolysaccharide (LPS)-induced central and peripheral insulin resistance within the body.28 The bacterial metabolic endotoxaemia is promoted by the reduced intestinal epithelial cell integrity in the absence of the protective effects of probiotics.18–20 The subsequent obesity can be reversed or prevented by the addition of probiotics of varying strains and combinations through the amelioration of the intestinal dysbiosis present.29 The maternal intestinal microbiome is shown to change significantly in both normal and abnormal pregnancies from the first (T1) to third trimesters (T3).30 T3 stool shows the strongest signs of inflammation and energy loss. When T3 stools were transferred to nonpregnant germfree mice, the T3 recipients exhibited greater adiposity, dyslipidaemia and insulin insensitivity compared to T1. Pregnancy itself can be considered a state of dyslipidaemia with rising triglycerides (TG) and cholesterols during the three trimesters.31 A recent metaanalysis shows that hypertriglyceridaemia precedes the onset of pre-eclampsia.32 The nonpregnant rat model shows a significant reduction in TG levels with probiotic intervention.33 Pregnancies destined to be complicated by gestational diabetes also show a first and second trimester dyslipidaemia in comparison to future unaffected pregnancies.34
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Probiotics in women's health shows great promise in influencing the microbiome
Spontaneous preterm birth (PTB) is associated with a plethora of lifestyle factors and concomitant maternal disease. The biological plausibility with the inflammatory process initiated by infection is well documented.26 Maternal infection as a cause for PTB and the potential influence by probiotic intervention shows great promise. Recent work from Canada has shown that the supernatant (bacteriocin) of Lactobacillus rhamnosus attenuated the LPS-induced inflammation and PTB in the mouse model.35 Concomitant maternal vaginal infections are also associated with PTB. Escherichia coli and Streptococcus agalactiae (GBS) being the main culprits. In vitro studies have shown that the antibactericidal activity against E. coli and GBS is mediated not only by the direct action of specific bacteriocins against the bacteria but also by inhibition of attachment by the pathogenic bacteria to the epithelium of the urogenital tract.36–38 A growing body of evidence is linking probiotics to changes in the central neuroendocrine and neurochemical status.39 Probiotics are known to attenuate the inflammatory response with resultant positive changes in brain neurotransmitters.40 B. infantis intervention in the maternal rat separation model attenuated and reversed the abnormal behavioural activity of the animal whilst normalising the immune response and noradrenalin levels in the brainstem.39 Interestingly, stress can have a negative effect upon the intestinal microbiome and in particular the bifidobacteria in humans.40 Women with first-onset postpartum psychosis show a significant over-activation of the monocyte system possibly due to reduced T-cell changes both in number and function.21
Clinical studies in women’s health and perinatology Safety of therapy in pregnancy and nonpregnancy states has been studied specifically and a recent meta-analysis confirmed the safety of specific types of probiotics.41 Though we automatically assume the safety of such bacteria existing as commensal organisms within our intestinal tract, human sepsis from such bacteria, though extremely rare, has been documented in severely immunocompromised patients. Thus, care needs to be employed when using probiotics in trials that a specific antibiotic does exist for treatment of host sepsis should the need arise. There has been great heterogeneity involved with the use of probiotics and clinical trials to date. The route of administration has varied between oral, vaginal and skin. The oral route has been shown to change the vaginal flora although no direct comparative studies exist with vaginal routes of administration. Preparation of specific vaginal pessaries is probably not justified on the basis that oral preparations with a simple gelatin or cellulose capsule are effectively dissolved in the vagina. The chosen probiotic intervention has varied from singular strains to combinations of strains. The probiotic load as measured by the colony forming unit can vary
greatly log103 = 3. Furthermore, quality control of the probiotic to determine exactly what the bacteria are (as compared to what the manufacturer states) and the quantitative mass is often lacking. Additionally, the confounding effect of antibiotics within treatment arms of controlled trials is not fully explored in most data analysis sets. A singular course of antibiotics can influence the microbiome for months after cessation.42 Although beyond the scope of this review, the examination of maternal dietary intake especially relating to prebiotic ingestion is lacking in most studies. The length of probiotic ingestion has varied from a couple of weeks to the entire course of pregnancy and beyond. For probiotics to be effective and in the presence of nonmodulating exogenous factors, the minimum time considered essential for the probiotic action to become clinically noticeable is probably 4 weeks.43 The human clinical studies discussed in this article are listed in Table 2.
Insulin, glucose and lipid metabolism The prima facie study igniting the clinical application of probiotic manipulation of maternal glucose metabolism originated in Finland.44 The three armed randomised controlled trial (RCT) examined the effects of dietary advice in women who were within the normal body mass index (BMI) range. The dietary advice group combined with probiotic intervention produced a 64% statistically significant reduction in gestational diabetes mellitus (GDM) incidence compared to the other two groups.45 A significant reduction in blood glucose levels was achieved in the same group compared to the control group along with reduced insulin levels and improved insulin sensitivity. Due to the influences of dietary education and a highly selective population within the Finnish population and despite the apparent reduction in GDM rate, the changes quoted above cannot be attributed solely to the probiotic used.45 From the same Finnish study population, a reduction in postpartum cholesterol and lipid profiles as well as a reduction in maternal waist line measurements was recorded.46 The same Finnish authors discussed above published a 10-year follow-up of childhood weight gain in the offspring of mothers treated with L. rhamnosus during the last month of pregnancy and for the first 6 months of the child’s life.47 The study was as an offshoot from a probiotic childhood allergies study. The results demonstrated a trend towards a reduction in obesity at the 4-year-old stage but no differences at the 10-year stage. In Iran, Asemi et al. using a probiotic enriched yoghurt as the delivery method for the intervention showed an attenuation in the rise of plasma insulin during a 9-week intervention.48 The Iranian study group showed a reduction in triglyceride levels from the baseline reading in both probiotic enriched yoghurt and traditional yoghurt.49 Three other papers from the same Iranian cohort of 70
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Table 2 Human studies microbiome manipulation in women Study details Metabolic Dietary advice and probiotic capsule intervention on gestational diabetes incidence, BPRCT, n = 256, normal BMI, 12 weeks gestation till 12 months post partum, Finland45–46
Probiotic capsule on childhood allergies and secondarily weight gain, BPRCT, n = 159, last month of pregnancy to 6 months of child’s age, Finland47 Yoghurt intervention from third trimester for 9 weeks, PRCT, n = 70, Iran48–52
Probiotic capsule intervention, BPRCT, n = 138, raised BMI, 4 weeks intervention 24–28 weeks, Ireland.53–56 Blood Pressure Dietary intake, POP, n = 33399, primiparous only, Norway.58
Preterm birth Dietary intake, POP, n = 18888, Norway66
Dietary intake, POP, n = 18888, Norway.67 Group B Streptococcus Oral probiotic, O, n = 20, USA.73
Perineal probiotic, non pregnant, BPRCT, n = 191, Sweden.72 Breast Feeding Antibiotic vs Probiotic for mastitis treatment, RCT, n = 352, Spain.77
Constipation Oral probiotic, O, n = 20, Netherlands.79 Recurrent UTI Vaginal probitoic, non pregnant, BPRCT, n = 100, USA.82
Intervention studied
Outcome in respect to intervention
Dietary advice, L. rhamnosus and B. lactis in capsule form
Reduced birthweight and length in GDM affected pregnancies Lowered maternal blood glucose levels Reduced insulin levels 64% reduction in incidence of GDM Reduced total cholesterol and low density lipoprotein (LDL) cholesterol ?attributable to dietary intervention Trend towards a reduction in weight gain at 4 years of age but not sustained at 10 years of age
Natural yoghurt with L. bulgaricus and Streptococcus thermophilus vs natural yoghurt enriched with B. animalis and L. acidophilus
No difference between groups in HDL or LDL cholesterols and triglycerides Reduced rise in glucose and insulin baseline levels in probiotic group Increased erythrocyte glutathione reductase activity Reduced maternal hs-CRP No difference between glucose, insulin or lipid/cholesterol levels Excellent patient compliance
L. salivarius or placebo capsule
Prospectively collected data on dietary intake of probiotic milk beverages containing various bacteria such as L. acidophilus, L. rhamnosus, B. Lactis
Frequency of intake inversely linked to incidence and severity of pre-eclampsia with up to 40% reduction in severe disease
Prospectively collected data on dietary intake of probiotic milk beverages containing various bacteria such as L. acidophilus, L. rhamnosus, B. Lactis Prospectively collected data on dietary intake of alliums and dried fruit
Intake of probiotic resulted in a small lowering of the sPTBR with a weak dose dependent effect
Probiotic capsule Florajen3 – L. acidophilus, B. Lactis and B. Longum
Reduced GBS vaginal load with probiotic but concomitant dietary intake of yoghurt reduced incidence of GBS Incidence of GBS inversely related to lactobacillus colonisation rates
L. plantarum via a daily panty liner for 4 months
Alliums (esp. Garlic) were strongly related to a reduced sPTBR
L. fermentum, L. salivarius or antibiotic
Significant and sustained reductions in bacterial count of probiotic group Improvement in clinical symptoms and reduction in relapse rate
B. Lactis, B. Longum, L. plantarum, L. casei for 4 weeks
Improvement in frequency, incompleteness, straining at and obstruction of defecation
L. Crispatus for 5 days and then once weekly for days
Six-fold reduction in recurrent UTI in high level colonisation with L. crispatus
RCT, randomised controlled trial; P, placebo controlled; B, blinded; DB, double blinded; O, observational; POP, population; n, number of patients; L, Lactobacillus; B, Bifidobacterium; sPTBR, spontaneous preterm birthrate; GBS, Group B Streptococcus.
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Probiotics in women's health shows great promise in influencing the microbiome
Preterm Delivery (PTD)
patients showed no changes in serum iron, calcium or liver function tests, an increase in erythrocyte glutathione reductase as a measure of reduced maternal oxidative stress and a decrease in maternal high-sensitivity Creactive protein.50–52 However, an Irish placebo-controlled RCT using probiotic capsules with a 4-week intervention period showed no changes in the fasting glucose.53 Lindsay et al. very succinctly addressed the pertinent issue that shortterm use of a probiotic showed no influence upon the metabolic complications of pregnancy.54,55 A positive aspect from this study was the demonstration of good patient compliance and acceptability to the intervention treatment.56 The largest prospective study to date involving probiotic intervention to reduce GDM is the SPRING study currently being conducted in Queensland.57 This placebocontrolled RCT involving 540 women is using the same probiotic preparation – L. rhamnosus GG and Bifidobacterium lactis as the Finnish study but in women with a BMI over 25. Another strong point of this study is that detailed dietary questionnaires on diet and fermented milk products are being undertaken as well as antibiotic use. The results of this study will be hopefully available in 2016.
From the MoBa population, a group of 18,888 women were explored for links with PTD.66 Within this group, there would appear to be an 18% reduction of PTD attributed to prebiotic food preparations.67 The PTD increased to 50% when garlic alone was considered in the analysis. Fermented milk product ingestion reduced PTD by 15% – greater than that of the population study concerning smoking bans in public places.68 Particularly interesting is that the background rate of PTD in Norway was 5%, which is one of the lowest rates in the world. In the final analysis, both Norwegian papers failed to control for the effect of probiotic or prebiotic exposure. No protective effect was found from the ingestions of LR and reduction of PTD in pregnancies with male fetuses contrary to recent animal studies. A meta-analysis in 2007 failed to show a reduction in PTD with the use of probiotics.69 However, the three studies examined were so diverse in the primary outcome, quality control of product, choice of probiotic and temporal administration of the probiotic that any metaanalysis concerning PTD is both scientifically and statistically challenging.
Pre-eclampsia
Bacterial Vaginosis
The strongest evidence to date regarding the prevention of hypertensive disorders in pregnancy is from the MoBa (mother and baby) population (observational) study.58 The MoBa study involved nearly 34000 mother and baby pairs during 2002 to 2008 in Norway. Part of the prospectively collected maternity lifestyle questionnaire directly addressed the quantity of fermented milk products ingested during pregnancy. The analysis demonstrated up to a 40% reduction in severe preeclampsia for women ingesting high levels of fermented milk products during pregnancy. This effect was dosedependent showing a lesser response with lower doses of ingested fermented milk products. A meta-analysis exploring the link between blood pressure and the ingestion of fermented milk products in nonpregnant normotensive and hypertensive individuals found a significant reduction in both systolic and diastolic measurements.59 Also, nonpregnant adult levels of vitamin D and fibrinogen can be increased and triglyceride levels reduced by probiotics ingestion.60,61 Interestingly, across studies designed to reduce the incidence of pre-eclampsia, the most effective intervention to date is aspirin. Aspirin is thought to act at the maternal vascular endothelial cell/platelet level in preventing preeclampsia.62 However, aspirin reduces the growth of Candida albicans via reducing the hyphae’s prostaglandin production.63 Aspirin is not alone as a member of nonantimicrobial drugs that have antibacterial activity that are potentially both antagonistic and agonistic to the microbiome.64,65 Aspirin may well be a major confounding variable within multicentre trials.
BV is a non-life-threatening disorder in the nonpregnant state and the over judicious use of antibiotics is leading to the problem of increasing antibiotic resistance within the human microbiome.7 Therefore, the use of probiotics may offer an alternative but effective management strategy.8 The most effective intervention placebocontrolled randomised trials regarding bacterial vaginosis (BV) have used high doses (greater than 107 CFU) of lactobacilli and the specific singular or combination of strains – L. rhamnosus, L. reuteri, L. salivarius, L. plantarum, L. acidophilus and L. brevis.70 The individual studies were underpowered to detect significant changes as well as each trial showing wide variation in the temporal intervention lengths. Overall, there was a trend towards a cure for BV. Compared to antibiotic treatment alone, the addition of probiotics does show a stronger trend towards improved cure rates and reduced relapse rates.71 Meta-analysis of antibiotic interventions has the advantage of reduced heterogeneity based upon a known preparation and a greater degree of professional familiarity. These two factors will possibly influence the clinicians prescribing activity. However, the growing body of scientific evidence shows that despite the lack of definitive studies, the use of probiotics is essential to consider when treating BV.
Group B Streptococcus (GBS) No convincing data exist at present for treating pregnant women testing positive for GBS with probiotics. However, a novel placebo-controlled RCT used a panty liner infused
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with L. plantarum.72 191 nonpregnant women wore the liner 24 hours a day for 4 months. The primary aim was to examine the genital microbiome relationship to vaginal pH and secondarily the possibility of transferring the probiotic from panty liner to the genital tract. The conclusion regarding the second aim was that the panty liner with the LAB increased genital tract colonisation, but these data were not presented in the paper. An observational study using a proprietary preparation (Florajen3) capsule showed that the incidence of GBS was inversely related to the ability of LAB to adhere to vaginal epithelial cells.73 However, the study suffered from many errors of design and multiple confounding variables. The finding of an inverse relationship between LAB and GBS was found in an earlier noninterventional, observational study from Iran.74 It would perhaps appear that simply increasing the ratio of probiotic to pathogenic bacteria has the propensity to ameliorate or prevent associated urogenital tract infections.
Breastfeeding There have been more randomised controlled trials in pregnancy surrounding neonatal/childhood outcomes than the sum of all other such studies in pregnant women. This has been driven by the interest in childhood allergic conditions and maternal diet. Data from the previously mentioned MoBa cohort found a 6% reduction in early childhood allergic skin and eye conditions in the offspring of women who ingested fermented milk products during pregnancy.75 This reduction, albeit small was confirmed in a recent meta-analysis of probiotic intervention in pregnancy.76 The authors concluded that probiotic intervention may reduce the incidence of eczema in infants aged less than 2 years of age. Biologically, there appears to be (undefined presently) a direct relationship between the microbiome of the maternal gut and the microbiome of the breast milk that is not due to contamination from the maternal skin or baby oral cavity.22 Only one clinical study has examined the treatment effects of the maternal ingestion of probiotics upon mastitis.77 Although the study has shortcomings in design and antibiotic use, this intervention improved clinical symptoms and reduced relapse rates.
Constipation Constipation is a common complaint in pregnancy. RCT data from nonpregnant adult women show positive results in using probiotics as an intervention for constipation.78 Only two small studies have examined this in pregnancy. The first, an observational study in 2012 used a patented multispecies mixture in constipated women with a mean gestation of 20 weeks.79 The results showed a reported (nonvalidated questionnaire) improvement over baseline in defecation. The second study was as an offshoot from a nonplacebo nonblinded RCT in 40 women examining the effects of probiotics vs 206
clindamycin for the successful treatment of bacterial vaginosis (no difference in results for the primary outcome).80 Defecation-related problems significantly reduced in the probiotic group.
Recurrent Urinary Tract Infections Nonpregnant women with recurrent urinary tract infections (rUTI) using antibiotic prophylaxis show a marked increased in antibiotic resistant bacteria over the treatment period.81 Vaginally administered Lactobacillus crispatus significantly reduced the risk of rUTI when compared to placebo but only in women who showed high quantitative levels of L. crispatus in the vagina on followup (Table 2).82
The future Biological plausibility to support clinical treatment and trials is slowly arriving for the action of probiotics by primary in vivo research. However, our enthusiasm as professionals must be tempered by the realisation that a significant portion of clinical studies performed have been sponsored by parties with a vested commercial interest in the outcome. Although the results are promising, there is also a large degree of conflict in conclusions as well as only small numbers of patients. However, the potential benefits of probiotics in pregnancy are already being realised by women in Australia. If the SPRING study proves that GDM is reduced by probiotics, every woman either contemplating or already pregnant in Australia will be advised to take probiotics by the popular press. Recruitment of patients, therefore, to any future RCT to truly address the null hypothesis is going to prove very difficult. Detailed dietary analysis of patients within studies will need to be undertaken as the confounding variables of concurrent prebiotic and probiotic ingestion could be of sufficient strength as to falsely influence the null hypothesis. Also, detailed antibiotic exposure will need to be collected, as well as the evolving influences of plastics, exercise and ethnicity. The confounding effects of concomitant medications especially aspirin have not been considered to date in any meta-analysis or intervention study. Group B Streptococcus infection should be a very viable target of a probiotic intervention clinical trial but perhaps with localised rather than systemic application. Most of the completed clinical studies reviewed here have not involved any direct examination of the maternal microbiome. However, with the advancement of metabolomic sequencing, samples from ongoing studies are being stored for future examination. Yet we are only just scratching the surface of a very deep, complex and unknown sea of life-changing science.83 As Bacon quoted, we must have an open mind when approaching the arena of probiotics. We need to revisit the past in an attempt to link the scientific validity and biological plausibility of the human microbiome with the historical clinical outcomes
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Probiotics in women's health shows great promise in influencing the microbiome
and not merely to rely upon what we find now. It is a tragedy that so many pregnant women have been exposed to probiotics within the trial setting (childhood allergies), but so little data have been collected for maternal outcomes. A much greater degree of cooperative research is needed between all the faculties involved in women’s health to broaden the understanding and thus the knowledge of the foundation of human life – our microbiome, and in due course, the manipulation of the microbiome with probiotics.
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predictor of low risk gestational diabetes in early pregnancy. Clin Chim Acta 2013; 418: 1–4. Yang S, Li W, Challis JR et al. Probiotic Lactobacillus rhamnosus GR-1 supernatant prevents lipopolysaccharideinduced preterm birth and reduces inflammation in pregnant CD-1 mice. Am J Obstet Gynecol 2014; 211: 44.e1–44e12. Kwok L, Stapleton AE, Stamm WE et al. Adherence of Lactobacillus crispatus to vaginal epithelial cells from women with or without a history of recurrent urinary tract infection. J Urol 2006; 176: 2050–2054; discussion 4. Ghartey JP, Carpenter C, Gialanella P et al. Association of bactericidal activity of genital tract secretions with Escherichia coli colonization in pregnancy. Am J Obstet Gynecol 2012; 207: 297 e1-8. Ruiz FO, Gerbaldo G, Garcia MJ et al. Synergistic effect between two bacteriocin-like inhibitory substances produced by Lactobacilli Strains with inhibitory activity for Streptococcus agalactiae. Curr Microbiol 2012; 64: 349–356. Desbonnet L, Garrett L, Clarke G et al. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 2010; 170: 1179–1188. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 2013; 36: 305–312. Didari T, Solki S, Mozaffari S et al. A systematic review of the safety of probiotics. Expert Opin Drug Saf 2014; 13: 227–239. Macfarlane S. Antibiotic treatments and microbes in the gut. Environ Microbiol 2014; 16: 919–924. Ciorba MA. A gastroenterologist’s guide to probiotics. Clin Gastroenterol Hepatol 2012; 10: 960–968. Laitinen K, Poussa T, Isolauri E. Probiotics and dietary counselling contribute to glucose regulation during and after pregnancy: a randomised controlled trial. Br J Nutr 2009; 101: 1679–1687. Luoto R, Laitinen K, Nermes M, Isolauri E. Impact of maternal probiotic-supplemented dietary counselling on pregnancy outcome and prenatal and postnatal growth: a double-blind, placebo-controlled study. Br J Nutr 2010; 103: 1792–1799. Hoppu U, Isolauri E, Koskinen P, Laitinen K. Maternal dietary counseling reduces total and LDL cholesterol postpartum. Nutrition 2014; 30: 159–164. Luoto R, Kalliomaki M, Laitinen K, Isolauri E. The impact of perinatal probiotic intervention on the development of overweight and obesity: follow-up study from birth to 10 years. Int J Obes (Lond) 2010; 34: 1531–1537. Asemi Z, Samimi M, Tabassi Z et al. Effect of daily consumption of probiotic yoghurt on insulin resistance in pregnant women: a randomized controlled trial. Eur J Clin Nutr 2013; 67: 71–74. Asemi Z, Samimi M, Tabasi Z et al. Effect of daily consumption of probiotic yoghurt on lipid profiles in pregnant women: a randomized controlled clinical trial. J Matern Fetal Neonatal Med 2012; 25: 1552–1556. Asemi Z, Esmaillzadeh A. Effect of daily consumption of probiotic yoghurt on serum levels of calcium, iron and liver enzymes in pregnant women. Int J Prev Med 2013; 4: 949– 955. Asemi Z, Jazayeri S, Najafi M et al. Effect of daily consumption of probiotic yogurt on oxidative stress in
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pregnant women: a randomized controlled clinical trial. Ann Nutr Metab 2012; 60: 62–68. Asemi Z, Jazayeri S, Najafi M et al. Effects of daily consumption of probiotic yoghurt on inflammatory factors in pregnant women: a randomized controlled trial. Pak J Biol Sci 2011; 14: 476–482. Lindsay KL, Kennelly M, Culliton M et al. Probiotics in obese pregnancy do not reduce maternal fasting glucose: a double-blind, placebo-controlled, randomized trial. Am J Clin Nutr 2014; 99: 1432–1439. Griffin C. Probiotic choices and biological plausibility for metabolic studies in pregnancy. Am J Clin Nutr 2014; 100: 1209. Lindsay KL, Brennan L, McAuliffe FM. Reply to C Griffin. Am J Clin Nutr 2014; 100: 1209–1210. Lindsay KL, Brennan L, McAuliffe FM. Acceptability of and compliance with a probiotic capsule intervention in pregnancy. Int J Gynaecol Obstet 2014; 125: 279–280. Nitert MD, Barrett HL, Foxcroft K et al. SPRING: an RCT study of probiotics in the prevention of gestational diabetes mellitus in overweight and obese women. BMC Pregnancy Childbirth 2013; 13: 50. Brantsaeter AL, Myhre R, Haugen M et al. Intake of probiotic food and risk of preeclampsia in primiparous women: the Norwegian Mother and Child Cohort Study. Am J Epidemiol 2011; 174: 807–815. Dong JY, Szeto IM, Makinen K et al. Effect of probiotic fermented milk on blood pressure: a meta-analysis of randomised controlled trials. Br J Nutr 2013; 110: 1188– 1194. Jones ML, Martoni CJ, Prakash S. Oral supplementation with probiotic L. reuteri NCIMB 30242 increases mean circulating 25-hydroxyvitamin D: a post hoc analysis of a randomized controlled trial. J Clin Endocrinol Metab 2013; 98: 2944–2951. Rajkumar H, Mahmood N, Kumar M et al. Effect of probiotic (VSL#3) and omega-3 on lipid profile, insulin sensitivity, inflammatory markers, and gut colonization in overweight adults: a randomized, controlled trial. Mediators Inflamm 2014; 2014: 348959. Fenton C, Hobson SR, Wallace EM, Lim R. Future therapies for pre-eclampsia: beyond treading water. Aust N Z J Obstet Gynaecol 2014; 54: 3–8. Mohammed A, Alem S, Douglas J. Effects of aspirin and other nonsteroidal anti-inflammatory drugs on biofilms and planktonic cells of Candida albicans. Antimicrob Agents Chemother 2004; 48: 41–47. Cederlund H, Mardh PA. Antibacterial activities of non-antibiotic drugs. J Antimicrob Chemother 1993; 32: 355–365. Price CT, Lee IR, Gustafson JE. The effects of salicylate on bacteria. Int J Biochem Cell Biol 2000; 32: 1029–1043. Myhre R, Brantsaeter AL, Myking S et al. Intake of probiotic food and risk of spontaneous preterm delivery. Am J Clin Nutr 2011; 93: 151–157. Myhre R, Brantsaeter AL, Myking S et al. Intakes of garlic and dried fruits are associated with lower risk of spontaneous preterm delivery. J Nutr 2013; 143: 1100–1108. Cox B, Martens E, Nemery B et al. Impact of a stepwise introduction of smoke-free legislation on the rate of preterm
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births: analysis of routinely collected birth data. BMJ 2013; 346: f441. Othman M, Neilson JP, Alfirevic Z. Probiotics for preventing preterm labour. Cochrane Database Syst Rev 2007; 1: CD005941. Mastromarino P, Vitali B, Mosca L. Bacterial vaginosis: a review on clinical trials with probiotics. New Microbiol 2013; 36: 229–238. Senok AC, Verstraelen H, Temmerman M, Botta GA. Probiotics for the treatment of bacterial vaginosis. Cochrane Database Syst Rev 2009; 4: CD006289. Ronnqvist PD, Forsgren-Brusk UB, Grahn-Hakansson EE. Lactobacilli in the female genital tract in relation to other genital microbes and vaginal pH. Acta Obstet Gynecol Scand 2006; 85: 726–735. Hanson L, Vandevusse L, Duster M et al. Feasibility of oral prenatal probiotics against maternal group B Streptococcus vaginal and rectal colonization. J Obstet Gynecol Neonatal Nurs 2014; 43: 294–304. Mogghaddam M. Recto-vaginal coloniszation of group B Streptococcus in pregnant women referred to a hospital in iran and its effect on Lactobacillus normal flora. J Biol Sci 2010; 10: 166–169. Bertelsen RJ, Brantsaeter AL, Magnus MC et al. Probiotic milk consumption in pregnancy and infancy and subsequent childhood allergic diseases. J Allergy Clin Immunol 2014; 133: 165–71 e1-8.
76 Dang D, Zhou W, Lun ZJ et al. Meta-analysis of probiotics and/or prebiotics for the prevention of eczema. J Int Med Res 2013; 41: 1426–1436. 77 Arroyo R, Martin V, Maldonado A et al. Treatment of infectious mastitis during lactation: antibiotics versus oral administration of Lactobacilli isolated from breast milk. Clin Infect Dis 2010; 50: 1551–1558. 78 Waitzberg DL, Logullo LC, Bittencourt AF et al. Effect of synbiotic in constipated adult women - a randomized, doubleblind, placebo-controlled study of clinical response. Clin Nutr 2013; 32: 27–33. 79 de Milliano I, Tabbers MM, van der Post JA, Benninga MA. Is a multispecies probiotic mixture effective in constipation during pregnancy? ‘A pilot study’. Nutr J 2012; 11: 80. 80 Facchinetti F, Dante G, Pedretti L et al. The role of oral probiotic for bacterial vaginosis in pregnant women. A pilot study. Minerva Ginecol 2013; 65: 215–221. 81 Grin P, Kowalewska P, Alhazzani W. Lactobacillus for preventing recurrent urinary tract infections in women: metaanalysis. Can J Urol 2013; 20: 6607–6614. 82 Stapleton AE, Au-Yeung M, Hooton TM et al. Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection. Clin Infect Dis 2011; 52: 1212–1217. 83 Canani RB, Costanzo MD, Leone L et al. Epigenetic mechanisms elicited by nutrition in early life. Nutr Res Rev 2011; 24: 198–205.
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DOI: 10.1111/ajo.12303
Review Article
Probiotics in obstetrics and gynaecology Christopher GRIFFIN* School of Women’s and Infants’ Health, The University of Western Australia and King Edward Memorial Hospital, Subiaco, WA, Australia
Despite the great advances in modern medicine, our understanding of the most basic function of our complete genetic makeup is extremely poor. Our complete genetic make up is complemented by 100 trillion cells living within or on our body and is called the microbiome. Manipulation of the microbiome is in the embryological stages of investigation but promises great hope in targeting both pregnancy specific and general medical / gynaecological conditions. This review presents an undertanding of the microbiome manipulation with probiotics in women's health in 2015. Key words: probiotics, obstetrics, gynaecology, gestational diabetes, vaginal discharge, group B streptococcus, pregnancy, constipation, pre-eclampsia, preterm birth.
Introduction ‘If a man will begin with certainties, he shall end in doubts; but if he will be content to begin with doubts he shall end in certainties’. Sir Francis Bacon, 17th Century Philosopher1 In 1878, Joseph Lister produced the first pure culture of lactic acid bacteria (LAB), Lactobacillus lactis.2 In the early 1900s, Henry Tissier, a French paediatrician, isolated Bifidobacteria and used the bacillus to treat infant diarrhoea.3 In the same period, Elie Metchnikoff, a Nobel Peace Prize winner, observed the longevity of life associated with drinking fermented milk products.4 Later, Alfred Nissle isolated a strain of Escherichia coli from a noninfected soldier during an outbreak of shigellosis and used this to treat and prevent shigellosis with some success.5 These ‘live micro-organisms when exogenously administered in adequate amounts to confer a health benefit on the host’ are known as probiotics.6 However, the advent of antibiotics more or less stopped any scientific interest in using microbiological manipulation for the treatment of infectious diseases. Today, we live in an era of potentially cataclysmic microbiological resistance to antibiotics.7 With our progressively greater understanding of the influence of
Correspondence: Dr Christopher Griffin, Consultant in Maternal and Fetal Medicine, School of Women’s and Infants’ Health, The University of Western Australia and King Edward Memorial Hospital, Subiaco, WA, Australia. Email: christopher.griffi[email protected] Received 15 July 2014; accepted 22 November 2014.
probiotics upon inflammation and the immune system, we have entered an era where an ideal climate prevails for the clinical extrapolation of in vitro experimentation to in vivo trials and treatments.8 This review will endeavour to cover the use of probiotics in both infectious and noninfectious diseases in relation to women’s health. The content of this review was obtained using the search terms probtiotic(s), pregnancy, women’s health and gynaecology within the PubMed, MEDLINE, EMBASE and Cochrane databases.
Microbiome isolation In 2010, the presence of maternally derived bacterial DNA was isolated in the fetal gut and placenta.9,10 In 2012, maternally ingested probiotics were shown to modulate the toll-like receptor (TLR)-related gene expression in the fetal intestine.11 In 2014, the placenta was shown to harbour a unique microbiome that was influenced by maternal systemic infections during pregnancy.12 This rapid accumulation of facts was not possible using traditional culture-based technologies. Instead, researchers relied on the relatively stable 16s ribosomal RNA (16s rRNA) portion of the bacteria.13 However, in the past 2 years, the 16s rRNA method for identification has been paralleled and in some eyes surpassed by shotgun metabolomic sequencing (SMS).13 SMS uses the induced fragmented DNA from bacteria rather than the RNA for identification purposes. SMS has the advantage of bypassing the potential errors of culture techniques prior to analysis as well as most importantly to exhibit smaller frequency cell lines. Currently, the understanding of influences of the human microbiome and
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Table 1 Common Mechanisms and Actions of Lactobailli Action
Mechanism
Direct bactericidal activity17
Lactic acid production Bacteriocins Hydrogen peroxide production Glucose metabolism Short-chain fatty acid synthesis Inhibition of EC apoptosis Attenuation of chemically induced EC damage Maintenance of EC intercellular tight junctions Reduction of toxins from pathogenic bacteria to the EC Production of oligosaccharides to prevent attachment of Gram-negative bacilli to EC Increased Goblet cell mucus production Direct reduction in pathogenic bacteria load Direct contact with sub epithelial immune cells via toll-like receptors Activation of Peyer’s patches to secrete IgA Changes to toll-like receptor expression in maternal and fetal tissue to support down regulation of inflammatory processes Decrease in TGF-beta2 in breast milk
Reduction of energy substrate availability in the gut17 Protection of (EC) barrier18–20
Alteration of the host inflammatory response21,22
EC = epithelial cell barrier; TGF-beta 2 = Transforming growth factor-beta 2.
in particular the vaginal microbiome upon pregnancy is still in its embryological stage.14,15
Actions of probiotics The main actions of live whole probiotics are summarised in Table 1. Within the gut mucosa, pathogenic bacteria induce an inflammatory response, whilst commensal bacteria cohabit without inducing an inflammatory response. A balancing act needs to be achieved between over and under stimulation of the inflammatory response. Interestingly, one of the probiotic bactericidal mechanisms via high hydrogen peroxide levels is also self-inhibitory upon the growth of lactobacilli.16 The activation of Peyer’s patches to secrete IgA has been shown to occur in a dose-dependent manner and promotes the clearance of pathogenic bacteria at the luminal surface of the gut epithelium.17 However, probiotics do not have to be alive and whole to exert influences upon the host. Fragments of bacterial DNA, oligonucleotides, are capable of eliciting a host immune reaction.18 Dead, whole or fragmented bacteria act through the same presumed mechanisms as that of live bacteria. This latter effect is at a much lower level than that seen for live bacteria.18,19 Furthermore, it is hypothesised that nondistinct pathways of communication between the gut may exist to effect changes in end organ function and also the end organs microbiological content – brain, heart and breast.20–22
Inflammation, Infection and Pregnancy From implantation to delivery, pregnancy imposes marked inflammatory and immune changes upon the host23,24
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This burden, when exaggerated, that is pro-inflammatory or depressed host anti-inflammatory reaction, is hypothesised to be linked with pre-eclampsia, preterm birth and gestational diabetes.25–27 This link can be further extrapolated to broader adult diseases, that is the fetal origins of adult disease. An attractive in vitro derived hypothesis of interaction between the body’s metabolic function and microbiome is well described showing a complex interplay between dietary fatty acids increasing toll-like receptors to facilitate bacterial lipopolysaccharide (LPS)-induced central and peripheral insulin resistance within the body.28 The bacterial metabolic endotoxaemia is promoted by the reduced intestinal epithelial cell integrity in the absence of the protective effects of probiotics.18–20 The subsequent obesity can be reversed or prevented by the addition of probiotics of varying strains and combinations through the amelioration of the intestinal dysbiosis present.29 The maternal intestinal microbiome is shown to change significantly in both normal and abnormal pregnancies from the first (T1) to third trimesters (T3).30 T3 stool shows the strongest signs of inflammation and energy loss. When T3 stools were transferred to nonpregnant germfree mice, the T3 recipients exhibited greater adiposity, dyslipidaemia and insulin insensitivity compared to T1. Pregnancy itself can be considered a state of dyslipidaemia with rising triglycerides (TG) and cholesterols during the three trimesters.31 A recent metaanalysis shows that hypertriglyceridaemia precedes the onset of pre-eclampsia.32 The nonpregnant rat model shows a significant reduction in TG levels with probiotic intervention.33 Pregnancies destined to be complicated by gestational diabetes also show a first and second trimester dyslipidaemia in comparison to future unaffected pregnancies.34
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Spontaneous preterm birth (PTB) is associated with a plethora of lifestyle factors and concomitant maternal disease. The biological plausibility with the inflammatory process initiated by infection is well documented.26 Maternal infection as a cause for PTB and the potential influence by probiotic intervention shows great promise. Recent work from Canada has shown that the supernatant (bacteriocin) of Lactobacillus rhamnosus attenuated the LPS-induced inflammation and PTB in the mouse model.35 Concomitant maternal vaginal infections are also associated with PTB. Escherichia coli and Streptococcus agalactiae (GBS) being the main culprits. In vitro studies have shown that the antibactericidal activity against E. coli and GBS is mediated not only by the direct action of specific bacteriocins against the bacteria but also by inhibition of attachment by the pathogenic bacteria to the epithelium of the urogenital tract.36–38 A growing body of evidence is linking probiotics to changes in the central neuroendocrine and neurochemical status.39 Probiotics are known to attenuate the inflammatory response with resultant positive changes in brain neurotransmitters.40 B. infantis intervention in the maternal rat separation model attenuated and reversed the abnormal behavioural activity of the animal whilst normalising the immune response and noradrenalin levels in the brainstem.39 Interestingly, stress can have a negative effect upon the intestinal microbiome and in particular the bifidobacteria in humans.40 Women with first-onset postpartum psychosis show a significant over-activation of the monocyte system possibly due to reduced T-cell changes both in number and function.21
Clinical studies in women’s health and perinatology Safety of therapy in pregnancy and nonpregnancy states has been studied specifically and a recent meta-analysis confirmed the safety of specific types of probiotics.41 Though we automatically assume the safety of such bacteria existing as commensal organisms within our intestinal tract, human sepsis from such bacteria, though extremely rare, has been documented in severely immunocompromised patients. Thus, care needs to be employed when using probiotics in trials that a specific antibiotic does exist for treatment of host sepsis should the need arise. There has been great heterogeneity involved with the use of probiotics and clinical trials to date. The route of administration has varied between oral, vaginal and skin. The oral route has been shown to change the vaginal flora although no direct comparative studies exist with vaginal routes of administration. Preparation of specific vaginal pessaries is probably not justified on the basis that oral preparations with a simple gelatin or cellulose capsule are effectively dissolved in the vagina. The chosen probiotic intervention has varied from singular strains to combinations of strains. The probiotic load as measured by the colony forming unit can vary
greatly log103 = 3. Furthermore, quality control of the probiotic to determine exactly what the bacteria are (as compared to what the manufacturer states) and the quantitative mass is often lacking. Additionally, the confounding effect of antibiotics within treatment arms of controlled trials is not fully explored in most data analysis sets. A singular course of antibiotics can influence the microbiome for months after cessation.42 Although beyond the scope of this review, the examination of maternal dietary intake especially relating to prebiotic ingestion is lacking in most studies. The length of probiotic ingestion has varied from a couple of weeks to the entire course of pregnancy and beyond. For probiotics to be effective and in the presence of nonmodulating exogenous factors, the minimum time considered essential for the probiotic action to become clinically noticeable is probably 4 weeks.43 The human clinical studies discussed in this article are listed in Table 2.
Insulin, glucose and lipid metabolism The prima facie study igniting the clinical application of probiotic manipulation of maternal glucose metabolism originated in Finland.44 The three armed randomised controlled trial (RCT) examined the effects of dietary advice in women who were within the normal body mass index (BMI) range. The dietary advice group combined with probiotic intervention produced a 64% statistically significant reduction in gestational diabetes mellitus (GDM) incidence compared to the other two groups.45 A significant reduction in blood glucose levels was achieved in the same group compared to the control group along with reduced insulin levels and improved insulin sensitivity. Due to the influences of dietary education and a highly selective population within the Finnish population and despite the apparent reduction in GDM rate, the changes quoted above cannot be attributed solely to the probiotic used.45 From the same Finnish study population, a reduction in postpartum cholesterol and lipid profiles as well as a reduction in maternal waist line measurements was recorded.46 The same Finnish authors discussed above published a 10-year follow-up of childhood weight gain in the offspring of mothers treated with L. rhamnosus during the last month of pregnancy and for the first 6 months of the child’s life.47 The study was as an offshoot from a probiotic childhood allergies study. The results demonstrated a trend towards a reduction in obesity at the 4-year-old stage but no differences at the 10-year stage. In Iran, Asemi et al. using a probiotic enriched yoghurt as the delivery method for the intervention showed an attenuation in the rise of plasma insulin during a 9-week intervention.48 The Iranian study group showed a reduction in triglyceride levels from the baseline reading in both probiotic enriched yoghurt and traditional yoghurt.49 Three other papers from the same Iranian cohort of 70
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Table 2 Human studies microbiome manipulation in women Study details Metabolic Dietary advice and probiotic capsule intervention on gestational diabetes incidence, BPRCT, n = 256, normal BMI, 12 weeks gestation till 12 months post partum, Finland45–46
Probiotic capsule on childhood allergies and secondarily weight gain, BPRCT, n = 159, last month of pregnancy to 6 months of child’s age, Finland47 Yoghurt intervention from third trimester for 9 weeks, PRCT, n = 70, Iran48–52
Probiotic capsule intervention, BPRCT, n = 138, raised BMI, 4 weeks intervention 24–28 weeks, Ireland.53–56 Blood Pressure Dietary intake, POP, n = 33399, primiparous only, Norway.58
Preterm birth Dietary intake, POP, n = 18888, Norway66
Dietary intake, POP, n = 18888, Norway.67 Group B Streptococcus Oral probiotic, O, n = 20, USA.73
Perineal probiotic, non pregnant, BPRCT, n = 191, Sweden.72 Breast Feeding Antibiotic vs Probiotic for mastitis treatment, RCT, n = 352, Spain.77
Constipation Oral probiotic, O, n = 20, Netherlands.79 Recurrent UTI Vaginal probitoic, non pregnant, BPRCT, n = 100, USA.82
Intervention studied
Outcome in respect to intervention
Dietary advice, L. rhamnosus and B. lactis in capsule form
Reduced birthweight and length in GDM affected pregnancies Lowered maternal blood glucose levels Reduced insulin levels 64% reduction in incidence of GDM Reduced total cholesterol and low density lipoprotein (LDL) cholesterol ?attributable to dietary intervention Trend towards a reduction in weight gain at 4 years of age but not sustained at 10 years of age
Natural yoghurt with L. bulgaricus and Streptococcus thermophilus vs natural yoghurt enriched with B. animalis and L. acidophilus
No difference between groups in HDL or LDL cholesterols and triglycerides Reduced rise in glucose and insulin baseline levels in probiotic group Increased erythrocyte glutathione reductase activity Reduced maternal hs-CRP No difference between glucose, insulin or lipid/cholesterol levels Excellent patient compliance
L. salivarius or placebo capsule
Prospectively collected data on dietary intake of probiotic milk beverages containing various bacteria such as L. acidophilus, L. rhamnosus, B. Lactis
Frequency of intake inversely linked to incidence and severity of pre-eclampsia with up to 40% reduction in severe disease
Prospectively collected data on dietary intake of probiotic milk beverages containing various bacteria such as L. acidophilus, L. rhamnosus, B. Lactis Prospectively collected data on dietary intake of alliums and dried fruit
Intake of probiotic resulted in a small lowering of the sPTBR with a weak dose dependent effect
Probiotic capsule Florajen3 – L. acidophilus, B. Lactis and B. Longum
Reduced GBS vaginal load with probiotic but concomitant dietary intake of yoghurt reduced incidence of GBS Incidence of GBS inversely related to lactobacillus colonisation rates
L. plantarum via a daily panty liner for 4 months
Alliums (esp. Garlic) were strongly related to a reduced sPTBR
L. fermentum, L. salivarius or antibiotic
Significant and sustained reductions in bacterial count of probiotic group Improvement in clinical symptoms and reduction in relapse rate
B. Lactis, B. Longum, L. plantarum, L. casei for 4 weeks
Improvement in frequency, incompleteness, straining at and obstruction of defecation
L. Crispatus for 5 days and then once weekly for days
Six-fold reduction in recurrent UTI in high level colonisation with L. crispatus
RCT, randomised controlled trial; P, placebo controlled; B, blinded; DB, double blinded; O, observational; POP, population; n, number of patients; L, Lactobacillus; B, Bifidobacterium; sPTBR, spontaneous preterm birthrate; GBS, Group B Streptococcus.
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Preterm Delivery (PTD)
patients showed no changes in serum iron, calcium or liver function tests, an increase in erythrocyte glutathione reductase as a measure of reduced maternal oxidative stress and a decrease in maternal high-sensitivity Creactive protein.50–52 However, an Irish placebo-controlled RCT using probiotic capsules with a 4-week intervention period showed no changes in the fasting glucose.53 Lindsay et al. very succinctly addressed the pertinent issue that shortterm use of a probiotic showed no influence upon the metabolic complications of pregnancy.54,55 A positive aspect from this study was the demonstration of good patient compliance and acceptability to the intervention treatment.56 The largest prospective study to date involving probiotic intervention to reduce GDM is the SPRING study currently being conducted in Queensland.57 This placebocontrolled RCT involving 540 women is using the same probiotic preparation – L. rhamnosus GG and Bifidobacterium lactis as the Finnish study but in women with a BMI over 25. Another strong point of this study is that detailed dietary questionnaires on diet and fermented milk products are being undertaken as well as antibiotic use. The results of this study will be hopefully available in 2016.
From the MoBa population, a group of 18,888 women were explored for links with PTD.66 Within this group, there would appear to be an 18% reduction of PTD attributed to prebiotic food preparations.67 The PTD increased to 50% when garlic alone was considered in the analysis. Fermented milk product ingestion reduced PTD by 15% – greater than that of the population study concerning smoking bans in public places.68 Particularly interesting is that the background rate of PTD in Norway was 5%, which is one of the lowest rates in the world. In the final analysis, both Norwegian papers failed to control for the effect of probiotic or prebiotic exposure. No protective effect was found from the ingestions of LR and reduction of PTD in pregnancies with male fetuses contrary to recent animal studies. A meta-analysis in 2007 failed to show a reduction in PTD with the use of probiotics.69 However, the three studies examined were so diverse in the primary outcome, quality control of product, choice of probiotic and temporal administration of the probiotic that any metaanalysis concerning PTD is both scientifically and statistically challenging.
Pre-eclampsia
Bacterial Vaginosis
The strongest evidence to date regarding the prevention of hypertensive disorders in pregnancy is from the MoBa (mother and baby) population (observational) study.58 The MoBa study involved nearly 34000 mother and baby pairs during 2002 to 2008 in Norway. Part of the prospectively collected maternity lifestyle questionnaire directly addressed the quantity of fermented milk products ingested during pregnancy. The analysis demonstrated up to a 40% reduction in severe preeclampsia for women ingesting high levels of fermented milk products during pregnancy. This effect was dosedependent showing a lesser response with lower doses of ingested fermented milk products. A meta-analysis exploring the link between blood pressure and the ingestion of fermented milk products in nonpregnant normotensive and hypertensive individuals found a significant reduction in both systolic and diastolic measurements.59 Also, nonpregnant adult levels of vitamin D and fibrinogen can be increased and triglyceride levels reduced by probiotics ingestion.60,61 Interestingly, across studies designed to reduce the incidence of pre-eclampsia, the most effective intervention to date is aspirin. Aspirin is thought to act at the maternal vascular endothelial cell/platelet level in preventing preeclampsia.62 However, aspirin reduces the growth of Candida albicans via reducing the hyphae’s prostaglandin production.63 Aspirin is not alone as a member of nonantimicrobial drugs that have antibacterial activity that are potentially both antagonistic and agonistic to the microbiome.64,65 Aspirin may well be a major confounding variable within multicentre trials.
BV is a non-life-threatening disorder in the nonpregnant state and the over judicious use of antibiotics is leading to the problem of increasing antibiotic resistance within the human microbiome.7 Therefore, the use of probiotics may offer an alternative but effective management strategy.8 The most effective intervention placebocontrolled randomised trials regarding bacterial vaginosis (BV) have used high doses (greater than 107 CFU) of lactobacilli and the specific singular or combination of strains – L. rhamnosus, L. reuteri, L. salivarius, L. plantarum, L. acidophilus and L. brevis.70 The individual studies were underpowered to detect significant changes as well as each trial showing wide variation in the temporal intervention lengths. Overall, there was a trend towards a cure for BV. Compared to antibiotic treatment alone, the addition of probiotics does show a stronger trend towards improved cure rates and reduced relapse rates.71 Meta-analysis of antibiotic interventions has the advantage of reduced heterogeneity based upon a known preparation and a greater degree of professional familiarity. These two factors will possibly influence the clinicians prescribing activity. However, the growing body of scientific evidence shows that despite the lack of definitive studies, the use of probiotics is essential to consider when treating BV.
Group B Streptococcus (GBS) No convincing data exist at present for treating pregnant women testing positive for GBS with probiotics. However, a novel placebo-controlled RCT used a panty liner infused
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with L. plantarum.72 191 nonpregnant women wore the liner 24 hours a day for 4 months. The primary aim was to examine the genital microbiome relationship to vaginal pH and secondarily the possibility of transferring the probiotic from panty liner to the genital tract. The conclusion regarding the second aim was that the panty liner with the LAB increased genital tract colonisation, but these data were not presented in the paper. An observational study using a proprietary preparation (Florajen3) capsule showed that the incidence of GBS was inversely related to the ability of LAB to adhere to vaginal epithelial cells.73 However, the study suffered from many errors of design and multiple confounding variables. The finding of an inverse relationship between LAB and GBS was found in an earlier noninterventional, observational study from Iran.74 It would perhaps appear that simply increasing the ratio of probiotic to pathogenic bacteria has the propensity to ameliorate or prevent associated urogenital tract infections.
Breastfeeding There have been more randomised controlled trials in pregnancy surrounding neonatal/childhood outcomes than the sum of all other such studies in pregnant women. This has been driven by the interest in childhood allergic conditions and maternal diet. Data from the previously mentioned MoBa cohort found a 6% reduction in early childhood allergic skin and eye conditions in the offspring of women who ingested fermented milk products during pregnancy.75 This reduction, albeit small was confirmed in a recent meta-analysis of probiotic intervention in pregnancy.76 The authors concluded that probiotic intervention may reduce the incidence of eczema in infants aged less than 2 years of age. Biologically, there appears to be (undefined presently) a direct relationship between the microbiome of the maternal gut and the microbiome of the breast milk that is not due to contamination from the maternal skin or baby oral cavity.22 Only one clinical study has examined the treatment effects of the maternal ingestion of probiotics upon mastitis.77 Although the study has shortcomings in design and antibiotic use, this intervention improved clinical symptoms and reduced relapse rates.
Constipation Constipation is a common complaint in pregnancy. RCT data from nonpregnant adult women show positive results in using probiotics as an intervention for constipation.78 Only two small studies have examined this in pregnancy. The first, an observational study in 2012 used a patented multispecies mixture in constipated women with a mean gestation of 20 weeks.79 The results showed a reported (nonvalidated questionnaire) improvement over baseline in defecation. The second study was as an offshoot from a nonplacebo nonblinded RCT in 40 women examining the effects of probiotics vs 206
clindamycin for the successful treatment of bacterial vaginosis (no difference in results for the primary outcome).80 Defecation-related problems significantly reduced in the probiotic group.
Recurrent Urinary Tract Infections Nonpregnant women with recurrent urinary tract infections (rUTI) using antibiotic prophylaxis show a marked increased in antibiotic resistant bacteria over the treatment period.81 Vaginally administered Lactobacillus crispatus significantly reduced the risk of rUTI when compared to placebo but only in women who showed high quantitative levels of L. crispatus in the vagina on followup (Table 2).82
The future Biological plausibility to support clinical treatment and trials is slowly arriving for the action of probiotics by primary in vivo research. However, our enthusiasm as professionals must be tempered by the realisation that a significant portion of clinical studies performed have been sponsored by parties with a vested commercial interest in the outcome. Although the results are promising, there is also a large degree of conflict in conclusions as well as only small numbers of patients. However, the potential benefits of probiotics in pregnancy are already being realised by women in Australia. If the SPRING study proves that GDM is reduced by probiotics, every woman either contemplating or already pregnant in Australia will be advised to take probiotics by the popular press. Recruitment of patients, therefore, to any future RCT to truly address the null hypothesis is going to prove very difficult. Detailed dietary analysis of patients within studies will need to be undertaken as the confounding variables of concurrent prebiotic and probiotic ingestion could be of sufficient strength as to falsely influence the null hypothesis. Also, detailed antibiotic exposure will need to be collected, as well as the evolving influences of plastics, exercise and ethnicity. The confounding effects of concomitant medications especially aspirin have not been considered to date in any meta-analysis or intervention study. Group B Streptococcus infection should be a very viable target of a probiotic intervention clinical trial but perhaps with localised rather than systemic application. Most of the completed clinical studies reviewed here have not involved any direct examination of the maternal microbiome. However, with the advancement of metabolomic sequencing, samples from ongoing studies are being stored for future examination. Yet we are only just scratching the surface of a very deep, complex and unknown sea of life-changing science.83 As Bacon quoted, we must have an open mind when approaching the arena of probiotics. We need to revisit the past in an attempt to link the scientific validity and biological plausibility of the human microbiome with the historical clinical outcomes
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and not merely to rely upon what we find now. It is a tragedy that so many pregnant women have been exposed to probiotics within the trial setting (childhood allergies), but so little data have been collected for maternal outcomes. A much greater degree of cooperative research is needed between all the faculties involved in women’s health to broaden the understanding and thus the knowledge of the foundation of human life – our microbiome, and in due course, the manipulation of the microbiome with probiotics.
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