microbiome in women's health
TRANSCRIPT
Cynthia Belew, CNM, WHNP-‐C Associate Clinical Professor University of California San Francisco [email protected]
I have no disclosures or conflicts of interest
Educate pts re dietary intake of fiber and fermented foods to preserve both physical and mental wellbeing Assist paKents to reclaim tradiKonal and indigenous fermented foods
Use probioKcs where there is abundant evidence on benefits Use expert guidelines to select probioKc strains for specific indicaKons
View inflammatory disorders as symptoms of gut dysbiosis and consider prebioKcs, probioKcs and fermented foods
Use probioKcs for BV treatment and prevenKon Decrease anKbioKc use: carefully consider evidence and clinical indicaKons for anKbioKc prescripKon Decrease presumpKve Rx of UTI Decrease overuse of abx for URI Don’t treat asymptomaKc BV in pregnancy
Be informed about gluten sensiKvity disorders Consider probioKcs for GDM: decrease risk, supporKve mgmt
Decrease GBS colonizaKon: fiber, fermented, immune support, specific probioKc strains Engage shared decision-‐making for GBS prophylaxis – develop decision aids Minimize duraKon of exposure to IAP by using clinical triggers to iniKate anKbioKcs Consider ways to decrease perinatal anKbioKc use: prophylaxis for CS, MROP Intriguing but limited evidence: restoring vag MB aWer CS, MasKKs, Colic Develop paKent educaKon handouts and guides for providers
Humans as ecosystem a collecKon of human & microbial cells that work in harmony
IntesKnal microbiome as “control center” for human biology, wired into immune system, metabolism, brain
Pregnancy & birth – key impact on health
Sonnenburg & Sonnenburg 2014
Key Concepts Improving the Microbiome AnKbioKcs Clinical pracKce suggesKons
Women’s Primary Care Antepartum and Intrapartum Care
Perinatal development of the Microbiome Perinatal disruptors of the Microbiome
Impact of intrapartum/antepartum anKbioKcs GBS prophylaxis and shared decision-‐making
Strategies to minimize perinatal anKbioKc use Including use of clinical triggers for IAP
Restoring the neonatal microbiome
CharacterisKcs & FuncKons IntesKnal Barrier FuncKon Selected Body Systems Diversity and ExKncKon
Abundance – trillions Complexity and Diversity
~ 1000 species per individual human gut
Variability DisKnct by body site, by individual human,
Microbial cross-‐talk and cross-‐feeding Interface of the self and environment
Much research in animal models Human research mostly descripKve CorrelaKon vs causaKon Randomized controlled trials: 1800 on probioKcs 300 on prebioKcs
1) Preserve barrier funcKon of gut mucosa SCFA butyrate energy source for colonic epihelium
2) ImmunomodulaKon
3) Interact with CNS
4) Regulate metabolic funcKon
5) DetoxificaKon of drugs, hormones, toxins
6) AbsorpKon of minerals Murtaza e al (2017). Gastroenterology Clin N Amer, 46(1), 49-‐60Alcock 2014
Plant-‐derived -‐ Dietary fiber, complex CHO
Animal-‐derived -‐ Collagen – (gelaKn) Vast variaKon of types of MACs
Each type nourishes SPECIFIC microbes
1) Koropatkin, Cameron & Martens 2012; 2) Sonnenburg ED & JL Sonnenburg, 2014
FermentaKon end-‐products absorbed into circulaKon Butyrate, Proprionate, Acetate, others
Diet alters raKos and concentraKons of SCFA
Arpaia et al 2013; Furusawa et al 2013; Smith et al 2013; Trompeme et al 2014; De Vadder 2014, Neyrinck et al 2012
Energy source for colonic cells Potent anK-‐inflammatory effects Increase number of T-‐reg cells
Regulate metabolism Improve insulin sensiKvity Protect against obesity
NeuroprotecKve
Lynch SV (2016). Annals Amer Thoracic Soc, 13 Suppl 1, S51-‐S54. Hamer et al (2008) Alimentary pharm & ther 27(2), 104-‐119 De SabaKno 2005; Hallert 2003
hmps://www.thinkbiome.com/prebioKcs/
Microbiota Gut Barrier
Short Chain Fatty Acids
Intes-nal Barrier Func-on
Single layer of cells
Barrier between gut microbiota and host
Dynamic Gatekeeper Tightly controls anKgen trafficking
Zonulin Fasano 2009, 2011, König et al (2016). Clinical translaKonal gastroenterology 7(10) e196-‐e196.
Gate stuck open Uncontrolled influx of anKgens TranslocaKon of bacteria/endotoxins Localized inflammaKon
Systemic inflammaKon Chronic inflammatory disease.
De Punder 2013, Teixeira 2011, Fasano 2011
Fasano 2009, 2011, König et al (2016). Clinical translaKonal gastroenterology 7(10) e196-‐e196.
Autoimmune disease Inflammatory bowel disease Celiac disease MulKple Sclerosis Rheumatoid arthriKs Type 1 diabetes
Asthma, Eczema, Allergies Metabolic disease Mood disorders, stress response, cogniKon
Fasano 2009, 2011, König et al (2016). Clinical translaKonal gastroenterology 7(10) e196-‐e196.
Fasano, A. (2012). Annals NY Acad of Sciences, 1258, 25-‐33. Sturgeon & Fasano(2016). Tissue barriers, 4(4), e1251384-‐e1251384
Leaky gut a necessary precursor to development of autoimmune disease
Need three factors: geneKc suscepKbility environmental trigger intesKnal permeability
Must have all three
Sturgeon & Fasano (2016).Tissue barriers 4(4), e1251384-‐e1251384.
IntesKnal dysbiosis
Gliadin (in Gluten)
Fasano, A. (2012). Annals NY Acad of Sciences, 1258, 25-‐33. Sturgeon & Fasano(2016). Tissue barriers, 4(4), e1251384-‐e1251384
IntesKnal permeability 6% esKmated prevalence IBS paKents :GF diet plus gluten powder/ placebo
84% improved w placebo 26% improved w gluten powder
GI bloaKng, foggy mind and depression more severe with low-‐dose gluten than placebo
ExtraintesKnal: headache, joint and muscle pain
Bernardo D, Garrote JA et al 2009; Di SabaKno et al 2015; Shahbazkhani et al 2015
Be educated about and have index of suspicion for gluten sensiKvity disorders
Be alert for extra-‐intesKnal manifestaKons of celiac and non-‐celiac sensiKvity
GALT Maintain tolerance to benign organism Regulate host defenses to infecKon
Modulates both innate and adapKve immunity, Resistance to GI infecKon, airway infecKon, systemic and CNS infecKon
Mediates cancer development, progression and response to treatment Mediate inflammaKon – T-‐reg and T-‐effector cell acKvity
Thaiss et al 2016 Nature 535, 65-‐742) Brown, & Clarke (2017). Immunology, 150(1), 1-‐6. 3) Pope et al. (2017) TranslaKonal Research, 179, 139-‐154.
Stress response Mood CogniKon Behavior
Eisenstein M 2016 Nature
The Gut-Brain Axis
MB produces NTs
Vagus nerve
Dysbiosis
AlteraKons in MB composiKon implicated in a wide range of neurologic and psychiatric condiKons, including depression, anxiety, chronic pain
The behavior of lab animals and humans is changed by changing the microbiome
Mamhew R, Hillmire et al Psych Res 2015; St-‐Onge MP et al J Clinc Sleep Med 2016; Schmidt, Cohen, harmer 2014)
Gut microbiota in early life play a role in programming the HPA axis and stress
reacKvity over the lifespan
Buffington, S. A., Di Prisco, G. V., Auchtung, T. A., Ajami, N. J., Petrosino, J. F., & Costa Matoli, M. (2016). Microbial ReconsKtuKon Reverses Maternal Diet-‐Induced Social and SynapKc Deficits in Offspring. Cell, 165(7), 1762-‐1775.
Gut Microbes may: Generate cravings for foods that nourish them or suppress their compeKtors Induce dysphoria unKl we eat foods that enhance their fitness
Mechanisms: Produce hormones that alter hunger and saKety Structurally similar to ghrelin and lepKn
Alter taste receptors Alcock, J., Maley, C., AkKpis, C. A. (2014). Is eaKng behavior manipulated by the gastrointesKnal microbiota? EvoluKonary pressures and potenKal mechanisms. BioEssays, 36(10), 940-‐949.
Obesity Diabetes
Increase energy harvest from food Increased gut permeability/translocaKon InflammaKon Altered producKon of saKety hormones
Disturbed metabolic signaling
Low MB diversity More common in obesity More weight gain over Kme
Lean mice inoculated with MB from obese mice or obese humans become obese Insulin sensiKvity in humans w metabolic syndrome improved by transferring gut MB from lean donors
Alcock, J., Maley, C., AkKpis, C. A. (2014); Le Chatelier et al 2013; Vrieze et al. 2012. Gastroenterology 143; 913-‐16;
RaKo of estrogen metabolites in women’s urine directly correlated w MB composiKon and diversity Diverse MB assoc w favorable raKo estrogen metabolites
ConnecKons of dysbiosis and anKbioKc use with increased Breast Cancer risk via higher levels of circulaKng estrogens Dietary phytoestrogens metabolized by MB
Chen & Madak Erdogan (2016).Trends endocrin metabol, 27(11), 752-‐755; Yang et al (2016). Breast Cancer, Oct 5 2016 epub
HydroxylaKon Phase I Liver Cytochrome
450
MethylaKon Cysteine Folate B12, B6
Magnesium Zinc
2-‐OH
16-‐OH
4-‐OH
GlucuronidaKon Bile -‐ Gut – Microbiome Chen & Madak Erdogan (2016).Trends
endocrin metabol, 27(11), 752-‐755;
Dysbiosis- intestinal reabsorption of
estrogens
Dysbiosis - Altered ratio of
estrogen metabolites
People w more MB diversity are leaner and have bemer metabolic funcKon
Low diversity: Increased adiposity, insulin resistance, LDL and markers of inflammaKon
Associated with several autoimmune disorders
1) CoKllard et al 2013, Le Chatelier 2013; Yan Yang, Long Gang, 2014
Our guts resemble a “landscape in decline” Gut ecosystem is malleable but also fragile. Lost species may never be recovered
Sonnenburg & Sonnenburg (2014). Cell metabolism, 20(5), 779-‐786.
Volunteers fed successively w different control diets over 10 weeks-‐blooms of specific bacterial groups occurred rapidly aWer each diet change
High vs low fiber changes in MB within 24 h
David, Maurice Carmody et al 2014 Nature; Walker, Ince et al 2011; Wu, Chen et al 2011
Non-‐modern socieKes – Greater diversity Different composiKon Lower rates of chronic disease
Intake of hunter-‐gatherers: 150 grams
Average daily fiber intake USA: 15 grams
Recommended intake: 35 grams
190,000y 10,000y
Sonn
enbu
rg, E. D
., Sonn
enbu
rg, J. L. (2014).
Starving our m
icrobial se
lf:. Cell m
etabolism
, 20(5), 779-‐786.
Low fiber diet over several generaKons results in progressive loss of diversity Bacterial species may be irreversibly lost in the individual AND IN THEIR OFFSPRING Recovery requires BOTH replacement of the missing species AND dietary MAC
Sonnenburg et al (2016). Nature, 529(7585), 212-‐215.
Starving microbes begin to digest the mucus lining of the gut and eventually the epithelial lining of the gut itself, triggering immune reacKons and chronic inflammaKon
Lower diversity-‐less ability to resist opportunisKc pathogens like C difficile or Salmonella
Impaired gut barrier integrity
Nourish
Dietary fiber Prebiotics
Replace
Fermented Probiotics
Restore microbiome diversity Improve quality of sleep Higher fiber diet = bemer sleep quality Higher simple carb intake – more nightme awakening
Decrease estrogen levels Decrease visceral fat
St-‐onge MP, Roberts et al 2016; Deehan & Walter 2016; Hairston et al (2012). Obesity, 20(2), 421-‐427.
JusKn & Erica Sonnenburg, directors Stanford Microbiome Lab
Dietary Fiber
Abundance Variety
Beans and legumes Nuts and seeds Vegetables and Fruits Root vegetables Garlic and onion family plants COLD potato, rice Resistant starch
Herbs: Dandelion, burdock
Whole grains
Synthesis of new compounds B-‐vitamins: folate, riboflavin, B12
AnK-‐inflammatory, neuro-‐modulatory Gut protecKve
Increased bioavailability of nutrients Strong associaKon w weight maintenance Yogurt: reduced risk CVD, diabetes
Karczewsk, Troost et al Am Jo Physiol Liver Physiol 2010; 298:G851-‐859; Marco et al (2016). Current opinion biotech, 44, 94-‐102.
Weight loss: Obese women who added KimChi to diet had more weight loss than w placebo Insulin sensiKvity: in Pre-‐diabeKc women dietary Kimchi increased insulin sensiKvity and BP, vs placebo
Patra JK et al 2016; An SY et al 2013; Kimchi review; Ahn SJ 20007
ModulaKon of HPA axis Fermented dairy product for 4 weeks modulates brain acKvity and decreases social anxiety, compared w a placebo group Fermented food intake in 700 college students: decreased social anxiety, independent of exercise and fruit/veg intake.
Kim et al (2016). PrevenGve nutriGon and food science, 21(4), 297-‐309; Tillische 2013; (Hilimire DeVylder & Forestell 2015)
Aid digestion Displace pathogens Synthesize vitamins
Decrease chronic disease Restore gut after antibiotics
Variety Small amounts adequate Live cultures Weight management, insulin sensiKvity, anxiety Integrate into Centering Pregnancy Help paKents re-‐claim tradiKonal fermented foods
Fermented Foods
ProbioKcs Live bacteria when delivered in adequate amounts, confers a health benefit on the host Transient
PrebioKcs Non-‐digesKble compound Selec.vely fermented by gut microbes Modulate composiKon and/or acKvity of the gut MB Confers a health benefit on the host.
Steinert et al. (2016). European Jo Clin Nutr 70(12), 1348-‐1353; Sánchez et al (2017). Molecular nutriGon & food research, 61(1)
Steinert et al. (2016). European Jo Clin Nutr 70(12), 1348-‐1353
Maintain intesKnal barrier funcKon
Increase mineral absorpKon
Modulate mulKple neurotransmimers
Modulate stress hormones
Steinert et al. (2016). European Jo Clin Nutr 70(12), 1348-‐1353
Diabetes: improved metabolic funcKon Bone: improves bone turnover markers Normalizes corKsol pamerns Increases focus on posiKve rather than negaKve sKmuli AnxiolyKc effects similar to that seen with SSRI
GOS galactooligosaccharide Schmidt, K., Cowen, P. J., Harmer,. (2015); Aliasgharzadeh et al 2015; Weaver CM 2015
More than 200 RCTs Repair the gut Modulate the immune system Weight management
Dozen RCTs for improving insulin sensiKvity, decreasing inflammaKon
Fernandes et al (2016). Clinical nutriGon; Liu et al (2017).. Europ Jo Clin Nutri, 71(1), 9-‐20; Shoaib et al. (2016). CHO polymers, 147, 444-‐54; Firmansyah et al (2016). Asia Pac Jo Clin Nutri, 25(4), 652-‐675.
Inexpensive Easy
Consider for immune, metabolic disorders, weight management, anxiety/stress START WITH LOW DOSE and increase gradually TheoreKcal concerns of decreasing diversity – context of dietary counseling re fiber Play with genome sequencing of your MB
Prebiotic Supplements
CiKzen science projects run by MB researchers Sequence a sample, change diet or add a prebioKc, repeat test
Sánchez et al (2017). Molecular nutriGon & food research, 61(1)
Effects are strain-‐specific
Effects depend on the host characterisKcs
Difficult to accumulate a body of knowledge because varying strains, doses, routes, duraKon of treatment and selecKon criteria are used.
Sánchez et al (2017). Molecular nutriGon & food research, 61(1)
PrevenKon of anKbioKc associated diarrhea PrevenKon and treatment of C. difficile disease PrevenKon and treatment of travelers diarrhea Childhood infecKous diarrhea – treatment Irritable bowel syndrome Inflammatory bowel disease Eczema treatment/prevenKon VaginiKs/vaginosis
Flock MH & WA Walker, 2015
EffecKve in several meta-‐analyses 39% reducKon in cases of C. difficile n=45,000 L acidophilis CL1285, L casei LBC80R and L rhamnosus CLR2 Available commercially
Maziade PJ et al 2015; Gao XW et al 2010; Goldenberg JZ et al 2013; Johnson Maziade et al 2012; Johnston BC et al 2012
Lactobacillus rhamnosus GG Acute gastroenteriKs Rx (11 RCTs)
PrevenKon of AAD (10 RCTs)
PrevenKon of nosocomial diarrhea PrevenKon of URI in children in day care
Saccharomyces boulardii Acute gastroenteriKs Rx (20 RCTs)
PrevenKon of AAD (21 RCTs)
PrevenKon of C dificile Travelers diarrhea IBS
Commercial products easily available
Depression/anxiety improved Decreased signs of psychological stress and improved task funcKon in healthy women MulKple sclerosis:
RCT, favorable effects on mulKple parameters of health and funcKon
,
Kouchaki, Tamtaji et al 2016; Akbari, Asemi et al 2016; Pirbagiou et al 2016
Clinical evidence for the strain /condiKon USP logo
Correct labeling, potency, purity Strain names, colony count, expir. Dates
Labeled w “live content at expiraGon date” not at Kme of manufacture”
At least 1 billion CFU (fewer for some strains) Ck company website: info about studies
Interna-onal Scien-fic Associa-on for Probio-cs and Prebio-cs World Gastroenterology Organiza-on Prac-ce Guideline on Prebio-cs and Probio-cs Systema-c review and meta-‐analyses for the specific condi-on
Commercially available products
Level of evidence rated Website and app “USprobioKcguide”
Easy to use!
hmp://usprobioKcguide.com/
CriKcal illness Immunosuppression Structural heart disease Presence of central venous catheter
Szajewska, H., Konarska, Z., Kołodziej, M. (2016). ProbioKc Bacterial and Fungal Strains: Claims with Evidence. DigesKve diseases, 34(3), 251-‐259.
Use probioKcs where there is abundant evidence on benefits UKlize guidelines to select probioKc strains for specific indicaKons
View inflammatory disorders as signs of gut dysbiosis, consider prebioKcs, probioKcs, fermented foods, dietary fiber Anxiety, depression, Obesity, diabetes
One-‐third of anKbioKcs given in the outpaKent setng are unnecessary
40% of adults and 70% of children take one or more anKbioKc every year
Fleming-‐Dutra, Hersh and Shapiro (2016) JAMA; 315(17)P1864-‐1873
Abx use not only depletes Microbiota, also destroys intesKnal epithelium Impairs mitochondrial fx – epithelial cell death occurs
Disrupts mucosal immunity Impacts a gene criKcal to communicaKon between host an microbe
Morgun (2015). Gut, 64(11), 1732-‐1743 hmps://www.sciencedaily.com/releases/2015/02/150210212634.htm
Obesity Allergies ColiKs Inflammatory bowel disease C-‐difficile and Salmonella growth Disrupted glucose metabolism Depression, anxiety
Morgun (2015). Gut, 64(11), 1732-‐1743
Single dose Clindamycin or Cephalosporin
Loss of 90% of normal flora lasKng for several months
Emergence of C difficile
Long-‐term suscepKbility to C diff coliKs
Buffie (2012). InfecGon and immunity, 80(1), 62-‐73.
One-‐week courses Placebo or Clindamycin Cipro, Amoxicillin,
DramaKcally decreased butyrate-‐producing bacteria Butyrate lowers inflammaKon
Broadest and Longest impact with Cipro Decreases one-‐third of taxa
Zaura e al(2015).. mBio, 6(6), e01693-‐e01615. Dethlefsen 2008
Two courses of Cipro in healthy adults “Profound and rapid” loss of diversity and shiW in composiKon Increased deteriora.on with the second round of abx, making it less likely to recover to original state Return to ini.al state o:en incomplete
Clindamycin causes overgrowth of species that produces metabolites known to be
neurotoxic.
Carefully consider evidence and clinical indicaKons for each anKbioKc prescripKon
Decrease presumpKve Rx of UTI Avoid unnecessary use of abx for URI Consider learning about the evidence-‐based use of herbal medicine for URI management
Give probioKcs with anKbioKcs to: Decrease risk AAD and C. difficile Decrease inflammaKon, heal gut mucosa
Early development of the MB Perinatal impacts on MB: ProbioKcs during pregnancy ImplicaKons for Intrapartum management Group B Streptococcus Vaginal Seeding
The Development of the Human Microbiome
ComposiKon of infant MB associated w
Maternal Diet in Last Trimester, Independent of Mode of Delivery
and Maternal Obesity
Chu DM et al. 2016. Genome Med 8, 77 Hu J et al. 2013 PLoS One 8, e78257
Maternal transmission of bacteria to fetal gut via DendriKc Cells
Maternal oral cavity shapes placental MB
Meconium reflects placental MB
MB-‐driven priming of fetal immune system starts in utero
Kuperman & Koren, 2016 BMC Med 14(1):91 Chu DM, Ma, Prince et al. 2017. Nature Medicine accessed online: hmp://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4272.html
Dynamic / rapid changing 1st three years
“Primary succession” series of ecologic events
InoculaKon at birth defines the condiKons of the ecosystem and influences subsequent pamerns of colonizaKon.
Lynch SV 2016. Gut Microbiota and Allergic Ds, New Insights
Microbiome controls development of the immature neonate immune system
Childhood Obesity Asthma Seizure disorders
Mueller et al 2015. Into J Obesity 39(4):665-‐70; Lapin et al 2015 Ann Allergy Asthma Immunol; 114(3);2-‐3-‐7
Laura M. Cox, Shingo Yamanishi, Jiho Sohn, Alexander V. Alekseyenko, Jacqueline M. Leung, Ilseung Cho, Sungheon G. Kim, Huilin Li, Zhan Gao, Douglas Mahana, Jorge G. Zárate Rodriguez, Arlin B. Rogers, Nicolas Robine, P’ng Loke, Martin J. Blaser Altering the Intestinal Microbiota during a Critical Developmental Window Has Lasting Metabolic Consequences; null, Volume 158, Issue 4, 2014, 705–721. http://dx.doi.org/10.1016/j.cell.2014.05.052
Late-pregnancy Low-dose PCN vs controls
Abdominal and liver adiposity
at mid-adulthood
Prenatal abx has bigger impact than at weaning
Backhed et al 2015 Cell Host & Microbe 17(5);690-703 http://dx.doi.org/10.1016/j.chom.2015.04.004
Cesarean associated with Disruped MB
Dominguez-‐Bellow, Blaser et al 2011
Asthma, Eczema, Allergies Type 1 Diabetes Obesity
Up unKl age 7 or older
Cuppari et al. 2015 Allergy Asthma Proc; 36(5):344-‐51
Lynch, S. V. (2016).. Annals of the Amer Thor Soci 13 Suppl 1, S51-‐S54.
Asthma Obesity
Eczema
Epilepsy
Diabetes
Adult Autoimmune and Metabolic Disease
Precautionary Principle
Single doses harms MB MB may never recover
Risk-benefit has changed
Kuperman & Koren, 2016 BMC Med 14(1):91
Infant MB with different composiKon and decreased diversity PersisKng to one year of life Increased risk atopic dermaKKs w IAP use for > 24 hours
Mazzola et al (2016). PLoS One, 11(6), e0157527-‐e0157527 Aloisio et al (2016). Applied Microbiology and Biotechnology, 100(12), 5537-‐5546. Azad et al (2016).. BJOG 123(6), 983-‐993.
AnKbioKc use 2nd/3rd trimester: 84% higher risk of obesity at age 7
Accounted for confounding variables: sex, ethnicity, birth weight, prepregnancy BMI, feeding method
Cesarean: 46% higher risk of childhood obesity
Mueller et al. (2015). InternaGonal Jo Obesity, 39(4), 665-‐670
BV associated with higher risk PTB Several meta-‐analyses
Treatment of Asymptomatic BV in Pregnancy
does not Reduce the Risk of Preterm Birth
Brockelhurst et al 2013 Cochrane Database Syst Rev; Nygren et al 2008 Ann Intern Med 148(3):220; Lamont et al 2011 Am J Ob Gyn 205(3):177
Risk of post-‐op infecKon varies ROM status, labor status
1000 receive abx to prevent 10 cases of infecKon Adapt current risk-‐scoring strategies for pregnancy Give abx aWer cord clamping
Ledger & Blaser (2013). BJOG: intl jo ob gyn, 120(12), 1450-‐1452.
A common pracKce that has not been shown to reduce the occurrence of endometriosis or puerperal fever aWer manual delivery of the placenta WHO: recommendaKon is based on low quality evidence
Chibueze (2015).. BMC Pregnancy and Childbirth, 15(313). World Health OrganizaKon (2012). WHO recommendaGons for the prevenGon and treatment of postpartum haemorrhage. Retrieved from hmp://apps.who.int/rhl/guidelines/9789241548502/en/
Clinical Triggers to IniKate Intrapartum AnKbioKcs
RecommendaKons for at least 4 hours of abx prior to delivery Our understanding of the Kme course of delivery is imperfect IniKaKon of abx early in labor results in excessive exposure to anKbioKcs occurs How to balance this?
Hamar, Illuzi & Funia, 2006
Clinical triggers to initiate IAP Delaying anKbioKcs unKl either In acKve labor (subjecKve evaluaKon of the clinician or 4 cm)
Receives narcoKcs or epidural Shorter anKbioKc duraKon, with adequate duraKon of abx therapy, compared w starKng abx at admission Works for nullips, not mulKps.
Clinical Trigger for Initiation of Abx
% rec’d > 4h abx
Mean duration abx (hr)
At admission 90.8 10.1 When oxytocin started 83 9.8 4 cm dilation 76.7 6.6 ACTIVE Labor: clinician eval of labor pattern or pain score >6 out of 10 (subjective criteria)
79.7 7.4
PAIN (epid. or narcotic) 75 7.0 LABOR (Active or 4 cm) 82.6 7.5
PAIN + LABOR 86.2 8.1
N U L L I P S
Narrowest spectrum and shortest duraKon Avoid Rx of AsymptomaKc BV in Pregnancy Use clinical triggers to minimize duraKon of exposure to IAP Exposure > 24hr linked w atopic disease
InvesKgate risk scoring strategies for anKbioKc prophylaxis at Cesarean, MROP
Source of GBS is the gut Prevent gut dysbiosis Dietary fiber, fermented foods
Persistence of GBS colonizaKon is dependent on host immune response Host immune response crucial in clearing vaginal colonizaKon Support maternal immune funcKon Fermented foods
Patras et al. (2015). Mucosal immunology, 8(6), 1339-‐1348.
FSE in GBS-colonized women and infection risk
FSE in GBS colonized women associated with: More than doubled the risk of neonatal GBS disease aWer adjustment for confounders
(Adair et al 2003) Odds RaKo: 2.24; 95% CI 1.22-‐4.13)
Increased risk of chorio (Soper) Odds RaKo: 2.01; 95% CI 1.68-‐2.41
FSE for > 12h: 7-‐fold increased risk of neonatal sepsis
(Yancey et al 1996) Odds RaKo: 7.2 95% CI 1.6-‐32.2)
CDC 2010: “however, lack of randomizaKon in observaKonal studies can result in confounding…
Healthy pregnant women, 35-‐37 wks GA , GBS GBS culture changed to negaKve in:
43% in the probioKc group 18% in the placebo group P=0.0007
Longer duraKon of treatment might be beneficial Products available commercially L. rhamnosus GR-‐1 and L. reuteri RC-‐14
Ho et al (2016). Taiwanese Jo ObGyn, 55(4), 515-‐518.
Candida glabrata Inhibit biofilms in vitro, shuts down metabolism of all C. glabrata
C albicans Inhibits ability to infect cells/induce inflammaKon
Bacterial vaginosis and E. coli Disrupts biofilms
(Petrova 2016; (Chew 2015; Karlsson; McMillan; MarKnez
Adheres to vag epithelium Displaces pathogens Increases abundance of L. crispatus Decreases vag inflammaKon
iners (Macklaim 2015) (Bisanz); Anukam 2006
Augments metronidazole in curing BV 88% cure w abx/probioKc vs 40% in abx/placebo p=<0.001
Restores normal flora in women w BV 61% vs 27% p< 0.001 n-‐544
Improves cure rate of fluconazole in Candidiasis
(MarKnez 2009) (Anukam 2006) (MarKnez 2009)
Start probioKc at around 30 weeks Especially if at high risk of GBS colonizaKon
Health care workers High BMI GBS colonized in prior pregnancy Black women
Cochrane review Four RCTs conducted 20 years ago involving 852 GBS+ women, and they were not well designed
“IAP is not supported by conclusive evidence”
(Ohlsson & Shah 2010)
IAP based on poor-‐quality evidence A variety of valid strategies are used in various countries Serious outcomes of GBS in term infants rare Several reports of zero mortality w term EOGBSD It should be a SDM process with woman’s decision respected
Sheehy, Davis & Homer. (2013) Women and birth, 26(2):152-‐157
Increased SDM, Improve the IC process Improve quality of care, Reframe the quesKon from consent to choice AND not increase duraKon of the encounter
Juliet HunKngton, CNM, UCSF Masters Comprehensive Paper 2016
Standards Exist to guide development and evaluaKon of decision aids Present absolute risk Use visual aids -‐ icon arrays
OpKons Grid CollaboraKve Dartmouth InsKtute for Health Policy Provides guidance and support for development
Decrease GBS ColonizaKon Support preg MB and immune funcKon Fermented foods, fiber
Consider probioKc in early 3rd trimester Esp if high risk for GBS L. rhamnosus GR-‐1 and L. reuteri RC-‐14
Develop decision aids for IAP Use probioKcs to treat/augment treatment for Bacterial Vaginosis
AssociaKon of CS with allergic and AI disease DisKnctly different infant MB by mode of delivery
MulKple studies
Numerous confounders: AnKbioKcs, NSAIDs, co-‐morbidiKes, exposure to labor, infant feeding method, maternal obesity
Azad M et al 2013; Chu DM, Ma, Prince et al. 2017. Nature Medicine accessed online: hmp://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4272.html
CS-‐born infants – less diversity at Kme of birth
At 4-‐6 weeks of age, no detectable difference in MB composi.on by mode of delivery (p=0.057)
Strongest factors impacKng infant colonizaKon: Intrapartum an.bio.cs
Cesarean-‐with-‐labor vs Cesarean-‐without-‐labor
Chu DM, Ma, Prince et al. 2017. Nature Medicine accessed online: hmp://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4272.html
Any supposiKon relaKng relaKve abundance and less abundance of imortant mb to cesarean delivery per se bust be treated w cauKon
Maternal Outcomes GestaKonal Diabetes Preeclampsia Reduced risk masKKs Reduced postpartum central adiposity Outcomes in the offspring Reduced risk of eczema RestoraKon of MB in Cesarean-‐born infants
Six RCT’s, one prospecKve cohort study Significant reducKons in:
Maternal fasKng glucose Incidence of GDM Incidence of preeclampsia Severe preeclampsia OR 0.61, 95% CI 0.43-‐0.89
Levels of C-‐reacKve protein Central adiposity at six months postaprtum (OR 0.30)
Lindsay KL, Walsh CA,Brennan L and FM McAuliffe 2013; VanderVusse L et al 2014
Decreased GDM incidence three-‐fold (Luoto) 13% w probioKc 36% with no intervenKon p=0.003 Also reduced fetal macrosomia L rhamnosus GG and B lacGs Bb12 Single products available, Nestle just filed for a patent for this combo
In women with GDM: Improved FPG, serum insulin, insulin sensiKvity in women with GDM, all staKsKcally significant (Karamali; Dolatkhan)
Six weeks of L acidophylus, L casei, B Bifidum vs placebo Modulate inflammatory markers in GDM (VSL3) Decrease wt gain and FBG
Karamali et al (2016). Diabetes & metabolism, 42(4), 234-‐241. Jafarnejad et al(2016). Jo Nutri Metabolism, 2016, 5190846-‐5190846; Luoto et al (2010). BriKsh Jo NutriKon, 103(12), 1792-‐1799; Dolatkhah et al (2015). Jo Health, Pop Nutr, 33, 25-‐25
Dietary counseling plus probioKc or placebo, first trimester Central adiposity: risk lower at 6 mo postpartum OR 0.03; 95% CI 0.11-‐0.85
Glucose regulaKon bemer during pregnancy and unKl 12 months postpartum P=0.013
L rhamnosus GG ATCC53103 and B lacGs
Ilmonen et al(2011). Clinical nutri, 30(2), 156-‐164; LaiKnen e al (2009). BriKsh Jo Nutr, 101(11), 1679-‐1687.
Prenatal probioKc use decreased incidence eczema World Allergy AssociaKon: approved for prevenKon of eczema if there is a family history of eczema Less evidence for asthma, food allergy, allergic rhiniKs EffecKve species:
L rhamnosus GG 53103 Bifidobacteria lacKs Bb-‐12
West, Jenmalm et al 2016; Kuitunen et al 2009, Pelucchi et al 2012,, Panduru et al 2015; Kalliomäki et al (2003) The Lancet, 361(9372), 1869-‐1871
Consider prenatal use of probioKcs for decreased risk of eczema in the offspring, in women with a family history of allergic disease
Consider use of prebioKcs, fermented foods, dietary fiber and probioKcs as a supporKve measure in prevenKon and treatment of diabetes Improve insulin sensiKvity Decrease inflammaKon
Isolated from breast milk; used in mulKple infant disorders, Commercially available in drops Cesarean-‐born infants:
62 infants: vaginal and CS, probioKc or placebo ProbioKc parKally restored MB of CS infants towards that of those born vaginally at 4 months
No impact on MB of vaginally born babies
Garcia Rodenas et al (2016). Jo of ped gastroenterology nutri, 63(6), 681-‐687.
PrevenKon of AAD in children Infant colic Colic, regurgitaKon and consKpaKon Infant consKpaKon FuncKonal abdominal pain in children Reduce bronchial inflammaKon in children w asthma NecroKsing enterocoliKs in VLBW infants, nosocomial infecKon in PT infants Diarrhea and URI in children
Kolodziej et al BMJ 2017; Chau et al 2015 J Pediatr 166:74-‐78; (Szajewska et al J Pediat 2013; 162:257-‐262; Indrio et al 2014 JAMA Pediatr 168;228-‐233; Coccorullo et al 2010; J Pediatr 157;598-‐602; Jadresin et al 2016 J Ped Gastroent ; Nutr’ Miraglia del Giudice et al 2012 J Biol Reg 26;35-‐40; AgusKna et al 2012
Four studies, 1125 infants, term and preterm No difference in early-‐onset GBS disease May be a reducKon in neonatal colonizaKon with GBS Low quality evidence Wipes out normal flora
Ohlsson, Shah & Stade 2014 Cochrane Review
Buffington, S. A., Di Prisco, G. V., Auchtung, T. A., Ajami, N. J., Petrosino, J. F., & Costa Matoli, M. (2016). Microbial ReconsKtuKon Reverses Maternal Diet-‐Induced Social and SynapKc Deficits in Offspring. Cell, 165(7), 1762-‐1775.
Infants -‐ L Reuteri DSM 17938 Cesarean infants developed a microbiome more similar to that found aWer VB Infant colic in breast-‐fed infants Reduce incidence of diarrhea in children in day care centers Mgmt of acute gastroenteriKs
Rodenas CL et al 2016, Chau, Lau, Greenberg et al 2015, Urbanska, Szajewska 2014; Buffington et al (2016). Cell, 165(7), 1762-‐1775
hmps://www.scienceandsensibility.org/p/bl/et/blogid=2&blogaid=825
18 mom-‐infant pairs (11 CS, 7 VB); swab in hour preceding scheduled CS, swab infant within 2 min aWer birth (mouth, face, body) 1500 samples analyzed in 1st month of life Exposing neonates born by CS to maternal vaginal fluids parKally normalizes the microbiota to resemble that of vaginally delivered infants Successful even in cases w abx exposure
Health outcomes have not yet been assessed Inclusion criteria:
GBS negaKve, no viral or bacterial infecKons, no signs BV, acidic vaginal pH <4.5
Concerns: transfer of pathogens GBS infecKon or unknown GBS status STI’s, CT, GC, Herpes
Increasingly common DIY by parents Inadequate knowledge about what IS a healthy vaginal MB. Varies by race. Need deeper understanding Clinical trial in process w 78 mom/infant pairs through first year of life
Clemente, J. C., Dominguez Bello, M. G. (2016). Safety of vaginal microbial transfer in infants delivered by caesarean, and expected health outcomes. BMJ. BriKsh medical journal, 352, i1707-‐i1707.
Theory is biologically plausible but data is scant No assessment of clinical outcomes Transfer of maternal pathogens could result in severe adverse consequences for the infant: GBS Herpes Chlamydia Gonorrhea
Recommend AGAINST this pracKce unKl bemer data available
Fernández et al (2016). Clinical infect dis, 62(5), 568-‐573; Arroyo et al(2010). Clin infect ds, 50(12), 1551-‐1558.
PrevenKon: ProbioKc 30 weeks GA unKl birth MasKKs in first 3 months postpartum decreased: 25% probioKc, 47% placebo P=0.001
InfecKons less severe w probioKc lower colony counts and pain scores L salivarius PS2, available commercially
Treatment: Cure higher in probioKc than anKbioKc group by colony counts (p<0.01) By pain symptoms
Recurrence rate higher in abx group (p< 0.001) L fermentum CECT5716 or L salivaris CECT5713
Working Group to create a shared decision-‐making tool for GBS prophylaxis Guide to evidence on prenatal use of probioKcs for providers Project to recover knowledge of tradiKonal and indigenous fermented foods Develop risk-‐scoring strategy for anKbioKc prophylaxis at Cesarean
List of resources follows this slide References available upon request
Recommended Resources
American Gut The Good Gut The Gut InsKtute Human Microbiome Project Center for Microbiome InformaKcs and TherapeuKcs at MIT Emeran Mayer, UCLA on gut-‐brain UCLA Ctr for Neurobiology of stress and resiliance microbiome secKon
Gregor Reid, vaginal MB MarKn Blaser, director NYU Human Microbiome Program JusKn and Erica Sonnenberg, directors Stanford Microbiome Project Rob Knight, UCSD Susan V Lynch, UCSF Emeran Mayer Maria Domenguez-‐Bello Int’l ScienKfic Assoc for ProbioKcs and PrebioKcs
Chris Kresser InsKtute for FuncKonal Medicine/FuncKonal Forum Human Food Project Ancestral Health SocietyGut Microbiota for Health Experts Exchange Terry Wahls TED talk (MD controls her MS w diet) Ubiome My New Gut Project Living AnKbioKcs Tight JuncKons blog
Body Ecology Cultures for Health FermentWorks