به نام خدا 1. BREASTMILK Dr. Sadeghnia Immunologic Significance of Human Milk Leukocytes Concentration is same in pripheral blood Predominant cell

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BREASTMILKBREASTMILK

Dr. SadeghniaDr. Sadeghnia

Immunologic Significance of Human Immunologic Significance of Human MilkMilk

LeukocytesLeukocytes Concentration is same in pripheral bloodConcentration is same in pripheral blood Predominant cell is macrophage:Predominant cell is macrophage:

90% of the leukocytes90% of the leukocytes 2000 to 3000/mL2000 to 3000/mL

Lymphocytes make 5% to 10% of the cellsLymphocytes make 5% to 10% of the cells T cells in colostrum are 50% of lymphocytesT cells in colostrum are 50% of lymphocytes T cells in milk are 80% of lymphocytesT cells in milk are 80% of lymphocytes


Macrophages:Macrophages:– Phagocytosis of fungi and bacteriaPhagocytosis of fungi and bacteria– Interaction with lymphocytesInteraction with lymphocytes– Storage and transport of Storage and transport of

immunoglobinimmunoglobin– Production:Production:

»C3, C4, lysosome, lactoferrine, lysozyme, C3, C4, lysosome, lactoferrine, lysozyme, IgA, lactoperoxidase and cellular growth IgA, lactoperoxidase and cellular growth factorfactor

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Polymorphonuclear:Polymorphonuclear:– Colostrum contains 100,000 to Colostrum contains 100,000 to

5×1000,000 leukocytes/mL and 40% to 5×1000,000 leukocytes/mL and 40% to 50% are PMNs50% are PMNs

– Mature milk has 100,000 Mature milk has 100,000 leukocytes/mL with 20% to 30% PMNsleukocytes/mL with 20% to 30% PMNs

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Lymphocytes:Lymphocytes:– T cells are 80% of the lymphocytes in breast T cells are 80% of the lymphocytes in breast

milkmilk– The B cells synthesize IgA antibodyThe B cells synthesize IgA antibody– The B cells in human milk include IgA, IgM, The B cells in human milk include IgA, IgM,

and IgG on the surfaceand IgG on the surface– Larger thymus at breastfed infantLarger thymus at breastfed infant– Response to rubella, CMV, mumps, K1Ag of E. Response to rubella, CMV, mumps, K1Ag of E. colicoli

– Remaining viable in upper GI tract for a weekRemaining viable in upper GI tract for a week

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Immunoglobulins:Immunoglobulins:– More than 30 components have been More than 30 components have been

identified (12 are found exclusively in identified (12 are found exclusively in milk)milk)

– IgA is the most important immunoglobulin IgA is the most important immunoglobulin in milk (90% of all immunoglobulins)in milk (90% of all immunoglobulins)

– sIgA is the highest in colostrum sIgA is the highest in colostrum – sIgA stimulate of GI production of sIgA stimulate of GI production of

immunoglobulinimmunoglobulin

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FactorFactor Active againstActive against

Secretory IgASecretory IgA PoliovirusPoliovirus

CoxsackievirusCoxsackievirus

EchovirusEchovirus

HerpesvirusHerpesvirus

CMVCMV

HIVHIV

E coliE coli

ShigellaShigella

SalmonellaSalmonella

KlebsiellaKlebsiella

ClostridiumClostridium

GBSGBS

IgM, IgGIgM, IgG CMVCMV

RSVRSV

RotavirusRotavirus

RubellaRubella

IgEIgE PV B19PV B19 8


Bifidus Factor (nitrogen-containing Bifidus Factor (nitrogen-containing carbohydrate)carbohydrate)

Bifid bacteria (gram-positive, Bifid bacteria (gram-positive, nonmotile, anaerobic bacilli):nonmotile, anaerobic bacilli):– Lactobacillus bifidusLactobacillus bifidus– Bifidobacterium bifidumBifidobacterium bifidum– Bifidobacterium infantisBifidobacterium infantis– Bifidobacterium longumBifidobacterium longum

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Resistance factor (free fatty acid):Resistance factor (free fatty acid):– Antistaphylococcal factorAntistaphylococcal factor

Lysozyme:Lysozyme:– EnterobacteriaceaeEnterobacteriaceae– Gram-positive bacteriaGram-positive bacteria

Complement (opsonic factor):Complement (opsonic factor):– C3C3– C4C4

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Lactoferrin:Lactoferrin:– Depriving the microorganism of iron; a Depriving the microorganism of iron; a

bacteriostatic effect on gram-positive and bacteriostatic effect on gram-positive and gram-negative aerobes, anaerobes, viruses, gram-negative aerobes, anaerobes, viruses, parasites, and fungi parasites, and fungi

– Direct action on bacterial surface Direct action on bacterial surface – Binding bacterial host cell blockingBinding bacterial host cell blocking– Changing the permeability of the fungal cell Changing the permeability of the fungal cell

surfacesurface– Immune-modulating effectImmune-modulating effect

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InterferonInterferon– Produced by T cells & NK cellsProduced by T cells & NK cells– Strong antiviral activity Strong antiviral activity

Vit B12-Binding proteinVit B12-Binding protein– B12 unavailable for bacteriaB12 unavailable for bacteria

GlycansGlycans– AntipathogenAntipathogen– Immunomodulatory (by affecting DCs) Immunomodulatory (by affecting DCs)

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Interleukins:Interleukins:– IL-6IL-6

» Increase production of IgAIncrease production of IgA» Enhancing phagocytosisEnhancing phagocytosis

– IL-7IL-7» Enhances T-cell proliferationEnhances T-cell proliferation

– IL-8IL-8» Activating neutrophilsActivating neutrophils

– IL-10IL-10» Antiinflammatory (decreasing of Inf-Antiinflammatory (decreasing of Inf-γγ))

– IL-12IL-12» Enhance IgG, IgA, IgMEnhance IgG, IgA, IgM

– IL-18IL-18» Macrophage activation, production of GM-CSFMacrophage activation, production of GM-CSF

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Cytokines:Cytokines:– Preventing of NECPreventing of NEC

»EGFEGF»EPOEPO»G-CSFG-CSF

– Stimulating IgA productionStimulating IgA production»TGF-TGF-ββ

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Nucleotides:Nucleotides:– ATP (available cellular energy)ATP (available cellular energy)– Nucleic acid (precursors for DNA and Nucleic acid (precursors for DNA and

RNA)RNA)– ADP (platlet aggregation)ADP (platlet aggregation)– CAMP, CGMP (messenger):CAMP, CGMP (messenger):

»Effect on immune systemEffect on immune system»Growth of intestinal and hepatic cellsGrowth of intestinal and hepatic cells»Enhance the growth of bifidobacteriaEnhance the growth of bifidobacteria

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Oligosaccharides (prebiotic):Oligosaccharides (prebiotic):– Facilitating the growth of probiotic Facilitating the growth of probiotic

bacteriabacteria»Lactobacillus rhamnosusLactobacillus rhamnosus»Bifidobacteria bifidusBifidobacteria bifidus»Saccharomyces boulardiiSaccharomyces boulardii»Streptococcus thermophilus Streptococcus thermophilus »Bifidobacteria infantisBifidobacteria infantis»Bacillus subtilisBacillus subtilis

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IMMUNOLOGIC BENEFITSIMMUNOLOGIC BENEFITSHealth Risk For Formula-Fed vs. Brestfed BabiesHealth Risk For Formula-Fed vs. Brestfed Babies

2 to 7 times allergies, eczema2 to 7 times allergies, eczema 3 times ear infections3 times ear infections 3 times gasteroenterities3 times gasteroenterities 3.8 times meningitis3.8 times meningitis 2.6 to 5.5 times UTI2.6 to 5.5 times UTI 2.4 times diabetes, type 12.4 times diabetes, type 1 2 times SIDS2 times SIDS 1.5 to 5 times pneomonia1.5 to 5 times pneomonia 1.5 to 1.9 times IBD1.5 to 1.9 times IBD 1 to 6.7 Hodgkins lymphoma1 to 6.7 Hodgkins lymphoma High likely to be obeseHigh likely to be obese Daughters are at higher risk of breast cancerDaughters are at higher risk of breast cancer

Medications in Breast MilkMedications in Breast Milk

Analgesics:Analgesics:– Heroin (appear in milk at high levels)Heroin (appear in milk at high levels)– CodeineCodeine– MeperidineMeperidine– DiazepamDiazepam– Aspirin (salicylate appears in the milk and Aspirin (salicylate appears in the milk and

can occur metabolic acidosis)can occur metabolic acidosis)– Acetaminophen is well toleratedAcetaminophen is well tolerated– Ibuprofen (400 mg twice per day)Ibuprofen (400 mg twice per day)

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Antibiotics:Antibiotics:– Sulfa drugs (G6PD deficiency should never Sulfa drugs (G6PD deficiency should never

recieve)recieve)– Chloramphenicole is contraindicated in nursing Chloramphenicole is contraindicated in nursing

because for idiosyncratic reactionbecause for idiosyncratic reaction– Tetracycline causes staining of teeth and Tetracycline causes staining of teeth and

abnormalities of bone growth abnormalities of bone growth – Erythromycine appears in higher amounts in Erythromycine appears in higher amounts in

milk than in plasma and can decreasing the milk than in plasma and can decreasing the clearance of carbamazepine, digoxin, clearance of carbamazepine, digoxin, theophylline, anticoagulantstheophylline, anticoagulants

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Antibiotics:Antibiotics:– Aminoglycosides readily appear in the milkAminoglycosides readily appear in the milk– Metronidazole appear in milk at levels equal in Metronidazole appear in milk at levels equal in

serumserum» Gel or cream is poorly absorbedGel or cream is poorly absorbed

– Amoxicillin and cephalosporins are safe during Amoxicillin and cephalosporins are safe during lactation, but affected the flora of the gut; the lactation, but affected the flora of the gut; the milk half-lives is 2 times and neonate serum milk half-lives is 2 times and neonate serum half-lives is 4 times longer than the serum half-half-lives is 4 times longer than the serum half-lives in motherlives in mother

– Fluoroquinolones are safe for nursing Fluoroquinolones are safe for nursing

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Anticholinergics:Anticholinergics:– These medications (Atropin, These medications (Atropin,

scopolamine, Hyoscine) enter the milkscopolamine, Hyoscine) enter the milk– Infants are particularly sensitive to Infants are particularly sensitive to

these drugsthese drugs»Milk secretion may decreaseMilk secretion may decrease»ConstipationConstipation»Urinary retentionUrinary retention

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Gastrointestinal medications:Gastrointestinal medications:– Cimetidine (milk concentrations higher than in Cimetidine (milk concentrations higher than in

maternal plasma)maternal plasma)» Interfere with phenytoin, warfarin, propranololInterfere with phenytoin, warfarin, propranolol

– Omeprazole level is lower in the milk than Omeprazole level is lower in the milk than cimetidinecimetidine

– SulfasalazineSulfasalazine» Sulfapyridine is absorbed from the colon and Sulfapyridine is absorbed from the colon and

metabolized in liver and appear in the milk in lower metabolized in liver and appear in the milk in lower concentration than in the serumconcentration than in the serum

» 5-aminosalicylic acid is partly absorbed and rapidly 5-aminosalicylic acid is partly absorbed and rapidly excreted in the urineexcreted in the urine

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Anticoagulants:Anticoagulants:– Heparin and LMW heparins does not Heparin and LMW heparins does not

pass into breastpass into breast– Heparin and LMW heparins are not Heparin and LMW heparins are not

absorbed from the GI tractabsorbed from the GI tract– warfarin is the drug of choice in warfarin is the drug of choice in

lactationlactation

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Antithyroid Drugs:Antithyroid Drugs:– Iodide pass into the milk in higher level than Iodide pass into the milk in higher level than

in the maternal plasmain the maternal plasma» Asthema preparations and cough medicinesAsthema preparations and cough medicines

– Thiouracil appears in higher concentration in Thiouracil appears in higher concentration in milk than in blood milk than in blood

– Methimazole and Carbimazole are pass into Methimazole and Carbimazole are pass into the milkthe milk

– Propylthiouracil is compatible with Propylthiouracil is compatible with breastfeedingbreastfeeding

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Caffein and methylxanthines Caffein and methylxanthines (Theophylline, Dyphylline, (Theophylline, Dyphylline, Theobromine) are present in milk Theobromine) are present in milk and can make wakeful or and can make wakeful or hyperactive infantshyperactive infants

Steroids are excreted in the milk in Steroids are excreted in the milk in low doseslow doses

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Galactagogues:Galactagogues:– MetoclopramideMetoclopramide– Sulpiride (antidepressant)Sulpiride (antidepressant)– Domperidone (fewer extrapyramidal Domperidone (fewer extrapyramidal

side effect)side effect)

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Cardiovascular:Cardiovascular:– Digitalis (peak plasma levels occur 1.5 to 3 hours Digitalis (peak plasma levels occur 1.5 to 3 hours

after ingestion & concentration of milk is 59% of after ingestion & concentration of milk is 59% of the maternal plasma level)the maternal plasma level)

– Propranolol was found in the milk (monitoring Propranolol was found in the milk (monitoring plasma levels of the infant may be helpful)plasma levels of the infant may be helpful)

– Atenolol levels in milk are also higher than in the Atenolol levels in milk are also higher than in the maternal serum maternal serum

– Metoprolol is safestMetoprolol is safest– Nadolol and Acebutolol must be used at or less Nadolol and Acebutolol must be used at or less

than 400 mg/daythan 400 mg/day

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Diuretics:Diuretics:– Most diuretics little passes into milkMost diuretics little passes into milk– Chlorothiazide have greatest risk for Chlorothiazide have greatest risk for

producing free bilirubinproducing free bilirubin– Chlorothiazide and hydrochlorothiazide Chlorothiazide and hydrochlorothiazide

are safe for breastfeeding are safe for breastfeeding – Furosemide displace bilirubin from Furosemide displace bilirubin from

albumin and slowly excreted by the albumin and slowly excreted by the newbornnewborn

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Central Nervous System Drugs:Central Nervous System Drugs:– Phenytoin and phenobarbital (level in infant Phenytoin and phenobarbital (level in infant

have been less than 5% of the therapeutic have been less than 5% of the therapeutic dose for infants)dose for infants)

– Valproic acid have risk of accumulation Valproic acid have risk of accumulation (variations in sleeping and feeding)(variations in sleeping and feeding)

– Carbamazepine associated with cholestatic Carbamazepine associated with cholestatic hepatitishepatitis

– Difficulty establishing of lactation and poor Difficulty establishing of lactation and poor weight gain are common weight gain are common

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Psychotherapeutic Agents:Psychotherapeutic Agents:– Lithium is presented in breast milk and infants Lithium is presented in breast milk and infants

become hypotonic, flaccid, and depressedbecome hypotonic, flaccid, and depressed– Chlorpromazine or phenothiazine appears in Chlorpromazine or phenothiazine appears in

the milk in small amountthe milk in small amount– Lorazepam is safe for multiple dose therapyLorazepam is safe for multiple dose therapy– Chlordiazopoxide and Clorazepate metabolites Chlordiazopoxide and Clorazepate metabolites

are also active and therefore half-life is are also active and therefore half-life is prolongedprolonged

– Meprobamat has M/P ratio greater than 1 Meprobamat has M/P ratio greater than 1

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Psychotherapeutic Agents:Psychotherapeutic Agents:– Tricyclic antidepressants presented in Tricyclic antidepressants presented in

milk about 1% of maternal dosemilk about 1% of maternal dose– SSRI peak plasma time varies from 1.5 SSRI peak plasma time varies from 1.5

to 12 hoursto 12 hours– Sertraline, Paroxetine, Citalopram Sertraline, Paroxetine, Citalopram

may be better choicesmay be better choices

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Medical Complication of MothersMedical Complication of Mothers

Diabetes Mellitus:Diabetes Mellitus:– Fewer infants of mothers with diabetes are Fewer infants of mothers with diabetes are

put to the breast in the first few days put to the breast in the first few days – First time at 35± 5 hrsFirst time at 35± 5 hrs– Less insulin while lactating Less insulin while lactating – Many women with diabetes report a feeling Many women with diabetes report a feeling

of well-being during lactationof well-being during lactation– Breast feeding has been associated with Breast feeding has been associated with

prevention of DM-2 in woman with prevention of DM-2 in woman with gestational diabetesgestational diabetes

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Diabetes Mellitus:Diabetes Mellitus:– Breastfeeding is associated with reduce Breastfeeding is associated with reduce

BS, postpartum weight loss, reduce long BS, postpartum weight loss, reduce long term obesityterm obesity

– Lower incidence of IDDM in breastfed Lower incidence of IDDM in breastfed infantinfant

– Strongest protective effect of Strongest protective effect of breastfeeding during first 4 month and breastfeeding during first 4 month and incidence of IDDM in the first 7 years of incidence of IDDM in the first 7 years of lifelife

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Maternal Hypothyroidism:Maternal Hypothyroidism:– Medication should be continued and Medication should be continued and

breastfeeding encouraged breastfeeding encouraged – Particular care should be used to rule Particular care should be used to rule

out hypothyroidism in the infantout hypothyroidism in the infant Maternal Hyperthyroidism:Maternal Hyperthyroidism:

– PTU is ionized and protein bound PTU is ionized and protein bound

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Epilepsy:Epilepsy:– Attention must be paid undernutrition Attention must be paid undernutrition – Sufficient stimulus to the breast Sufficient stimulus to the breast

(electric pump)(electric pump)– Supplementary feedingSupplementary feeding– WithdrawalWithdrawal

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Crohn Disease and Ulcerative Colitis:Crohn Disease and Ulcerative Colitis:– Sulfisoxazole must be discontinued in Sulfisoxazole must be discontinued in

the third trimester and replace with the third trimester and replace with salazosulfapyridine (SASP)salazosulfapyridine (SASP)

– Sulfapyridine (SP) M/S=0.4Sulfapyridine (SP) M/S=0.4– SP serum infant is 10% maternal serumSP serum infant is 10% maternal serum– Prednisone therapy is safe because Prednisone therapy is safe because

levels in milk are low levels in milk are low

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Cardiac, Liver, and Renal Cardiac, Liver, and Renal Transplantation:Transplantation:– AzathioprineAzathioprine

» Level of serum IgA is not affected in infantLevel of serum IgA is not affected in infant

– 6-mercaptopurine6-mercaptopurine»Therapeutic level is 50 ng/mL and in the Therapeutic level is 50 ng/mL and in the

milk is 3.4 ng/mLmilk is 3.4 ng/mL

– Methyl-prednisolone (prednisone)Methyl-prednisolone (prednisone)– Cyclosporine Cyclosporine

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به نام خدا 1. BREASTMILK Dr. Sadeghnia Immunologic Significance of Human Milk Leukocytes Concentration is same in pripheral blood Predominant cell