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When traditional interventions for

insufficient milk just don’t work

Hidden genetic, nutritional &

environmental culprits

Marsha Walker, RN, IBCLC

Marshalact@gmail.com

Disclosure

Sufficient Milk Production Has Always

Been Important!

• Ancient writings describe

numerous reasons for

diminished milk supply

and recommend dozens

of remedies

• Many writings show

awareness of some

causes of insufficient

milk but do not relate

remedies to causes

Incidence of Insufficient Milk

Is it real or perceived?• Most frequent reason given

for supplementing or abandoning breastfeeding

• Probably 1-2% of the general population of women are anatomically or physiologically unable to produce sufficient milk

• 3,977,745 births in 2015– 1% = 39,777 mothers primary

insufficient milk production

– 2% = 79,555 mothers with primary insufficient milk

– 5% = 198,887 mothers with primary insufficient milk

Oh no! You ran out of milk?

Milk synthesis is a

very complex process

• Estrogen, progesterone,

prolactin, placental

lactogen transition breast

from non-secreting to

secreting organ

• Alveolar cells � expression

of lactogenic genes

(secretory differentiation)

• Secretory activation with

delivery of placenta

• Tight junctions between

lactocytes close,

limiting passage of ions

like sodium and

chloride

• Important for

establishment of

lactation and facilitation

of milk secretion

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Milk secretion from lactocytes

• Regulated by complex

milieu of reproductive

and metabolic

hormones

– Prolactin

– Glucocorticoids

– Insulin

– Insulin-like growth factor 1

– Growth hormone

– Thyroid hormone

• These hormones can

act directly on the

lactocyte or

indirectly by altering

endocrine response

and nutrient delivery

to the mammary

gland for milk

production

Also need an appropriately developed

and differentiated breast

• Up to a two-fold

increase in glandular

tissue during lactation

• Disruption of

appropriately

developed and

differentiated breast

tissue

– PCOS

– Environmental

exposures

Volume of colostrum

• First 24 hours colostrum

ingested by healthy full

term 6lb 13oz (3.1 kg)

infants

– 15 + 11mL colostrum

total

• Santoro et al, 2010

– 13mL/kg/d (39mL total)

• Casey et al, 1986

– 9.6mL/kg/d (28.8mL

total)

• Dollberg et al, 2001

Milk volume• Mothers of healthy term

infants should be able to produce 500-600 mL (17.8 oz-21.4 oz) of milk by day 4-7– Hill PD et al. Journal of Perinatal and

Neonatal Nursing 19: 273-282, 2005.

• Full milk production is generally reached by 14 days

• If milk production is <440mL (15.7oz) by day 7 and birth weight not regained,

• Kent et al. Nutrients 2016; 8(12):756

Risk factors for insufficient milk

• Primip

• Cesarean

• Infertility

• Polycystic ovary syndrome

• Obesity

• Hyperandrogenism

• Insulin resistance

• Advanced maternal age

• Mammary hypoplasia

• B12 deficiency

• Endocrine disruptors exposure

• Prolactin deficiency

• Prolactin receptors

• Thyroid hormones

• Milk ejection problems

• Serotonin

• Hypertension

• Breast injury

• Placenta encapsulation

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Risk factors for insufficient milk

• Retained placenta

• Breast surgery

• Infrequent breastfeeding (FIL)

• Ineffective breastfeeding

• Preterm or late preterm birth

• Diabetes

• Infant with oral anomalies, birth defects

• Postpartum hemorrhage

• Anemia

• Certain medications

• Smoking

• Certain contraceptives

• Breast pump and pumping issues

• Genetics

• Environment

• Maternal diet

• Aripiprazole (Abilify) is an atypical antipsychotic drug that is also used with other medications to treat depression

• A common adverse effect of some antipsychotic medications is hyperprolactinemia (high prolactin levels)

• Aripiprazole can be and is given to patients to reduce prolactin levels

• Breastfeeding mothers taking aripiprazole should be monitored carefully for milk sufficiency and their infants monitored for appropriate weight gain

– Li X, Tang Y, Wang C. Adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia: metaanalysis of randomized controlled trials. PLoS One. 2013;8(8):e70179.

– Walker T, Coursey C, Duffus ALJ. Low dose of Abilify (Aripiprazole) in combination with Effexor XR (Venlafaxine HCL) resulted in cessation of lactation: A case report. Clinical Lactation 2019; 10:56-58.

Aripiprazole (Abilify)

Polycystic ovary syndrome (PCOS)

• PCOS is the leading cause of infertility

– Polycystic ovaries

– Obesity

– Hyperandrogenism

– Anovulation

• Failure to ovulate results in low progesterone which inhibits mammary tissue growth

– Insulin resistance

• Co-morbidities– Hypothyroidism

– Metabolic syndrome

– Hypertension

– Glucose intolerance

– Diabetes

Polycystic ovary syndrome (PCOS)

Hypoplastic breasts• Excess of one or more

male hormones– Ovarian theca-lutein cyst

• Estrogen and progesterone receptor deficit

• Androgens inhibit breast development and limit breast growth by opposing the stimulatory effects of estrogen– Hirsutism

– Alopecia

– Adult acne

Insulin resistance

(may go undiagnosed for years)

• Study of mammary gland RNA in samples of

breast milk (a chain of molecules that are

blueprints for making specified proteins)

• Orchestrated switching on and off of genes as

breast transitions from colostrum to copious

milk production

• Insulin important to signaling in mammary

gland

– Lemay et al. PLoS One 2013, 8:e67531

Insulin resistance• Study links insulin

resistance or inefficient glucose metabolism with insufficient milk supply

• The intracellular signals triggered by the binding of the insulin with the cellular receptors get suppressed by the expression of the PTPRF gene

• This gene was found to be over expressed in insulin resistant mothers, linking the insulin resistance with insufficient milk supply. *protein tyrosine phosphatase, receptor type F

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Will improving insulin action be

effective for increasing milk supply?

• Interventions that lower maternal cortisol (a

suppressor of insulin action)

• Skin-to-skin care of the newborn

• Metformin therapy

• Fenugreek-may improve glucose tolerance

due to metformin-like biguanides

• Weight loss

• Stress reduction

Overweight/obesity

and Lactation

• Mothers with delayed lactogenesis II (>72 hours post

birth) are more likely to have high BMI

• Breastfeeding durations decrease as maternal BMI

increases

• Obesity alters the 24 hour spontaneous release of

prolactin

• Prolactin response to sucking is blunted in obese

mothers, decreasing by ~45ng/mL at 48 hours

postpartum and 100ng/mL at 7 days, during the time

period important for optimal milk production

Overweight/obese mothers experience a delayed onset of

lactogenesis II and reduced milk transfer at 60 hours

postpartum

• For each 1-unit (1 kg/m2) increase in pre-

pregnant BMI, a 0.5-hour delay in the onset of

lactogenesis II has been calculated

• Difference in onset of copious milk production

can be up to 10 hours later in a mother with a

MBI of 40 compared to a mother with a BMI

of 20

Obesity effect on lactating breast

• Mouse model showed that obesity impairs mammary gland development– Obese mice exhibited marked abnormalities in

alveolar development within the mammary gland

• Obesity also impaired lactogenesis; seen as lipid accumulation in the secretory epithelial cells, showing an absence of copious milk secretion

• Obesity-induced inflammation of the mammary gland with premature involution

• May increase local estrogen production which downregulates prolactin signaling and suppresses lactation

• Flint DJ, et al. 2005 Am J Physiol Endocrinol Metab• Lee & Kelleher 2016 AJP Endocrinol Metab

Breaking the Cycle of

Overweight/Obesity

• Breaking the cycle of overweight and obesity begins at the

beginning

– Overweight/obese mothers should breastfeed VERY frequently

during the first 7-10 days

� number of feedings critical in the first 12 hours for stimulating

lactogenesis II in mothers with IDDM

(Ferris, 1993)

– Infants need to be monitored more closely

– All of these mothers need a feeding plan before hospital

discharge and close follow-up thereafter

• May have decreased perceptions of breast fullness and

milk production

Breastfeeding Management

• Frequent feeds 10-12 times each 24 hours should continue until lactogenesis II has been confirmed and the baby is gaining weight well

• Alternate massage/breast compressions

• Large breasts should be supported with a rolled up towel or receiving blanket

• Flat nipples can be everted prior to each feeding with a modified syringe

• Nipples may flatten out due to

excess adipose tissue that stretches

the areola & flattens the nipple

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Pillows, props and

difficulty with positioning

• May need to breastfeed

in front of a mirror

• Positioning difficulties

may last longer for

obese others

• May have difficulty

finding large size bras

Problems with prolactin

• Autoantibodies that target prolactin-secreting cells

• Prolactin bioavailability, bioactivity or form

• Prolactin receptor numbers and action or inaction

• Prolactin receptor resistance

• Pituitary issues

• Prolactin replacement therapy (recombinant prolactin)

• Metoclopramide

• Domperidone

Do some mothers have

the wrong kind of prolactin?• 3 kinds of prolactin, 2 of which

are inactive

• Big prolactin and Big-Big prolactin (macroprolactin) are inactive

• All show up in normal blood prolactin test, making it look like normal levels

• Do moms with high prolactin levels and little milk have the wrong kind of prolactin?

• Rarely, autoantibodies recognize a subset of prolactin secreting cells impacting prolactin deficiency– Treated with recombinant

prolactin

Prolactin and suction/vacuum levels

• Association between suction pressure and prolactin response

• Low intraoral vacuum correlated with

– lower prolactin response to sucking

– Longer time to perceived onset of lactation

• Zhang et al. Breastfeeding Medicine 2016; 11:461-468.

• Mothers of infants with low intraoral vacuum will need increased monitoring of milk production

– Preterm, late preterm, neurological issues

• Assure proper positioning and latch, intact seal of lips, strengthening of muscles involved in sucking

Thyroid dysfunction• Hypothyroid during pregnancy may affect mammary

development

• Excessive iodine intake

• Hypothyroid– Thyroid responsible for cellular activity; decreased milk

production could result from slow down in milk-secreting cell activity (Synthroid etc)

– Fatigue, decreased energy, hair loss, weight gain, dry skin, muscle aches, constipation, poor concentration

• Hyperthyroid– Assess for suppression of milk ejection reflex

– Early, dramatic onset of lactation, painful engorgement, milk ejection problems

– Weight loss, nervousness, sweating, heart palpitations

– Prophylthiouracil; Tapazole

Impaired milk ejection

• Milk ejection issues may

contribute to

insufficient milk if

breasts are unable to

release the milk they

produce

• Thyroid dysfunction

• Stress

• Breast pump use

• Massage and hand expression

• Reverse pressure softening

• Warm compresses

• Oxytocin nasal spray

• Conditioning the milk ejection reflex

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Impaired milk ejection

• Gene mutation resulting in decreased levels of connexin43

– Gap junction protein expressed in myoepithelial cells

– Delayed development of mammary gland and impaired milk ejection

– High glucose levels alter connexin43 expression

– Does diabetes play a role here?

Prenatal SSRIsMarshall et al. J Clin Endocrinol Metab. 2010;95:837-846

•Serotonin acts as a neurotransmitter, a

type of chemical that helps relay signals

from one area of the brain to another

•Serotonin is a local regulator in the breasts

for lactation

•SSRIs like Paxil inhibit serotonin reuptake in

mammary epithelial cells and disrupt

serotonin regulation in the breasts

Serotonin

• Serotonin contributes to milk volume homeostasis

• Disruption of normal serotonin levels can lead to accelerated decreases in milk synthesis and involution of the mammary gland

• Delayed lactogenesis II

• Infant hypotonia

• Increased vigilance in infants whose mothers have taken prenatal SSRIs

• Feeding plan should include– Increased feedings during

prolonged colostral phase

– Frequent weight checks

– Documentation of milk transfer

– Pre and post feed weights if needed

– May need to pump milk to bolster production

Genetics, diet, and environment

Lee & Kelleher. 2016. Am J Physiol Endocrinol Metab 311: E405-E422

Genetic variation in genes that encode

for prolactin signaling• Mutation in prolactin and

prolactin receptors

• Prolactin signaling pathway represents a set of reactions induced by the binding of prolactin to the prolactin receptor

• Genetic variations (certain genes inactive or switched off) in prolactin signaling pathways

• Recombinant prolactin may be effective in increasing milk volume when this pathway has been affected

Cytokeratin 18 (CK18)

• CK18 is a marker for luminal epithelial cells

including lactocytes (milk making cells)

• High maternal BMI is linked with lower CK18

expression in breastmilk cells

• Suggests that women with larger body mass

index have less epithelial tissue capable of

synthesizing milk

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Zinc—who knew? Zinc transport mutations• Mutation of the protein ZnT2 which transports

zinc in specific body tissues– Low Zn in milkk

– Reduced mammary gland development

– Functional problems

• ZnT2 transports zinc by importing it into vesicles -- small organelles within the cell -- that then secrete zinc into the breast milk.

• Zinc is also necessary to trigger the growth of mammary glands, mammary epithelial cells and secretion pathways.

• Without functional ZnT2, zinc accumulates in the cytoplasm, becoming toxic to the cell.

Prolactin and ZnT2 are partners

• ZnT2 is critical for

mammary gland

expansion and

differentiation and milk

secretion

• Loss of ZnT2 results in

breast hypoplasia– Lee et al. J Biol Chem

2015;290:13064-13078

• Prolactin plays a primary

role in ZnT2 activity– Qian et al. Am J Physiol Cell

Physiol 2009; 297:C369-C377Kelleher et al. Genes & Nutrition 2009;

4:83-94

Genetic variants

• The common genetic variant S288 in ZnT2 causes

– oxidative stress in the lactocyte

– Impaired paracellularbarrier function

– Lysosomal mediated cell death

– Increased sodium content in breastmilk

• Lee et al. Scientific Reports 2018;8:3542

Looking for zinc

• It is possible to take a sample of saliva and sequence the gene for ZnT2 (SLC30A2) and see if there is a mutation directly

• Some companies can do this now

• Low zinc levels in mother’s milk would strongly suggest a defect in a zinc transporter

• The mom's serum zinc levels are not affected because low milk zinc is caused by a defect in her breast.

• However, if the mom's serum zinc levels were low, then she would likely be suffering from another issue (inflammation, diabetes, obesity, or very low dietary intake of zinc) that my also lead to low milk zinc levels.

What can we do?• Most women are marginally

low in zinc

• Adding a bit more of zinc to the diet would not be harmful but too much could be toxic

• Unknown if it would be therapeutic with the ZnT2 variants

• In some cases domperidonemay help.

• Since ZnT2 is regulated by prolactin and depending upon the defect in ZnT2, extra prolactin may help fix the problem

• Enrich the mother’s diet with antioxidants

• Most lactation defects seem to have an inflammation component

• The underlying consequence of a defect in ZnT2 may be inflammation

• So if we reduce inflammation, we can solve the problem that the defect in ZnT2 is actually causing

• Future drug that targets the particular pathway/mechanism

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Adding a little incentive to

pumping + an antioxidant!Photo courtesy of Barbara Wilson-Clay

Exposure to environmental toxins• Exposure to endocrine

disrupting compounds

during pregnancy can

affect mammary gland

development

• Exposure to chemicals

increase expression of

numerous genes, some

of which disrupt normal

differentiation and

development of the

milk production

apparatus in the breast

• Atrazine and dioxin– In herbicides

• Bisphenol A (BPA) and dibutylphthalate– In plastics

• Nonylphenol– In laundry and dish detergent

• Polybrominated diphenyl ethers– A flame retardant

• Perfluorooctanoic acid (PFOA)– In cleaning products and pesticides

• Perfluoroalkyl substances (PFAS)

• Perchlorate – Blocks iodine uptake by thyroid

causing hypothyroidism

– In fireworks, contaminated water, food from contaminated croplands (milk, spinach, lettuce, soy), food packaging

Herbal Galactogogues

• Need to understand what is contributing to insufficient milk production

• Avoid shotgun approach or simultaneous taking of numerous trial remedies at the same time

• Understand HOW a galactogogue works

– Directly

– Indirectly by addressing an inhibiting problem such as hyperandrogenism or insulin resistance

• Conflicting information, differing research methodology, and lack of standardization of herbal galactogogues makes it difficult to interpret what actually works

Improving mammary gland growth

• Fenugreek

– 2 dropperfuls tincture x2-3

– 2-4 500 mg capsules x3/d

– Tea is often not potent enough

• Goat’s rue

– 1-2mL tincture x4/d

– 1 capsule x1/d

– If >175 lbs, 2 capsules x3/d

– Lactogal Plus (Salatino 2017)

• Torbangun

• Blessed thistle

• Metformin

• Zinc supplementation

Fenugreek Cautions

• Baby may smell like maple syrup; physician should know this; Maple Syrup Urine Disease has same odor

• Not all mothers respond with �milk

• Nausea and GI distress may limit its use in some mothers; high fiber content may cause diarrhea

• Some mothers may see a drop in milk as dose is �

• May � blood glucose levels in mothers with diabetes

• Antigenic similarity to peanuts; mothers with severe peanut allergy should not take this herb

• Mothers on anticoagulant therapy should use with caution as herb has “blood thinning” capability

Herbal galactogogues• Shatavari (Asparagus racemosus)

– � prolactin production; mammary tissue growth?

• Torbangun (Indian borage; Coleus amboinicus lour)

– Proliferation of mammary secretory cells

• Milk thistle (Silybum marianum)

– Estrogenic property

• Moringa oleifera

– May increase prolactin levels

• Malunggay

– Stimulates prolactin levels

• Goat’s rue (Galega officinalis)

– Phytoestrogen content

• Fennel (Foeniculum vulgare)

– Estrogenic activity

• Anise (Pimpinella anisum)

– Estrogenic activity

• Is it the herbal or the psychological benefit?

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Combination herbals

• Many preparations on the market contain varying amounts and combinations of herbal preparations

• A combination of fenugreek, ginger, and turmeric was shown to increase milk volume as measured by a hand pump

– Bumrungpert et al. Breastfeeding Medicine. December 2018. ahead of print

• Mothers had a 49% increase in milk volume at week 2 and a 103% increase at week 4

Medications• Domperidone

– Dopamine antagonist, but does not cross blood-brain barrier, � likelihood of depression

– Stimulates milk production at doses of 10-20mg, 3-4 times daily

– Compounding pharmacies can formulate domperidone

– Caution if mother is also taking antacids, antifungals, Macrolides, HIV protease inhibitors, monoamine oxidase inhibitors

– Should not be given to mothers with cardiac arrhythmia or anomaly

– Does not work for all mothers; may not work unless maternal prolactin levels are low

• Human growth hormone

• Thyrotropin releasing hormone

• Recombinant human prolactin

• Kinesio tapeR was applied to the breasts using fan cuts for relaxing the pectoralis muscles and facilitating fluid movement.

• Mothers reported doubling or tripling the amount of milk they could pump after the tape was applied

Therapeutic taping Therapeutic taping

• May improve milk circulation by lifting the skin, increasing the space below

• Also has been used for blocked milk ducts

Valdez, Jet al. (2018). Abstract 81. Effects of Kinesio Tape application on breastmilk production. Breastfeeding Medicine, 13(S2), S36.

Acupuncture for insufficient milk

• Clavey (1996) reported

90% effectiveness for

insufficient milk when

started within 20 days

of delivery

• American Journal of

Acupuncture 1996;

24:35-46

• Wei et al (2008)

described electro-

acupuncture at Shaoze

(SI 1) as effective for

insufficient milk

• Wei, et al. (2008).

Journal of Traditional

Chinese Medicine

28:168-172

AcupressureEsfahani et al. 2015. Iran J Nurs Midwifery Res, 20:7-11.

• Acupressure for

enhanced milk

production

• Can be applied by the

mother• GB20 (in a depression between the

upper portion of the

sternocleidomastoid muscle and the

trapezius on the same level with

GV16), acupoint LI4 (on the dorsum

of the hand, between 1st and

2nd metacarpal bones), and acupoint

SI1 (1 cun posterior to the corner of

the nail on the upper side of the little

finger)

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http://www.newbornconcepts.com/pr

oducts#pumping_cdReflexology

• Another low tech intervention for increasing milk production

• Performed on the foot on kidney one, pituitary point on middle of toe, and points between 2, 3, and 4 metacarpals

• Showed increased milk output in preterm cesarean mothers during first 4 days

– Mohammadpour et al. Iran J NursMidwifery Res 2018;23:371-375.

Warmth

• The warming of tissues is a known therapeutic intervention that has the effect of increasing local blood flow and metabolism in tissues, facilitating excretion of tissue waste materials and phagocytosis, and enhancing tissue nutrition

• Warm compresses placed on the breasts have long been recommended to aid the let down reflex.

• Kent et al(2011) found that warmed pump flanges resulted in a larger amount of available milk removal.

Warmth• Yigit et al (2012) studied if warming the breast prior

to pumping would increase the volume of milk expressed from a warmed breast compared with the other breast which was not warmed.

• Mothers placed a warm compress (40.5C/104.9F) on one breast prior to pumping with an electric breast pump.

• The amount of milk obtained from the warmed breasts was significantly higher than that obtained from the non-warmed breasts.

• Warming probably has an enhancing effect on the milk ducts or milk flow, allowing more milk to be pumped, rather than increasing actual breastmilk production.

Music

• Keith et al (2012) found

that pump dependent

mothers who listened

to music while pumping

produced significantly

more milk with a higher

fat content

Why music?• Soothing music increases oxytocin levels

(Nilsson, 2009)

• Improved endothelial vasoreactivity

• Flute music experienced by 30 preterm

mothers during first week of lactation for 30

minutes, 15 of which during actual pumping

reduced anxiety

• Mothers who experienced music therapy had

a significantly increased amount of expressed

milk compared with mothers who did not

experience music

• Lowers stress and cortisol levels

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Hang in there Mama--

you got this!