SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

MEDICINES & LACTATION

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Objectives

To describe:

◦ How drugs pass into breast milk

◦ The potential effects of medicines taken by a mother, to a

breast-fed infant

◦ The drugs used to stimulate or suppress lactation

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Breast feeding
WHO
◦ Optimal form of infant feeding
◦ Meets all health & diet requirements (~6 months)
◦ Increases resistance to infection & disease

96% newborns initially breastfed (Australia - 2010)

69% receiving some breastmilk at 4 months (39% exclusively)
60% receiving some breastmilk at 6 months
WHO –
recommends exclusive breastfeeding for first 6 months of life, and
breast milk for 12 months of age at least
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
Proportion of children receiving any breastmilk, by age
(% ± confidence interval) (Australia)

Age (months) %
0 (less than 1 month) 90.2 ± 10.8
1 74.6 ± 1.9
2 72.7 ± 1.5
3 70.3 ± 1.5
4 68.7 ± 1.5
5 62.9 ± 1.6
6 60.1 ± 1.7
7–12 42.2 ± 2.3
13–18 18.2 ± 1.9
19–24 7.4 ± 1.3
Source: National Health Survey 2010
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
Benefits
Breastfed babies:
◦ Have less:
◦ diarrhoea
◦ necrotising enterocolitis
◦ respiratory illness
◦ middle ear infection
◦ Type I diabetes
◦ childhood leukaemia

◦ Enhanced cognitive development

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Benefits
Maternal:

◦ Faster recovery from childbirth

◦ Reduces risk of pre-menopausal breast cancers
◦ Reduces risk of ovarian cancer
◦ Reduced maternal depression

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Breast milk
1st week postpartum – colostrum
◦ IgG, IgA, IgM, Interferons, antibacterial substances
→ colonisation of GI tract

Complete nutrition
◦ ~ 600mL/day (increases in response to demand)
◦ Fat, protein, carbohydrate
◦ Vitamins, minerals, digestive enzymes, hormones

•Composition varies during the day, water:fat ratio

◦ foremilk – watery, low fat, high carbohydrate
◦ hindmilk - creamier

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Lactation
Post partum –
◦ At birth: fall in progesterone & increase in prolactin
→ milk production
Prolactin – regulated by hypothalamus
Oxytocin – contracts the alveoli to squeeze milk into ducts
◦ Milk ejection reflex (‘let-down’ reflex)

Dopamine – inhibits prolactin secretion

Dopamine antagonists –
◦ Metoclopramide
◦ Domperidone } ↑ milk production
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
 Galactagogues (↑ milk production)
Metoclopramide (S4)
◦ 10mg oral tds
7-14 days
Domperidone (S4)
◦ 10mg oral tds
7-10 days

Limited evidence – small trials

Less drowsiness with domperidone
Small quantities in breast milk – thought to be clinically insignificant
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
 Suppression of lactation
Medical reasons
Dopamine agonists → inhibits prolactin → ↓ milk production
Cabergoline (S4)
◦ 1mg oral stat on first day postpartum
Bromocriptine (S4)
◦ 2.5mg bd for 14 days postpartum
Other drugs:
◦ ergotamine
◦ oestrogens (OCP)
◦ pseudoephedrine
◦ diuretics?
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
 Drugs and breastfeeding
CMIs largely discourage breast feeding
Lack of evidence from humans – mainly animal studies
◦ Breast milk pH>7
◦ Cow’s milk pH<6.8

Nearly all drugs transfer into breast milk to some extent

Only use drugs if therapeutically indicated
◦ Consider risk vs benefit
On average <1% of maternal dose transferred to infant

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Factors affecting drug transfer into milk
Kinetics:

 Lipid solubility
 Molecular weight
 Blood level and plasma binding in maternal circulation
 pH and ionisation

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Lipid solubility
Highly lipid soluble drugs
→ Pass in to milk in higher concentrations

Hindmilk (milk at end of a feed) contains more fat

→ higher concentration of fat-soluble drugs
Foremilk (milk at start of feed) – higher water content

CNS active drugs (penetrate blood-brain barrier – lipid soluble)

→ expect higher levels in milk
? sub clinical amounts
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
 Molecular weight
Diffusion:
◦ Large molecules do not pass eg heparin, insulin

Secretion:
Plasma (maternal) → capillary walls → alveolar cells → alveolar cell
walls → milk ducts

During early life (up to 10 days old) – large gaps between alveolar cells
allow access of large molecules (eg maternal immunoglobulins,
lymphocytes) - and drugs
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
Blood level and plasma
binding in maternal circulation
High maternal plasma levels
◦ Higher penetration into breast milk
◦ Two-way diffusion

Protein binding
◦ Increased protein binding (albumin) eg phenytoin
→ Less free drug, less drug to pass into milk

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

pH and ionisation
Breast milk pH 7.2
Plasma pH 7.4
→ weakly basic drugs (higher pKa) transfer more readily
into breast milk eg barbiturates, iodides, lithium?
→ become trapped secondary to ionisation

Leads to high milk:plasma ratios

◦ M/P concentration ratio

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Oral bioavailability in the mother and the infant
Poor oral bioavailability - mother
◦ Lower plasma concentration, less transfer to milk

Infant acidic stomach

◦ poor absorption with calcium-rich milk
◦ Oral bioavailability

Generally:
<1% of a dose of a drug will reach the milk and subsequently the infant
◦ BEWARE OF EXCEPTIONS!

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Milk/plasma ratio
High ratio → more drug in milk
M/P ratio < 1 – only low concentrations of drug likely to be
transferred
M/P ratio > 1 – drug enters breast milk in higher concentrations
◦ eg M/P ratio = 4
◦ concentration of drug in milk is 4 x higher than in maternal
plasma
….BUT if maternal plasma concentration is low,
then absolute amount of drug in milk is also low;
…..ALSO time alters the M/P ratio

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Estimation of infant exposure
The infant's dose (Dinfant) received via milk can be calculated using:
- the maternal plasma concentration (Cmaternal),
- the Milk/Plasma ratio (M/PAUC) and
- the volume of milk ingested by the infant (Vinfant)
Vinfant estimated as 0.15L/kg/day

Dinfant (mg/kg/day) = Cmaternal (mg/L) x M/PAUC x Vinfant (L/kg/day)

Allows infant dose to be expressed as % of adult dose

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
 Infant exposure to drugs
‘Safe’ use of drugs in lactation:
◦ Infant dose ≤ 10% (weight adjusted) of maternal dose

Avoid drugs that produce greater exposure – potential toxicity:

◦ Lithium – infant dose up to 80% of maternal dose
◦ Amiodarone – infant dose up to 50% of maternal dose

Avoid drugs with greater potential toxicity:

◦ Cytotoxic agents, immunosupressives, isotretinoin

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Drugs in Pregnancy vs Drugs in Lactation
Safe in pregnancy ≠ Safe in lactation
Infant metabolism; Clearance; Bioavailability
Post-conceptual age Clearance of drug
(as % of adults)
24-28 weeks 5%

28-34 weeks 10%

→ 34-40 weeks

40-44 weeks
33%

50%

44-68 weeks 60%

>68 weeks 100%

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Estimating risk
Thomas Hale
◦ Medications and Mothers Milk

Drug monographs include:

◦ t1/2 (adult and child)
◦ milk/plasma ratio (M/P)
◦ time interval from administration of the drug until it
reaches the highest level in the mother’s plasma
◦ % of maternal protein binding (PB)

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Minimising risk
Monitor infant
◦ adverse effects
◦ failure to thrive

? Feed immediately prior to dose

◦ BUT milk concentration can lag behind plasma
concentration

Bottle feed (express and discard) – resume after drug

eliminated from maternal system (approx. 4 half-lives)

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Risk vs Benefit
Maternal dose /infant dose

Preference

Education & Communication

Follow up – mother & child

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 CONTRAINDICATED IN BREAST FEEDING:
DRUG ADVERSE EFFECTS
ANTINEOPLASTICS RISK OF NEUTROPENIA
CHLORAMPHENICOL BONE MARROW DEPRESSION
ERGOTAMINE DOPAMINERGIC ACTION (SUPPRESS
LACTATION)
GOLD RISK OF RASH, NEPHRITIS, HEPATITIS,
HEAMATOLOGICAL ABNORMALITIES

IMMUNOSUPRESSANTS RISK OF IMMUNOSUPRESSION

IODINE CONTAINING COMPUNDS RISK OF HYPOTHYROIDISM
(AMIODARONE)
LITHIUM RISK OF LITHIUM TOXICITY
RADIOPHARMACEUTICALS EXPOSURE TO RADIOACTIVITY
RETINOIDS (VITAMIN A RISK OF HYPERVITAMINOSIS A –
ANALOGUES eg ISOTRETINOIN) INCLUDES HAEMATOLOGICAL
ABNORMALITIES
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
Drugs use in breastfeeding
Frequently used medications:

Analgesics
Antibiotics
Antidepressants
Antihistamines
Anticoagulants
Anticonvulsants
Social drugs
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
 Analgesics
Paracetamol, Ibuprofen
◦ considered safe – low transfer into breast milk
Codeine: safe? However beware ultrafast metabolisers CYP2D6
Morphine
◦ Considered safe – low transfer into breast milk & high first pass
metabolism
Aspirin
◦ Avoid – low transfer but risk of Reye’s syndrome
Tramadol
◦ Limited data: low transfer, similiar to codeine
Sumatriptan
◦ Timing: t1/2 ~ approx two hours
◦ avoid infant exposure by expressing and discarding breast milk for
approximately eight hours after dosing.
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
 Antibiotics
 Penicillins, cefalosporins and macrolides - considered safe
◦ risks of alterations to infant bowel flora (diarrhoea) and
allergic sensitisation
 Metronidazole - controversial - possibility of high transfer
into breast milk - avoid high dose/prolonged course
◦ % of maternal dose = up to 36%
 Tetracyclines – transfer low - avoid - risk of inhibiting bone
growth or causing dental staining
 Quinolones – avoid - risk of arthropathies
 Sulphonamides – considered safe

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Antidepressants
Post natal depression – incidence 10-20%
SSRIs - Paroxetine – preferred - lowest transfer into milk
◦ Paroxetine % maternal dose = 1-3%
◦ Citalopram % maternal dose = 5%
◦ Fluoxetine % maternal dose = up to 14%
- norfluoxetine – t1/2 ~ 1-2weeks.

TCAs (eg amitriptyline) - low transfer – considered safe

MAOI-A (moclobemide) - low transfer – considered safe

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Antihistamines
1st generation
eg promethazine, dexchlorpheniramine, diphenhydramine
◦ Considered safe - monitor for irritability or excess
sedation

Less-sedating antihistamines
◦ Less data – low transfer – likely to be safe, no reports of
adverse effects

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Anticoagulants
Heparins (unfractionated and low molecular weight)
◦ Safe to use – do not pass (large molecular weight), poorly
absorbed.

Warfarin – low transfer - changes in prothrombin time have not

been detected
◦ ? monitor infant's prothrombin time

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Anticonvulsants
Carbamazepine, phenytoin and sodium valproate
◦ compatible with breastfeeding - observe for evidence of CNS
depression

Lamotrigine – avoid - transfer into breast milk may be

considerable

Gabapentin – insufficient data available.

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Social drugs
Caffeine:
◦ brewed coffee 50-100 mg/100 mL
◦ instant coffee, tea: 20-70 mg/100 mL
◦ cola drinks 10-20 mg/100 mL
◦ caffeine tablets 100mg (No-Doz ®)
◦ energy drinks average 30 mg/100 mL.

Caffeine - M/P (AUC) = 0.5-0.8

% of maternal dose = 0.6 - 21.0
Low intake probably safe.
Restlessness and irritability documented.
Prolonged half-life (80-100 hours) in neonates.
SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY
 Social drugs
Nicotine:

Nicotine M/P (AUC) = 2.92

% of maternal dose – insufficient data
(variability)
Cigarette smoking should be avoided due to health hazards
associated with smoking.
Use nicotine patches - compatible with breastfeeding &
favoured over smoking.

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Social drugs
Alcohol
◦ Infant exposure - up to 20%
◦ Associated with impaired development

◦ Avoid – safest option

◦ Minimise - limit to no more than 2 standard drinks/day

◦ Withold breastfeeding for ~ 2 hours after a standard alcoholic drink

1 standard drink = 10g alcohol

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Recommendations:
Avoid use of drugs known to cause serious toxicity in adults or children

Drugs licensed for use in infants do not generally pose a hazard

Neonates (and particularly premature infants) are at greater risk from

exposure to drugs via breast milk, because of immature excretory functions
and the consequent risk of drug accumulation

Choose a regimen and route of administration which presents the minimum

amount of drug to the infant

Infants exposed to drugs via breast milk should be monitored for unusual
signs or symptoms

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Choice of drug:
Consider:
◦ Mechanism of action
◦ Dose in infant
◦ Short t1/2
◦ High protein binding
◦ High molecular weight
◦ Low oral bioavailability

avoid – postpone – reduce dose – short term – timing – express

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

 Resources
New South Wales
MotherSafe
Ph: 02 9382 6539 or Toll free (NSW) 1800 647 848
www.mothersafe.org.au

• Drugs and Human Lactation

by: Bennett, P.N.
• Drugs in Pregnancy and Lactation
by Briggs, G.G., Freeman,F.K., Yaffe, S.J.
• Medications and Mother’s Milk
by Hale, T.W.
• Drugs & (pregnancy & ) breastfeeding
published by RWH, Melbourne https://thewomenspbmg.org.au/

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

Micromedex - Drugdex

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY

LactMed (US)
https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

SCHOOL OF BIOMEDICAL SCIENCES & PHARMACY