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The first stop

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Drugs in Lactation What to consider

Sarah Fenner

Laura Kearney

UK Drugs in Lactation

Advisory Service

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Aims

• Discuss importance of the continuation of breastfeeding

• The lactation process itself

• Available evidence

• Factors influencing drug passage into breast milk

• Estimating infant exposure

• Strategies to minimise risk

• Regulatory advice

• How to handle an enquiry

• Also going to do some:

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Current breastfeeding

recommendations & rates

• WHO recommends mothers worldwide to exclusively

breastfeed infants for the first six months

• Adopted by DoH in UK in 2003

• In Feb 2017, initiation of BF = 72.6% for England

• 6-8 week breastfeeding stats:

• 43% for England and Wales

• 40% for Scotland

• 26% for Northern Ireland

• At 6 months 1% (UK) worst worldwide

• Issue = maintenance rather than initiation

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Benefits of breast feeding

• Very good evidence which demonstrates benefit

• For the infant:

• less gastric, respiratory and urinary tract infections

• reduced obesity in later childhood

• reduced juvenile-onset diabetes mellitus

• reduced risk of sudden infant death

• Increased intelligence

• For the mother…

• reduced risk of breast cancer

• delayed resumption of menstrual cycle

• protect against ovarian cancer and type II diabetes

• Increased weight loss post pregnancy

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Lancet Series

• Very powerful piece of research

• Analysis of 28 systematic reviews and meta-analyses

• If breastfeeding increased to a universal level:

• prevent 823 000 annual deaths in children younger than 5 years

• Prevent 20 000 annual deaths from breast cancer

• Predicted that if UK increased BF rates to 45% (feeding

for 4 months) this would save the healthcare system

£17 million per annum

(By avoiding the treatment of hospital admission due to acute GI infection,

lower RTI; NEC; otitis media)

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Importance of providing

appropriate information

• Many factors may influence a mother’s decision to breast

feed

• Use of medicines may be a factor

• Overly cautious advice often given—PIL

• Availability of good quality advice, and an understanding

of the principles underpinning the risk assessment, are

essential to protect the breast fed infant.

Advising a mother not to breast feed is not a

“no risk” option

• The other side…

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Physiology of lactation

• Prolactin and oxytocin are essential for the initiation and

maintenance of lactation

• Successful lactation requires milk synthesis and milk

release (let down)

• Milk is produced on a supply and demand basis: when

the infant takes milk away from the breast, more is

produced. If milk is not taken away, no more milk is

produced.

• It takes around 24 hours for a new equilibrium to be

reached

• 6-8 weeks for the lactation process to be established

properly

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Lactogenesis

• Starts approximately 12 weeks prior to birth

• After delivery, colostrum secreted initially

• High protein milk of small volume (30-100mL/day)

• Rich in immunoglobulins

• Copious milk production around day 5.

• Over the next 10 days, the composition of milk slowly

changes to mature milk.

• Low protein, high fat, high lactose content

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Passage into breast milk

• Most drugs pass into breast milk, although transfer low

• Rarely do adverse effects occur

• Transfer is usually by passive diffusion through lipid

membranes of breast alveolar cells

• During the colostrum phase, large gaps exist between

alveolar cells

• increased passage of large molecules (e.g. maternal

immunoglobulins and proteins).

• increased passage of medicines

(although absolute dose transferred low due to volume)

• Allows passage of large drug molecules (e.g. mabs)?

• By the end of the first week, these gaps close.

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Evidence – or lack of it

• Very limited and poor evidence available

• NICE criteria

• Evidence often comes from single case reports or small

short term studies

• No, or very limited, long term data on infant development

• If there is no evidence, this does not automatically mean

a mum can’t breastfeed

• Risk assessment often has to be made on medicine

properties alone

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Factors influencing breast

milk drug concentration

Maternal plasma level

• Higher maternal plasma level = more drug available to

pass into breast milk

• Bioavailability

• Dose

• Route of administration

• Half-life

• Longer half-life = increased tendency to accumulate

→ inc. risk of side-effects

• Be aware of drugs with active metabolites

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Factors influencing breast

milk drug concentration

Protein binding

• Unbound fraction available to transfer into milk

• Higher protein binding = less likely to transfer

Molecular weight

• <200 readily pass into milk

• Higher mwt drugs have to dissolve in lipid layer (lipid

solubility also involved)

• Large molecules (>6000) excluded from milk • BUT natalizumab and infliximab

• Colostrum phase

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Estimating infant exposure

• Ideally, we would have the infant serum level

• The milk level is easier to obtain and usually what is

reported

• We then have to estimate the infant exposure

• 2 ways:

• Relative infant dose

• Milk:plasma ratio

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Relative Infant Dose

• A concept developed by WHO

• First, need to calculate the daily dose the infant receives:

Estimated daily dose (mg/kg/day) = Drug concentration in milk

x volume of milk ingested

(standardised as 150mL/kg/day)

• The infant dose can then be calculated as a % of the

maternal dose:

RID = infant dose (mg/kg/day) x 100

maternal dose (mg/kg/day)

• WHO: drugs with an RID greater than 10% might not be

safe (BUT no evidence was used to define this breakpoint)

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Milk:plasma ratio

• Measures extent of drug transfer into breast milk

• Based on paired or AUC samples of drug in plasma and

milk, collected at the same time points

• Can then be used to predict breastmilk concentrations,

when other dosages are used

• High M:P = predicted high concentration in milk

• However

• Blood and milk values do not usually rise and fall in parallel

• Even if have high M:P, if maternal plasma level is low (e.g. low

dose), conc. in milk will be low

• Although a ratio of less than 1 is stated as ‘safe’, again not

evidence based.

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Some further tips

• Single doses or short courses much less likely to cause

problems—chronic therapy can be problematic

• Topical or inhalation therapy usually result in low

maternal plasma levels and therefore lower milk levels

• Multiple maternal therapy can increase risk

• Older infants are ‘less risky’

• Dec. milk volume

• Better drug clearance and handling capacity

• Factors may also influence infant exposure:

• Drugs may be unstable/broken down in infants GIT e.g. heparin

• Drugs may be poorly absorbed by the infants GIT e.g. vancomycin

• Exposure in pregnancy means it is safe in breastfeeding?

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Premature Infants

• Extremely limited evidence

• Usually the risk assessment has to be made on

extrapolation of term data

• Consider health of the infant at the time (e.g. if respiratory function is compromised, avoid drugs with

respiratory depressant potential)

• Clearance is compromised due to functional immaturity

→ inc risk of drug accumulation and S/Es

• Ability to metabolise also compromised

• CYP P450 enzymes don’t reach full maturity until around 1 yr

• Low birth weight = higher dose per kg

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Monitoring

• An infant who is exposed to a drug can potentially experience

any of the adverse effect profile

• Practically, what is feasible to monitor?

• E.g. a mum can’t monitor for increased blood pressure, but a

neonatal unit can.

• Think about locality of the infant and who is doing the monitoring

• What could a mum monitor for which may be signs of the

adverse effect, e.g. pallor?

• ‘monitor for sedation’—but babies sleep a lot…don’t they?

• Should be waking up regularly for feeds if newborn

• If older, mum will know what a normal pattern is for her infant

• The infant should be feeding well and gaining weight

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Strategies to minimise risk

• The following can be considered, and may still offer a

better option than not breastfeeding at all

• They will reduce overall infant drug exposure

• However, the recommendation to try these must not be

taken lightly

• They can all potentially disestablish the lactation process

• Mixed feeding—Bottle and breast

• Timing of feeds • Need established feeding pattern

• Ideally, once daily dosing

• Periods of abstinence—5 x half-life

• None of these methods have been quantified

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Terminology

• Because there are so many unknowns, medicine

exposure in breastfeeding can never be described as

‘safe’ or indeed ‘unsafe’

• We describe the risk assessment in terms of

compatibility

• A medicine is deemed compatible if the benefits of

continuing to breastfeed outweigh any perceived risk that

the medicine may pose

• However, there will always be some element of risk

involved, no matter how small

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How to handle an enquiry

• Questioning

• Age of the infant (incl. if premature)

• Health of the infant?

• All medicines the mother is taking

• To help establish the full risk assessment

• Is the infant taking any medicines?

• Helps us risk assess the status of the infant

• Is the infant currently being breastfed?

• Infers the urgency of the enquiry

• Enquirer status

• How much detail should we go into to justify our response

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Processing the information

• Amount of drug is the infant likely to be exposed to?

• Ideally infant serum level

• If not what is the relative infant dose?

• How has this information been established?

• How many mother-infant pairs involved?

• When was the sample taken?

• Half-life (to indicate accumulation risk)

• Molecular weight (can it easily transfer)

• Relative toxicity of the drug

• Is it used in a paediatric setting?

• Practical tips to consider

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Resources

• SPS database information

• Check both drug monograph entry and therapeutic group summary

• User guide: https://www.sps.nhs.uk/articles/ukdilas/

• Suitable alternatives

• Hale—Good for PCK info, relative infant dose, and practical

recommendations

• LactMed—Good for inclusive evidence, effect on lactation itself

• Schaeffer—Puts treatment choices in context

• Briggs—unlikely to add anything further

• SPCs—for further PCK data and licensed status

• Paediatric texts—for use in infants/neonates

• Primary evidence

• American Academy of Paediatricians?

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The advice

• Is the drug compatible with breastfeeding?

• Is there any evidence which our advice is based on • or is it a theoretical assessment?

• Relative infant dose • a meaningful concept which most HCPs understand

• Risk of accumulation?

• Have any side-effects been reported?

• Additive side-effect potential of multiple drug exposure

• ** What monitoring is required **

• Best choice of drug in BF may not necessarily be best

choice for mum’s clinical condition

• Consider risk reducing methods if appropriate

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Regulatory Advice

• UKDILAS is an evidence driven service

• There are times when we do not fall in-line with

regulatory advice:

• MHRA: TNF alpha inhibitors and live vaccination

• FDA: warning re tramadol

• NICE: Guideline (antenatal and postnatal health)

• There are times when we do:

• Codeine

• Domperidone

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Summary

• Breastfeeding has many benefits and this should be

protected where possible

• No drug can ever be described as ‘safe’ in breastfeeding

• It is all about the risk assessment

• We look for information/evidence to allow the risk

assessment to be made with the ultimate aim of allowing

breastfeeding to continue wherever possible.

• If no evidence is available, there are many other pieces

of information which can be used to build the picture.

• Offer practical advice and think about what this means

for mum

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References

1.http://www.who.int/mediacentre/news/statements/2011/breastfeeding

_20110115/en/

2.https://www.gov.uk/government/uploads/system/uploads/attachment_

data/file/563003/2015_16_Annual_Breastfeeding_Statistical_Comm

entary.pdf

3. Victora CG, Bahl R, Barros AJ et al. Breastfeeding 1. Breastfeeding

in the 21st century: epidemiology, mechanisms and lifelong effect.

Lancet 2016;387:475-490

4. Rollins NC, Bhandari N, Hajeebhoy N et al. Breastfeeding 2. Why

invest, and what it will take to improve breastfeeding practices.

Lancet 2016; 387: 491-504

5. Anderson PO. What do all the numbers mean? Breastfeeding

Medicine 2016; 11 (6): 277-279

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