Pharmaceutical Care In Pregnant Women And Nursing Mothers
Pregnancy and breastfeeding are common conditions or situations that lead women to pharmacies for products, advice, or both. By virtue of their training, knowledge, and professional judgement, pharmacists should be well positioned to play a role in the selection and appropriate use of medications by pregnant and lactating women. Such a role is consistent with the responsibilities embodied in the pharmaceutical care concept and with pharmacists' high level of accessibility to patients.
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Pharmacist Responsibility Offering Pharmaceutical Care In Pregnant And Breastfeeding Mother
Pharmacists have developed skills in pharmacology and pharmacokinetics assessing the bio-availability of drugs identifying possible side effects and contraindications. Professional knowledge is used to establish the safety of medicines in particular situations. When we undertake a pharmaceutical assessment to inform patients of the balance of risk of benefit for herself and her baby of taking a drug and continuing to breastfeed, we are required to take responsibility for the accuracy of the information we provide and its use. We can use specialist contacts and may consult with other health care professionals (with the patient’s consent) to ensure the information we give is accurate. All sources of information and advice offered should be recorded so that in the event of any adverse events, details of the consultation are available. These records can be stored on the PMR as long as it is regularly backed-up; otherwise, they should be kept in a hard-back book or other secure manner.
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Difficulties arise when the drug of choice is being used outside of licence or off label. Pharmacist colleagues in secondary care are more accustomed to using medicines outside of the licence application on a regular basis, often following consultation with a senior medical colleague and/or extensive searches of databases to assess risk to the patient. It is not ethical to make an uninformed ‘guess’ at the risk, which would not only be a dereliction of duty to the patient, but would also place the pharmacist in jeopardy of a charge of professional misconduct or even prosecution.
In the event of an adverse drug reaction to a medicine used outside of licence, if a pharmacist can demonstrate that a peer in possession of similar knowledge might reach the same conclusion and act in a similar way, it is likely that he or she would not be deemed negligent.
Every pharmacist has a limit to his or her knowledge, skills, experience and sphere of competence, and appropriate referral to health care professionals and support workers to deal with specific issues is a core component of the pharmacist’s role, and all pharmacists should see referrals not only as an appropriate action in the patient’s best interests, but also as an opportunity to strengthen team working and increase their knowledge base. The professional input of pharmacists is invaluable to parents on these issues, and is potentially part of a lifetime of pharmaceutical care.
Involving Parents In Decision Making
Each mother and baby pair is unique. No two consultations regarding medicines to be taken during breastfeeding will be the same. Medicines used during pregnancy and breastfeeding have a background risk. The final decision to take the medicine should be the mother’s, and she will require sufficient information presented in a form she can access readily to make an informed choice.
Pharmacist need to explore with her the relative risks of:
1. Taking the medicine while pregnant or carrying on breastfeeding
2. Switching to an alternative medicine treatment
3. Taking the drug and temporarily or permanently Stopping breastfeeding
4. Not taking the medication
5. Breastfeeding at times when drug levels in the breast milk are at their lowest
Pharmacology Of The Transfer Of Medicines In Pregnant Women
The effect of drugs in the fetus can be thought of in terms of the dose-response based on a knowledge of the general principles by which drug is transferred from the mother to the fetus. Fetal drug concentration, which determines the fetal response, is a function of the maternal concentration, the placental permeability, the fetal drug clearance, and differences in protein binding and ionization between the maternal and fetal plasma.
Drugs administered to mothers have the potential to cross the placenta and reach the fetus. Under particular circumstances, the comparison of the drug concentration in the maternal and fetal plasma may give an idea of the exposure of the fetus to the maternally administered drugs.
Several drugs rapidly cross the placenta and pharmacologically significant concentrations equilibrate in maternal and fetal plasma. Their transfer is termed 'complete'. Other drugs cross the placenta incompletely, and their concentrations are lower in the fetal than in maternal plasma. The majority of drugs fit into 1 of these 2 groups. A limited number of drugs reach greater concentrations in the fetal than maternal plasma. It is said that these drugs have an 'exceeding' transfer. The impression prevails that suxamethonium chloride (succinylcholine chloride) and doxorubicin do not cross the placenta. However, a careful analysis of the literature suggests that this impression is wrong and that all drugs cross the placenta, although the extent of transfer varies considerably. The following parameters were considered as possible factors determining the extent of placental transfer: (i) the molecular weight of the drug; (ii) the pKa (pH at which the drug is 50% ionised); and (iii) the extent of drug binding to the plasma protein. Drugs with molecular weights greater than 500D have an incomplete transfer across the human placenta. Strongly dissociated acid drug molecules should have an incomplete transfer, but this does not seem to be an absolute rule. For example, ampicillin and methicillin transfer completely and they are strongly dissociated at physiological pH. The extent of drug binding to plasma protein does not influence the type of drug transfer across the human placenta.
Pharmacology Of The Transfer Of Medicines In Breastmilk
Determination of the level of a drug in breastmilk or in infant plasma is not routinely carried out in clinical practice – rather, it is a research tool used to inform particular studies. Measurement of the levels of any drug in breastmilk is a far from exact science. Consequently, assessment of risk for the breastfeeding infant becomes very difficult.
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Determination of the levels requires many variables to be taken into account. These include:
1. Whether the drug has reached a steady state (in general, it takes five drug half lives to reach this state)
2. Whether the level is measured pre or post feed: if the drug level is measured post feed, it may be concentrated in a small volume of milk remaining in the breast
3. The duration of lactation: colostrum (the milk made in the first few days after delivery) is high in protein, low in fats and gradually changes through transition milk to mature milk, which is low in protein and high in fats (the level of fats in breast milk significantly affects the absorption of fat-soluble drugs)
4. The time of day the milk was sampled: fat levels in breast milk vary diurnally, with very low levels in the early morning, rising to a peak mid-morning, then decreasing to the lowest level in early evening
5. The time elapsed since the medication was taken and whether the peak plasma level has been reached or exceeded
6. The volume of milk consumed by the infant per feed.
Pharmacokinetic Principles
In the absence of data in readily available texts, it may be worthwhile to consider pharmacokinetic principles to theoretically determine the extent of the passage of a drug into breastmilk. The following information should be considered.
The Size Of The Drug Molecule
The larger the molecule, the harder it is for it to pass into breast milk. Large molecular weight drugs can therefore safely be taken by breastfeeding mothers.
The Solubility Of The Drug
The greatest passage of drugs into breast milk occurs by simple diffusion. Water soluble materials pass through pores in the basement membranes and paracellular spaces. Extracellular fluid varies with age, being highest at birth (50%) and falling to 20-25% at one year. Water soluble drugs are usually acidic. From the low milk:plasma ratios, it can be seen that acidic, water soluble drugs do not pass readily into mature breast milk, although they pass more readily by simple diffusion, immediately after birth.
Fat Solubility
Un-ionised drugs that are lipid soluble usually dissolve in and pass through the lipid membrane of the alveolar epithelium of the breast. The average body fat contents of infants and neonates are significantly lower than in more mature babies and adults – 3% in premature infants, 12% in term neonates, 30% in 12-month olds and 18% of adults. Because of the relative deficit of fat tissue storage sites, drugs causing central nervous system (CNS) sedation (even in the relatively low doses found in breastmilk) have a greater effect on neonates than infants of one year. Many neuroleptic drugs have a high affinity for lipid-rich tissue and pass readily into breastmilk.
The Extent Of Plasma Protein Binding Of The Drug
Drug Half Life
The half life of a drug is defined as the time taken for the serum concentration to decrease by 50%. It is determined by the rate of absorption, metabolism and excretion. A drug with a short half life has to be taken more frequently than one with a long one. As stated above, approximately five half lives have to elapse before steady state is reached; similarly, after five half lives, almost all (98%) of the drug has been eliminated from the body. Infants, in general, do not metabolise or excrete medication as fast as adults due to immaturity of the hepatic system. The infant may therefore begin to accumulate a drug with a long half life. On this basis, treatment for a lactating mother with drugs with a shorter half life is preferable.
Immaturity Of The Infant’s Hepatic And Renal Function
The renal excretion of drugs by infants is lowest in newborns aged 3-9 days, but rises quickly within three months. Any drug to which a newborn may be exposed should be monitored; for instance, pethidine has a half life in an adult of three hours, but in a newborn it may be as long as 23 hours. The premature infant’s liver may be overwhelmed by breakdown products of haemoglobin due to the natural destruction of red blood cells present in the foetus during pregnancy. Even healthy neonates may have acetylation and oxidation processes hampered during the first week or so due to immature hepatic enzymes.
Peak Plasma Level
The point at which the maximum drug level is reached in maternal plasma generally corresponds to the highest rate of entry into milk. This is generally reached two hours after an oral dose of non-sustained release medication, or about 20 minutes after an intravenous injection.
Milk:plasma Ratio
This measurement refers to the concentration of the protein free fractions of a drug found in milk and plasma. Fluoxetine has a Milk:plasma ratio of 0.286, meaning that the level in the milk is 28.6% that of the medication in the maternal plasma. The Milk:plasma ratio of dexamphetamine is quoted as 2.8-7.5, which means the level in the milk is approximately 3-7.5 times that in the plasma – that is, it becomes concentrated in milk.
Breastmilk Production
Most breast milk is manufactured as the baby feeds, with very little being stored in the breast. If the baby feeds when the mother’s plasma level of the drug is high, exposure via milk will commensurately be higher. As stated above, the variability of milk composition day to day and during any day will alter the passage of drugs into milk. As the level of drug in the plasma falls, the reverse passage will permit flow from the milk back into the plasma. The level falls again with time after the peak plasma concentration is passed. If possible, the mother should feed or express immediately prior to the next dose of the drug to minimise the amount of drug passing to the infant.
Levels Of Evidence
There is little information out there on drug use in pregnancy and lactating mothers. Cost and morals in carrying out clinical trials in these sets of people is hindering such data. Few clinical trials are conducted into the safety of drugs passing through breastmilk. The level of evidence available needs to be taken into consideration when making a clinical decision.
The Scottish Intercollegiate Guidelines Network (SIGN) was formed in 1993 to improve the quality of health care for patients in Scotland by developing national, evidence-based clinical guidelines for effective practice. The grading system they use is commonly employed by practitioners in Scotland to evaluate the strength of a recommendation for practice.
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SIGN states that guideline recommendations are graded to differentiate between those based on strong evidence and those based on weak evidence. The judgement is made on the basis of an objective assessment of the design and quality of each study and a more subjective judgement on the consistency, clinical relevance and external validity of the whole body of evidence. The aim, SIGN claims, is to produce a recommendation that is evidence-based, but which is relevant to the way in which healthcare is delivered.
SIGN Grading System/levels Of Evidence
1++ High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias
1+ Well conducted meta- analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
1– Meta- analyses, systematic reviews of RCTs, or RCTs with a high risk of bias
2++ High quality systematic reviews of case-control or cohort studies. High quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal
2+ Well conducted case control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal
2– Case control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal
3– Non-analytic studies, e.g. case reports, case series
4– Expert opinion
Grades Of Recommendation
A. At least one meta analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or A systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results
B. A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+
C. A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++
D. Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+
Source Of Information
Pharmacists will search databases for available information and research where the information is not available immediately.
Books
1. Hale (2006) Medications and Mothers’ Milk 12th Edition. Pharmasoft. ISBN 09772268-3-2. Available from UNICEF Baby Friendly (www.babyfriendly.org.uk/resource.asp).
2. Briggs, Freeman and Yaffe (2005) Drugs in Pregnancy and Lactation, 7th Edition. Lippincott Williams and Wilkins. ISBN 0781756510
3. Lee, Inch and Finnigan (2000) Therapeutics in Pregnancy. Radcliffe Medical Press. ISBN 1857752694.
Useful Internet Sites
Internet use by patients and professionals is increasing. Validity of data and the authority of the site should be examined critically.
1. UKMI: www.ukmi.nhs.uk/
2. West Midlands and Trent are national specialist MI Centres for drugs in lactation for high risk situations such as prematurity: www.ukmicentral.nhs.uk/drugpreg/guide.htm
3. Dr Thomas Hale: http://neonatal.ttuhsc.edu/lact/
4. Motherisk (based at the Hospital for Sick Children in Toronto, this is a world-wide centre for excellence on research on safety of drugs in pregnancy and lactation): www.motherisk.org/updates/sept00.php3
5. The Breastfeeding Network: www.breastfeedingnetwork.org.uk
6. UK MI Central Medicines in Pregnancy and Breastfeeding site can be accessed at www.ukmicentral.nhs.uk/drugpreg/guide.html
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