1. DRUGS IN PREGNANCY AND LACTATION

2. AIMS
To update pharmacists and technicians on current opinion relating to the prescribing of drugs in pregnancy and breastfeeding.

3. OBJECTIVES
To be aware of the background and relevance of this specialised area of prescribing
To be able to find information regarding current drug use in pregnancy and breast feeding
To be able to interpret this in day to day cases encountered in working practice.

4. June Grant Princess Royal Maternity Glasgow
Pregnancy
June Grant
Princess Royal Maternity
Glasgow
Until the 1960’s there was no direct link to medicines and adverse outcomes following drug exposure in pregnancy. However this was to change with the introduction of a new sedative – hypnotic medicine introduced in 1957 in Germany that was claimed to be virtually free of side effects It was also indicated for a wide variety of different conditions including nausea and vomiting of pregnancy and influenza. Drug name?

6. Another image of a foetus around 30 weeks gestation.
Advances in ultrasound techniques allow 3D images such as this one above show much more detail and provides more information about the foetus.

7. Introduction Thalidomide
Fetal malformations occur in ~2% of population
65% - 70% of malformations are of unknown cause
With Thalidomide, it took till 1961 before the causal link was made and the drug withdrawn - with almost 6000 children born with thalidomide embryopathy. The babies were born with severe limb reduction defects, renal malformations and congenital cardiac problems. This high profile case hi ghlighted the risks of using drugs in pregnancy and led directly to setting up of the CSM in the UK.
Whilst the seriousness of this problem should never be taken lightly one should not forget that serious fetal malformations occur in about 2% of the population at birth (rising to < 5% by 5yrs of age). Chemical and drugs account for less than 1% of this figure % if all fetal malformations have an unknown cause.
 It is possible that drugs are a factor in problems such as spontaneous miscarriage in up to 20% of pregnancies.
Many women will have been taking drugs before they know that they are pregnant.
If a drug or chemical can cause physical or mental abnormalities in an unborn baby or foetus then it is known as a teratogen. In addition to malformations a teratogen can prevent implantation, cause spontaneous early abortion or produce intra-uterine death of the foetus.

8. Principles Of Teratogenesis
Dose dependent
Synergistic
Harmless to the mother but devastating to the embryo.
Timing and exposure is critical
Genetically determined?
1. Placental barrier does not exist.
The only exceptions being large molecular weight substances like Heparin and Insulin. Most other drugs will pass through by simple diffusion and it is only the rate that will vary. Although insulin does not pass through to the foetus if the mother has a period of hyperglycaemia the glucose will pass across, the foetus will produce its own insulin and this cannot be cleared.
Teratogenicity is usually dose dependent. E.g. alcohol
Teratogenic agents may be synergistic. E.g. 4%malformation rate with 1 AED rising to around 23 with 4 or more.
i.e. The higher the dose of Sodium Valproate the higher incidence and severity of side effects. Also in the epileptic mother the greater the number of agents prescribed the higher the incidence of abnormalities.
4. A teratogen may be harmless to the mother but devastating to the embryo. E.g. Retinoids for acne cause severe CNS, craniofacialand or cardiovascular anomalies.
5. Timing and exposure is critical ////// Slide of 1st trimester //////
One of the problems of potential teratogenicity is that the most susceptible period for the foetus is during the first trimester. At this stage cells are dividing the most rapidly and the patient may not even be aware of the pregnancy at that point. Usually in the first two weeks post conception drug exposure affects all of the cells. This most frequently (but not always) results in abortion or survival intact. However, the drug may have a long half life so the foetus may continue to be exposed after the initial “all or nothing” stage.
Whilst the first trimester is usually the most critical in terms of drug exposure some drugs may affect later stages. One example of this is the non-steroidal anti-inflammatory agents which should not be used after 34 weeks since they affect the foetal circulation
6. Susceptibility to teratogenesis is genetically determined. – e.g. response to AED ‘s alcohol related to individual’s hepatic enzyme pathways.
Teratogen – an agent or factor which can cause congenital malformations.
Any agent which when given to the pregnant mother causes or contributes to the malformation or abnormal physiological function or mental development of the fetus or child.

9. To summarise – risks of teratogenicity with drugs
To summarise – risks of teratogenicity with drugs.Some are potentially teratogenic in first trimester.
If given around delivery, the neonate may show signs of toxicity or drug withdrawal. E.g.
There are potential concerns over the child’s neurodevelopment with some psychotropic medicines.

10. Principles Of Prescribing
Evaluate every drug prescribed
Use drugs which have been widely used in pregnancy
Medico-legal
Basic principles of prescribing medicines in pregnancy.
Consider non drug management, avoid prescribing in 1st trimester.
Evaluate every drug prescribed to a pregnant or possibly pregnant woman and to consider whether or not alternative therapeutic measures could be employed. Avoid polypharmacy.
2. Use drugs which have been widely used in pregnancy for years in preference to more established ones.
3. In medico-legal terms a Doctor is immune from civil liability for the effects on the foetus of a drug if the drug is currently given in pregnancy as established medical practice.

11. Problems Encountered Anxious and emotional patients
Medico legal implications
Defensive Pharmaceutical Companies
Poor quality data
Media Scares
1. Anxious and emotional patients -
2. Medico legal implications
3. Defensive Pharmaceutical Companies - not prepared to conduct trials on pregnant women
4. Poor quality data- in uk we are very good at reporting the one bad outcome but not the many good outcomes following medicines use in pregnancy.
5. Media Scares. Eg. Konakion scare in 1990’s with link to childhood leukaemias, later refuted but remembered still and ongoing issues.
All these show the need for better prescribing information

12. Common Problems In Pregnancy
Asthma
Epilepsy
Hypertension
Depression
DVT
Diabetes
Asthma- treat as non pregnant patient – reduce morbidity
Epiliepsy – minimise medication if possible and monitor
Depression – treat appropriately - behavioural therapy or medicines as appropriate.

13. Inadvertent Drug Exposure
Identify drugs taken
Go to the SPC
Either contact the local medicines information unit or
Contact the Teratology Centre at Newcastle
INADVERTENT DRUG EXPOSURE
This is a very likely scenario in the community, where the patient has just found out she is pregnant but realises that she has taken
In the first instance take a full history.
Identify drugs taken e.g.- antimalarials - which ones. Find out gestational age at use for teratogenic effect.
WHERE TO GO FOR INFORMATION
1. Always go to the Data Sheet.
Virtually nothing is licensed for use in pregnancy. Usually the best you can hope for is that the Data Sheet will not say it is safe to use, but will state there is no known risk to the foetus. In which case reassure and refer them to the Doctor. Unfortunately it will often just state that the drug is “contra-indicated in pregnancy” This may mean that adverse effects have indeed been observed but may also mean nothing more than the drug is not licensed. This is the case with Adalat preparations. However, if you ring up the company and ask them for data on file, they will tell you that, although not licensed, it has been used successfully. 
2. Depending on your position either contact the local drug information unit or 
3. Contact the Teratology Centre at Newcastle. 
If potentially teratogenic exposure has occurred then refer them for detailed investigation and advice. However, try not to alarm them if possible!!!!

14. With inadvertent exposure we may be able to identify particular anomalies seen with this drug before which may be seen on scan. E.g. physical malformations such as extra or absent digits.
Generally, the UKTIS will give priority to following classes of substances women may be exposed to in pregnancy:
All environmental, domestic and occupational exposure.
All poisonings and overdoses both acute and chronic.
All black triangle drugs
All drugs of abuse, especially ecstasy and cocaine.

15. Updates On Drugs In Pregnancy And Breastfeeding
Antibiotics
Management of depression/SSRI’s
Vitamins
Breastfeeding
ACE Inhibitors/Angiotensin ll receptor antagonists

16. SOURCES OF INFORMATION
BNF
Drugs in pregnancy and Lactation – Briggs
Drugs during Pregnancy and Lactation – Schaefer
Toxbase
Reprotox via MI departments

17. BREAST FEEDING

18. DRUGS IN BREASTFEEDING
Healthcare professionals should always encourage breastfeeding. But data on excretion of drugs into breast milk is often poor or non-existent. Few drugs are absolutely contra-indicated in breastfeeding although care is required. Some drugs may increase or decrease milk yield.

19. ADVANTAGES OF BREAST FEEDING
Mother
Decreases risk of
Hip fracture
Osteoporosis
Ovarian Cancer
Pre-menopausal Breast Cancer
Psychological / convenience / cost

20. ADVANTAGES OF BREAST FEEDING
Baby
Protects against
UTIs SIDS IDDM IBD Lymphoma
Reduces incidence of
Diarrhoea Respiratory infections Otitis media Neonatal septicaemia NEC

21. BREAST FEEDING Potential problems Factors to consider
Clinical approaches to drug exposure
Protects against UTIs SIDS IDDM IBD Lymphoma Reduces incidence of Diarrhoea Respiratory infections Otitis media Neonatal septicaemia NEC

22. FACTORS AFFECTING THE EFFECT OF THE DRUG ON THE INFANT
Breast milk concentration
Volume of milk intake
Infant Dose
Maturation of liver and
Renal function
Bioavailability
Infant Plasma concentration
Pharmacological effect on infant
Receptor sensitivity

23. FACTORS PRODUCING POOR EXCRETION INTO BREAST MILK
High molecular weight
Highly protein bound
Weak Acid
Water soluble
Short acting preparation of drug
No active metabolites

24. COMPATIBILTY OF DRUGS WITH BREAST FEEDING
CHARACTERISTICS
COMPATIBLE
COMMENTS
ASPIRIN
pKa 3.5 variable plasma bound. Milk:plasma = 1.5:1 NO
?use of low dose ?Rey’s - thought to be of low risk. Withhold if baby pyrexial/unwell
PENICLLLINS
e.g. Amoxicillin Up to 20% protein bound
YES
Little excreted into milk ?diarrhoea in neonate
CIPROFLOXACIN
pKa % protein bound
Caution in children - potential for joint damage
HEPARIN
Large molecule
Destroyed in GIT Inactive orally
ANTIHISTAMINES Chlorphenamine
Loratadine
pKa 9.2
Approx 70% protein bound
Variable passage into milk
Very low excretion into milk
BNF drowsiness in infant avoid long acting preps Antihistamine of choice but BNF/ manufacturer says avoid.
METHYLDOPA
Minimal protein binding
Small amount in milk
FLUOXETINE
Long half life, Active metabolites
1 case of accumulation, irritability, diarrhoea, hyperglycaemia
PREDNISOLONE
70-90% protein bound, non­ionisable half life 2-8hrs
Doses up to 40mg-50mg day. Feed immediately after daily dose

25. SOURCES OF INFORMATION
Community
Limited time and resources
SPC
Hospital MI departments
Specialist texts – Medication in mother’s milk- Hale
Teratology centre, Newcastle
Drug company
SOURCES OF INFORMATION
In community with limited time and resources for the reference books, the best place to go straight to is the Data Sheet. The section in the Monograph usually gives some information. Few will say categorically it is safe to breastfeed. The best that can be hoped for is that it has been given for many years without apparent ill effect.
The Data Sheet may state that breastfeeding is contra-indicated. This is not as final as it might sound. If this is the case then the quickest option is to either ring the national Teratology Centre in Newcastle or the Drug Company. As long as you start off by saying that “you are well aware that the drug is not licensed for use in breastfeeding, but do they have any data on file that would suggest it may be okay to use”, they will normally tell you what papers have been published.