pregnancy

Question 1

describe reproductive toxicity

Answer 1

Female and male patients

May be medicines and/or environmental
damage sperm / excreted in semen
smoking, radiation, heavy metals, organic solvents, pesticides

Question 2

when are preg prev programmes considered

Answer 2

where the product has the potential for:

a teratogenic effect (can cause birth defects),

an adverse effect on the (neuro-) development of the child through exposure in-utero (in the womb)

Question 3

what is current MHRA advice on sodium valproate

Answer 3

‘Valproate medicines must no longer be used in women or girls of childbearing potential unless a Pregnancy Prevention Programme is in place’

Question 4

name other PPP

Answer 4

such as certain immunomodulatory drugs (e.g. thalidomide) and oral retinoids (e.g. isotretinoin)

Question 5

give reasons of using medicines in pregnancy

Answer 5

Treatment of common symptoms in pregnancy – e.g. antacids for heartburn

Treatment of more serious complications such as hypertension, pre-eclampsia, thrombosis, hyperemesis gravidarum

Continuing treatment of existing conditions

Treatment of fetal disease e.g. fetal tachycardia

Certain vaccines are also administered during pregnancy

Question 6

3 vaccines recommended in pregnancy in the UK

Answer 6

Influenza vaccine

Pertussis (whooping cough) vaccine

COVID-19 vaccines (booster for those already vaccinated)

Question 7

3 vaccines contraindicated in pregnancy

Answer 7

Live attenuated vaccines include:

MMR vaccine
BCG vaccine
Chickenpox vaccine
Oral typhoid vaccine (travel vaccine)
Yellow fever vaccine (travel vaccine)

Question 8

Why can medicines use be a problem in PregnancY?

Answer 8

Scarcity of data about safety

Pregnant women are usually excluded from clinical trials

So the information typically comes from case control or cohort studies and animal studies

Complex pharmacokinetics in pregnant woman – need to be considered when HCP is prescribing

Can lead to unwanted terminations due to fear of drug taking in pregnancy

Question 9

what features of pregnancy can cause a reduction in absorption of oral medicines

Answer 9

increase in prog (reduces gastric and small int motility)

nasusea and vomiting

Question 10

what feature of pregnancy can cause an Increase in IM/SC absorption and transdermal absorption

Answer 10

Increase in tissue perfusion

Question 11

what feature of pregnancy can cause Increase in absorption of drugs by inhalation

Answer 11

Increase in cardiac output, tidal volume, alveolar uptake

Question 12

what feature of pregnancy can cause a decrease in clinical effect (distribution)

Answer 12

Plasma volume increases by 150% by 24-28 weeks gestation
Volume of distribution increases

Question 13

what feature of pregnancy causes an altered drug metabolism

Answer 13

Elevated hormonal concentrations of various hormones such as oestrogen, progesterone, prolactin and placental growth hormone

Question 14

what feature of pregnancy causes Drugs to be excreted UNCHANGED by kidneys (increased elimination)

Answer 14

Increase in renal blood flow to the kidneys
Causes an increase of glomerular filtration rate (GFR) by 50% in the first trimester and by 80% in the 2nd trimester

Question 15

factors that affect Rate of drug transfer to the fetus

Answer 15

MW
decreased transfer as size increases

protein binding
highly protein bound drugs = lower fetal conc

lipid solubility
lipophilic, unionised drugs cross the placenta more easily than polar drugs

pKa
- weak bases can get ‘trapped’ in the fetal circulation

enzyme/drug efflux transporters in placenta
may facilitate or restrict the transfer of drug to fetus

Question 16

teratology: 4 types of teratogens

Answer 16

Physical agents (e.g. radiation, heat)

Maternal health conditions (e.g. malnutrition, uncontrolled diabetes)

Infection (e.g. toxoplasmosis, rubella)

Environmental toxins (e.g. mercury, lead)

Question 17

teratology: drugs

Answer 17

Certain prescription medications

Some OTC medications

Recreational drugs such as cocaine,
marijuana, ecstasy, and heroin

Alcohol

Tobacco

Question 18

When the fetus comes into contact with a teratogen it can cause:

Answer 18

Most famous teratogen is thalidomide – limb deformities

Physical malformations
Problems in behavioural or emotional development of the child
Decreased IQ
Preterm labours
Spontaneous abortions/miscarriages
Fetal death

Question 19

3 stages of fetal development

Answer 19

Pre- embryonic (germinal) stage

Embryonic stage

Fetal stage

Question 20

describe the germinal stage 0-2 weeks post conception

Answer 20

Period up to implantation of the fertilised ovum

Described as ‘all or nothing’ period

Most exposures lead to death or complete recovery and normal fetal development

Fetal malformations after drug exposure during this period are unlikely - but lack of robust data

Risk increases where half-life of drug is long enough to extend exposure to embryonic stage

Question 21

describe the embryonic stage 3-8 weeks post-conception

Answer 21

Organogenesis occurs mainly in this stage

Mostly complete by 10th week of pregnancy (apart from CNS, eyes, ears, teeth and external genitalia)

Exposure to drug during this period = greatest risk of major birth defects

Reason why women are advised to avoid/minimise drug use in 1st trimester

However, importantly, drug exposure in 2nd/3rd trimesters may still cause harm to fetus

Question 22

describe the fetal stage. 9-38 weeks post-conception

Answer 22

Fetus continues to develop, grow and mature and remains susceptible to some drug effects

Especially true for CNS, which can be damaged by exposure to certain drugs such as ethanol at any stage of pregnancy

ACE inhibitors if given in 2nd and 3rd trimesters can result in fetal renal damage and reduced amniotic fluid volume

NSAIDS should be avoided in the third trimester - pregnancy may result in premature closure of the fetal ductus arteriosus and fetal renal impairment

Question 23

Principles of drug teratogenicity: timing of exposure

Answer 23

Stage of pregnancy at which drug exposure occurs affects likelihood, severity or nature of adverse effect on the fetus

Risk between and within trimesters may vary

However, the precise period of teratogenic risk is not known for many substances

Folic acid antagonists (e.g. trimethoprim) increase risk of neural tube defects if exposure occurs before neural tube closure (3rd to 4th week post conception) but not after this period

Question 24

Principles of drug teratogenicity: dose

Answer 24

A threshold dose above which drug-induced malformations/ other adverse effects are more likely to occur is known for certain teratogens

Although, most have not
had a ‘safe dose’ determined

Recommendation to use lowest effective dose in pregnancy

Question 25

Principles of drug teratogenicity: species

Answer 25

Drug teratogenicity may be species dependent Preclinical thalidomide studies in mice and rats did not result in congenital malformation in the offspring Birth defects or other adverse reproductive outcomes can’t simply be extrapolated to humans Also, drug dose and route of administration in early animal studies may not be comparable with clinical use in humans

Question 26

Principles of drug teratogenicity: genotype and environmental interaction

Answer 26

Not all fetuses exposed to teratogenic drugs show evidence of having been affected It is unclear whether this variability is due to genetic differences in the mother, the fetal genotype, environmental factors or a combination of all three Malformations are reported to occur in only 20-50% of infants exposed to thalidomide during the period of greatest risk

Question 27

Pharmacological effects of drugs

Answer 27

Drugs may adversely affect the fetus indirectly via effects on the maternal circulation, or they may cross the placenta and exert a direct pharmacological effect on the fetus It is generally only at birth that signs of fetal distress are observed due to drug exposure in the womb (in utero) or the effects of abrupt discontinuation of the maternal drug supply The capacity of the neonate to eliminate drugs is reduced – this can result in significant accumulation and toxicity Neonatal side effects (e.g. CNS depression due to opioids, adrenal suppression due to high dose corticosteroids, neonatal bradycardia with betablockers) Withdrawal reactions in the neonate (e.g. opioid, benzodiazepine, SSRI/tricyclic antidepressant withdrawal) Withdrawal reaction risk if these drugs are used long term and/or near birth

Question 28

Drugs which can’t be handled in pregnancy: 5‐alpha‐reductase inhibitors (finasteride and dutasteride)

Answer 28

5‐alpha‐reductase inhibitors (finasteride and dutasteride) Dutasteride and finasteride can be absorbed through the skin and cause birth defects in male fetuses

Question 29

Drugs which can’t be handled in pregnancy: Cytotoxic medication (e.g. vincristine, fluorouracil)

Answer 29

Due to a lack of evidence indicating that occupational exposure to cytotoxic medication during pregnancy is without risk, caution is advised where possible or continued exposure during pregnancy may occur Use of personal protective equipment (PPE) and adherence to standard handling precautions is advised

Question 30

principles of prescribing in pregnancy

Answer 30

If possible, all drugs should be avoided during the first trimester, which is the period of greatest susceptibility to teratogenic effects Consider non-pharmacological treatments (e.g. acupressure wrist bands for morning sickness) Risk–benefit assessment should be carried out on an individual patient basis, with the most up-to-date evidence used Avoid polypharmacy - teratogenicity of a medicine may be enhanced by co-administration of a second medicine or more Monitoring of any chronic medical condition should be intensified during pregnancy because the pattern of disease may change, as well as response to medicines Control of underlying diseases, such as arthritis, inflammatory bowel disease, epilepsy, asthma, and thyrotoxicosis with appropriate drug therapy is likely to reduce adverse and neonatal outcomes