pregnancy Flashcards
describe reproductive toxicity
Female and male patients
May be medicines and/or environmental
damage sperm / excreted in semen
smoking, radiation, heavy metals, organic solvents, pesticides
when are preg prev programmes considered
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)
what is current MHRA advice on sodium valproate
‘Valproate medicines must no longer be used in women or girls of childbearing potential unless a Pregnancy Prevention Programme is in place’
name other PPP
such as certain immunomodulatory drugs (e.g. thalidomide) and oral retinoids (e.g. isotretinoin)
give reasons of using medicines in pregnancy
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
3 vaccines recommended in pregnancy in the UK
Influenza vaccine
Pertussis (whooping cough) vaccine
COVID-19 vaccines (booster for those already vaccinated)
3 vaccines contraindicated in pregnancy
Live attenuated vaccines include:
MMR vaccine
BCG vaccine
Chickenpox vaccine
Oral typhoid vaccine (travel vaccine)
Yellow fever vaccine (travel vaccine)
Why can medicines use be a problem in PregnancY?
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
what features of pregnancy can cause a reduction in absorption of oral medicines
increase in prog (reduces gastric and small int motility)
nasusea and vomiting
what feature of pregnancy can cause an Increase in IM/SC absorption and transdermal absorption
Increase in tissue perfusion
what feature of pregnancy can cause Increase in absorption of drugs by inhalation
Increase in cardiac output, tidal volume, alveolar uptake
what feature of pregnancy can cause a decrease in clinical effect (distribution)
Plasma volume increases by 150% by 24-28 weeks gestation
Volume of distribution increases
what feature of pregnancy causes an altered drug metabolism
Elevated hormonal concentrations of various hormones such as oestrogen, progesterone, prolactin and placental growth hormone
what feature of pregnancy causes Drugs to be excreted UNCHANGED by kidneys (increased elimination)
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
factors that affect Rate of drug transfer to the fetus
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
teratology: 4 types of teratogens
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)
teratology: drugs
Certain prescription medications
Some OTC medications
Recreational drugs such as cocaine,
marijuana, ecstasy, and heroin
Alcohol
Tobacco
When the fetus comes into contact with a teratogen it can cause:
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
3 stages of fetal development
Pre- embryonic (germinal) stage
Embryonic stage
Fetal stage
describe the germinal stage 0-2 weeks post conception
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
describe the embryonic stage 3-8 weeks post-conception
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
describe the fetal stage. 9-38 weeks post-conception
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
Principles of drug teratogenicity: timing of exposure
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
Principles of drug teratogenicity: dose
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
Principles of drug teratogenicity: species
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
Principles of drug teratogenicity: genotype and environmental interaction
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
Pharmacological effects of drugs
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
Drugs which can’t be handled in pregnancy: 5‐alpha‐reductase inhibitors (finasteride and dutasteride)
5‐alpha‐reductase inhibitors (finasteride and dutasteride)
Dutasteride and finasteride can be absorbed through the skin and cause birth defects in male fetuses
Drugs which can’t be handled in pregnancy: Cytotoxic medication (e.g. vincristine, fluorouracil)
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
principles of prescribing in pregnancy
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
