pregnancy Flashcards
what is Pregnancy prevention programmes (PPPs)
give an example
PPP is to be considered in situations 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)
The MHRA advises:
‘Valproate medicines must no longer be used in women or girls of childbearing potential unless a Pregnancy Prevention Programme is in place’
Designed to make sure patients are fully aware of the risks and the need to avoid becoming pregnant
Includes the completion of a signed risk acknowledgement form when their treatment is reviewed by a specialist, at least annually
Supported by smaller pack sizes to encourage monthly prescribing
a pictogram/warning image on valproate labelling
Programmes also for other drugs such as certain immunomodulatory drugs (e.g. thalidomide) and oral retinoids (e.g. isotretinoin)
why may medicines be used 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
what are the vaccines available during pregnancy
In the UK, three vaccines are recommended in pregnancy in the UK:
Influenza vaccine
Pertussis (whooping cough) vaccine
COVID-19 vaccines (booster for those already vaccinated)
The three vaccines recommended are not live vaccines and are not able to cause disease
what vaccines shouldnt be given during preg
Vaccines which contain live, weakened versions of an organism (live attenuated vaccines) are typically contraindicated during pregnancy as they can cause an infection in the baby
Live attenuated vaccines include:
MMR vaccine
BCG vaccine
Chickenpox vaccine
Oral typhoid vaccine (travel vaccine)
Yellow fever vaccine (travel vaccine)
Generally recommended to delay these vaccinations until after giving birth. In some cases where there is a high risk of infection, these vaccines may be given to pregnant women
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
Pharmacokinetic changes in Pregnancy
Absorption: Increase in progesterone - Reduces gastric and small intestine motility - Reduces absorption of oral medicines
Absorption: - Nausea and vomiting - Decrease in absorption of oral medications
Absorption: Increase in tissue perfusion - Increase in IM/SC absorption and transdermal absorption
Absorption: increase in cardiac output, tidal volume, alveolar uptake - Increase in absorption of drugs by inhalation -(inhaled drugs used to treat asthma such as steroids may have increased absorption into blood– but no studies have shown increased toxicity)
Distribution - Plasma volume increases by 150% by 24-28 weeks gestation - Volume of distribution increases- Clinical effect decreases
Metabolism- Elevated hormonal concentrations of various hormones such as oestrogen, progesterone, prolactin and placental growth hormone - Altered drug metabolism
Excretion - 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 - Drugs excreted unchanged by kidneys show increased elimination
Rate of drug transfer to the fetus depends on:
Molecular weight (MW) of drug - decreased transfer as size increases. Most drugs have a molecular weight < 600 and diffuse easily across placenta
Protein binding -highly protein bound drugs tend to have higher maternal and lower fetal concentrations
Lipid solubility - so lipophilic, unionised drugs cross the placenta more easily than polar drugs
pKa – is the hydrogen ion concentration (pH) at which 50% of the drug exists in its ionized form
pKa - weak bases can get ‘trapped’ in the fetal circulation because of the slightly lower pH (>H+ ions) compared with the maternal plasma. They get trapped in their ionised form (BH+) and can’t cross the placenta to return to maternal circulation
Enzymes/drug efflux transporters in placenta - may facilitate or restrict the transfer of drug to fetus
what is teratology
Defined as: ‘Science that studies the causes, mechanisms, and patterns of abnormal development.’
Effect is dependent on duration of exposure, amount of teratogenic substances and the stage of development.
Teratogen:
Defined as : ‘Any agent that results in structural or functional abnormalities in the fetus, or in the child after birth, as a consequence of maternal exposure during pregnancy.’
Teratogenic mechanism for most drugs remains unclear – may be due to direct effects of drug on fetus and/or due to indirect physiological changes in the mother or fetus
what is the 4 types of tetrology
Teratogens are classified into four types:
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)
Drugs
tetrology drugs
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:
When the fetus comes into contact with a teratogen it can cause:
Physical malformations
Problems in behavioural or emotional development of the child
Decreased IQ
Preterm labours
Spontaneous abortions/miscarriages
Fetal death
Most famous teratogen is thalidomide – limb deformities
External anomalies such as limb abnormalities maybe obvious at birth ( for e.g. thalidomide)
But some defects may take many years to be identified (e.g. behavioural/developmental disorders due to sodium valproate exposure)
Gestation period is 38 weeks post conception
Conventionally divided into 1st, 2nd, 3rd trimesters – each lasting 3 months
When assessing the risks of drugs in pregnancy, it is more useful to classify the stage of pregnancy according to the stage of embryo-fetal development
Three stages:
Pre- embryonic (germinal) stage
Embryonic stage
Fetal stage
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
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
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
Gestation period is 38 weeks post conception
Conventionally divided into 1st, 2nd, 3rd trimesters – each lasting 3 months
When assessing the risks of drugs in pregnancy, it is more useful to classify the stage of pregnancy according to the stage of embryo-fetal development
Three stages:
Pre- embryonic (germinal) stage
Embryonic stage
Fetal stage
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
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
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
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
Thalidomide exposure between day 20 and 36 post conception is associated with a higher risk of congenital malformation
Principles of drug teratogenicity
- timing of exposure
-dose
-species
Genotype and environmental interaction
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
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
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
