5. Pregnant women drug orphan Flashcards
applications of pharmaceuticals in pregnancy
Treating pre-existing maternal conditions
Preventing infections in pregnancy (vaccination)
Treating or preventing pregnancy-induced maternal conditions
Treating or preventing placental disorders
Treating or preventing fetal disorders
Anaesthesia or analgesia for surgical procedures
How does the body change during pregnancy
Respiratory:
- increase in tidal volume and minute ventilation
Gastrointestinal:
- nausea and vomiting, delayed gastric emptying, prolonged small bowel transit time, gastrointestinal reflux
Endocrine:
- liver changes in oxidative liver enzymes such as cytochrome, P450
Urinary:
- increases in renal blood flow and glomerular filtration rate
Cardiovascular
- Increases in plasma volume, cardiac output, stroke volume and heart rate
- Decreases in serum albumin concentration and serum colloid osmotic pressure
- Increases in coagulation factors and fibrinogen
- Compression of the inferior vena cava by the uterus
Breasts
Other notable changes
- Sex steroid levels
- Insulin and other metabolic regulators
- Inflammation and oxidative stress
- Immunity (monocytes, neutrophils, T-cells)
- Immune tolerance
- Susceptibility to infectious disease
- Severity of autoimmune diseases
PRESCENCE OF THE FETUS
which ways does the body in pregnancy change the effects of drugs
- Potency of drug
- How its distributed
- Metabolised and cleared
- Pregnant vs non pregnant will change efficacy
- Almost all drugs given to mother reach the fetus to some extent
○ Some times mother gets more, sometime fetus gets more, depends on how well they cross the placenta
○ Then metabolites from fetus are excreted through the mother
What are some possible negative effects of drugs on the fetus
- Teratogenicity (e.g. thalidomide) - readily detected at, or shortly after, birth
- Long term latency (e.g. diethylstilbestrol took 15 to 20 years)
- Impaired intellectual or social development (e.g. exposure to phenobarbitone - alters programming of brain)
- Predisposition to metabolic diseases (i.e. “Barker hypothesis” - low birthweight associated with increased risk of diabetes, hypertension, heart disease in adulthood)
Drug administration in pregnancy
- More than 50% of pregnant women receive some form of drug during pregnancy (mainly category B e.g. antibiotic good evidence of safety but no clinical trials and C)
- Drug administration is more common earlier in pregnancy, when the developing fetus is most susceptible to xenobiotics, sometimes unaware they’re pregnant
- Up to 1:20 pregnant women (5%) take a category D or X drug in their pregnancy
○ Sometimes the risk of not taking the drug is higher than taking the drug - However, the percentage of congenital defects directly attributable to drug exposure is low (<10%)
- The background rate of congenital malformations if 1-3% so a small increase in incidence is hard to attribute to drug exposure with confidence
Problems with current drug adminisations in pregnancy
- Prescribing medications in pregnancy off-label (~85%)
○ Decisions based on data from animal studies and extrapolating from males and non pregnant females
○ No accounting for pregnancy-induced changes in drug disposition and metabolism (dose uncertainty) - Over 90% of clinically approved drugs lack appropriate information on efficacy & safety:
○ efficacy, safety, teratogenicity and pharmacokinetics in pregnancy - Prescribing advised by data from pregnancy drug registries
○ Small number of women for most drugs
Uncontrolled data, reporting errors & inaccuracies
Top 10 drug classes administered to pregnant women
- Vitamins
- Iron preps
- Anti-infectives
- Analgesics
- Glucose regulators
- Oral contraceptives
- Bronchodilators
- Thyroid medications
Antiemetics
non prescription drugs taken during pregnancy
- > 95% or pregnant women take over the counter drugs or supplements during pregnancy
- > 75% take something other than vitamins etc
- > 60% take OTC medicines
- 4% use herbal remedies (risks unknown)
>10% take four or more medications (greater risk)
Thalidomide generation
- Late 1950s early 1960s
- Sold as a sedative, for coughs/colds, nervousness/neuralgia, migraine/headaches, asthma, nausea
- Sold in 11 European countries, 7 African countries, 17 Asiatic countries and 11 others (including Canada, Australia and New Zealand). Not sold in the USA (FDA approval not granted).
- Sold in many forms, either alone (25/100 mg tabs or in liquid form), or combined with other drugs (aspirin, quinine, bacitracin, dihydrostreptomycin):
- Tow bad side effects
○ Paraesthesia: ends of your fingers and toes go numb to sensation which was reversable upon stopping drug
○ Cause limb defects and heart defects (died in utero) - 13-16,000 affected fetuses in total
paracetamol in pregnancy
- Evidence that it alters brain development and causes behavioural issues in childhood from autism to learning difficulties
- Took years for them to reach this conclusion
Zika virus vaccination
Despite the fact that fetus were at risk of the virus pregnant women were still excluded from trials
Reccomendations from ACOG committee to get pregnant women involved
- Encourage recruitment of pregnant women to trials
- Identify and address obstacles to recruitment
- Research design to address inclusion and diversity
- Pregnant women are “scientifically complex” not “vulnerable population”
- Requirement for contraception in participants to be tailored to actual risk
- Partner consent is not warranted or ethically justified
- Risks of mother and/or fetus needs to be balanced with importance of trial inclusion and data
summary of why pregnant women are excluded
- Pregnant women are EXCLUDED from drug trials
- Lack of current legislation stating that pregnant women need to be included in clinical trials
- Lack of funding/investment from ‘big pharma’
- Fear of harm to fetus, threat of liability
- Lack of evidence on dosing and metabolism & clearance
- Difficult to get adequate evidence of safety & effectiveness
