18 - Pregnancy & Lactation Flashcards
What percentage of pregnant women take medication during their pregnancy?
60%
What percent of pregnancies in North America are unplanned?
Around 50%
What are the problems w/ medication use in pregnancy?
- First physician visit often weeks into pregnancy
- Lack of into on safety of medications in pregnancy
- Societal beliefs (exaggerated perception of risk leads to increased rate of abortion)
- Litigation (overly cautious approach by HCPs)
- Risks to mother/fetus of not taking medications
What are some conditions that may require drug use during pregnancy?
- N/V of pregnancy
- Cough, cold, allergic rhinitis
- UTI
- Hypertension, preeclampsia
- Gestational diabetes
- Asthma
- Depression
- Epilepsy
What is a teratogen? Give examples
- Agent that acts to irreversibly alter growth, structure, or function of the developing embryo or fetus
- Ex: viruses, environmental factors, chemicals, drugs
What is teratology?
- Study of birth defects
- Looks at the causes, mechanisms, and patterns of abnormal development
What was thalidomide marketed as for pregnant women?
Sedative/anxiolytic and for morning sickness
What effect did thalidomide have on developing fetuses?
- Limb malformations
- Ear, CV, GI anomalies
What period of gestation do upper limbs form?
27-30 days
What period of gestation do lower limbs form?
30-33 days
Exposure to a teratogen during ___ gestation will cause a duodenal atresia (absence or abnormal narrowing)
40-47 days
What period during pregnancy is the embryo/fetus most at risk from exposure to teratogens?
2-8 weeks after conception
What is the pre-implantation period of pregnancy?
- Time from conception to implantation (first 2 weeks)
- All or nothing phenomenon (if the embryo is exposed to a teratogen, it will either kill it or it will recover w/ no harm)
What is the embryonic period of pregnancy? What occurs during this phase?
- 2-8 weeks post conception
- Organogenesis (development of organs and specialized tissues)
- Greatest period of vulnerability to teratogens
What is the fetal period of pregnancy?
- 9 weeks to birth
- Period of growth and maturation of organs
- Anomalies can still occur
Which drugs have potential adverse effects of spontaneous abortion?
- Warfarin
- Toluene
- Cocaine
- NSAIDs
Which drugs have potential adverse effects of congenital anomalies?
- Anticonvulsants
- Isotretinoin
- Lithium
Which drugs have potential adverse effects of fetal growth restriction?
- Beta blockers
- Nicotine
What are the mechanisms of fetal toxicity?
- Receptor-ligand interactions
- Covalent bonding
- Peroxidation of lipids and proteins
- Interference/inhibition of protein and enzyme function
What are some physiological changes that occur in the mother during pregnancy that affect pharmacokinetics?
- Decreased gastric motility (affects absorption)
- Increased maternal blood volume and decreased plasma protein (affect distribution)
- Altered liver activity (affects metabolism)
- Increased renal blood flow (affects excretion)
- Decreased AUC, peak plasma and SS concentration, t1/2, and increased clearance in about 50% of drugs
How do the majority of drugs cross the placenta?
Passive diffusion
What are characteristics of a drug that is likely to cross the placenta?
- Lipophilic
- Unionized
- Low molecular weight
- Low protein binding
What is the criteria for a compound to be considered teratogenic?
- Defect can be characterized
- Drug proven to be able to cross placenta
- Exposure occurs during critical development period for the specific defect
- Association is biologically possible
- Consistent epidemiological findings
- Teratogenicity in animals (not always a direct correlation)
What are some known teratogenic drugs?
- Alcohol
- ACE inhibitors
- Isotretinoin
- Lithium
- Methotrexate
- Phenytoin
- Thalidomide
- Valproic acid
What teratogenic effect do anticonvulsants have?
- Neural tube defects
- Craniofacial anomalies, cleft palate
What teratogenic effect do ACE inhibitors have?
- CV malformations
- Microcephaly
- Spina bifida
- Renal failure, death
What teratogenic effect do coumadin derivatives have?
- “Warfarin syndrome” = hypoplasia of nose/extremities, eye abnormalities, scoliosis, deafness
- Fetal hemorrhage
What teratogenic effect does methotrexate have?
- Craniofacial, skeletal malformations
- Neural defects, mental retardation
What teratogenic effect does isotretinoin have?
- Craniofacial abnormalities
- Cardiac defects, hydrocephalus
- Spontaneous abortion
What are the signs and symptoms of fetal alcohol syndrome?
- Dysmorphic features (small eye openings, flattened cheekbones, indistinct philtrum)
- Prenatal/postnatal growth retardation
- Cognitive deficits
- Behavioural and learning problems
Is there a correlation to amount smoked during pregnancy and birth weight of the child?
Yes, more cigarettes = lower birth weight
What are the various FDA categories for teratogens?
- Class A = controlled studies showed no risk to humans
- Class B = no evidence of risk in humans
- Class C = risks can’t be ruled out in humans
- Class D = clear evidence of risk in humans (benefits may outweigh the potential risk)
- Class X = drugs contraindicated in human pregnancy
What are some drawbacks of FDA classifications? What should be concluded?
- Often based on limited data (animal studies, case-report, limited or no human data)
- Infrequently updated
- Inconsistent assignment (some teratogens or those w/ serious fetal effects listed as C or D)
- Over simplifies a complex topic
- Don’t use outdated FDA classifications
Which source is used by majority of OB/GYN and physicians?
Briggs (drugs in pregnancy and lactation)
What are the new changes to FDA labelling rules?
- 3 sections – pregnancy, lactation, and females and males of reproductive potential
- Pregnancy – summary of risk of adverse developmental outcomes on all relevant data; risk of disease, dose adjustments, maternal adverse effects
- Applies to all new drugs, and older drugs phased in gradually
- OTCs not included
What is the role of the pharmacist when dealing w/ teratogenic drugs?
- Discuss risk for women of child-bearing age BEFORE they become pregnant
- Discuss risk to mother and unborn infant if condition untreated
- Consider non-pharm options
What should be done if therapy w/ a teratogenic drug is required?
- Monotherapy at lowest effective dose for shortest amount of time
- Older drugs w/ more information generally preferred
What is the role of the pharmacist after a teratogenic drug has been used in pregnancy?
- Determine timing of exposure
- Review available information (don’t rely on old FDA classifications)
- Discuss relative risk (may only be 1-2% above basline; population birth defect rate is 1-3%)
- Consult prescribed for further background info if required
- Consider referral to information center (ex: MotherRisk)
What are some benefits to breastfeeding?
- Ideal nutrients that can’t be replicated by formula
- Lower rate of infections
- Decreased incidence of SIDS
- Enhanced neurocognitive performance
- Benefits for mother
How can drugs transfer into breast milk?
- Transcellular diffusion – small unionized lipid soluble molecules transverse capillary wall
- Intercellular (paracellular) diffusion – large molecules avoid alveolar cell entirely (spaces are larger during earlier stages of breastfeeding)
- Ionophore – polar molecules enter via binding to carrier proteins w/in cell membrane
What are some drug properties that affect transport into breast milk?
- Molecular size (better chance if less than 200-300 daltons)
- Ionization (must be unionized)
- Lipid solubility (better chance if highly lipophilic)
- Plasma protein binding (better chance if poorly protein bound)
- pKa
What can happen to basic drugs w/ higher pKa w/ respect to breast milk? What happens to acidic drugs?
- Greater amount of ionized drug will be in milk, thus “trapped” (must be unionized to cross lipid membrane)
- Can result in milk/plasma ratio > 1
- Opposite effect for acidic drugs (more in plasma)
What drug factors should be considered when determining use during lactation?
- Amount transferred into breast milk
- Type of drug and adverse effect profile (ex: increased BP vs. diarrhea)
- PK properties (high bioavailability = more absorbed by infant; long half life = greater chance of accumulation)
- Prescribed for infants? and relative infant dose
What patient factors should be considered when determining use during lactation?
- Indication (essential? other alternatives available?)
- Duration of therapy (greater risk of accumulation w/ prolonged tx)
- Underlying conditions (ex: renal dysfunction)
- Age of infant and ADME
What is the milk/plasma ratio? What value is given when drug concentrates in milk to a large degree?
- Drug concentration in milk / drug concentration in plasma
- Values over 1-5
How can infant dosage and daily dose be calculated using drug concentration in mothers milk?
- Infant dosage = drug concentration in milk * volume of milk
- Daily dose = average drug concentration in milk * volume of milk ingested in 24 h
What is the most common calculation done for expressing actual drug exposure in lactation? How is it calculated? What is an ideal value?
- Relative infant dose
- [Infant dose (mg/kg/day) / maternal dose (mg/kg/day)] * 100
- RID under 10% generally considered safe
Which antibiotics are concerning during lactation?
Tetracyclines and fluoroquinolones
Are acetaminophen and NSAIDs safe in breastfeeding?
- Acetaminophen yes
- NSAIDs yes except ASA
Can opioids be used during lactation?
- Morphine, methadone and hydromorphone considered safe
- Codeine safe unless mother is an ultra-metabolizer
- Caution w/ oxycodone, and meperidine
Can antidepressants and antipsychotics be used during lactation?
- SSRIs compatible (sertraline, paroxetine, fluvoxamine, and fluoxetine less preferred)
- Tricyclic antidepressants are safe (avoid doxepin)
- Atypical antipsychotics are less studied
- Lithium has a high RID, but can be used if no other option
Can BZDs be used during lactation?
- Lorazepam is compatible
- Diazepam is okay for short-term use
- Choose drugs w/ short t1/2 and duration
Can vaccines be given during lactation?
Yes, except yellow fever vaccine
Can alcohol be consumed by the mother during lactation?
- Yes
- Avoid chronic use
- Delay breastfeeding 2 hours after drink
Is smoking safe during lactation?
No, should be avoided (increased risk of SIDS)
What are galactagogues used for?
- Stimulate lactation
- Dopamine antagonists that stimulate prolactin production
Which drugs should be used w/ caution in lactation?
- Amiodarone
- Certain beta blockers (atenolol, sotalol)
- Lamotrigine
- Lithium
- Mycophenolate
Which drugs are contraindicated in lactation?
- Cytotoxic (antineoplastic) drugs
- Radiopharmaceuticals
- Drugs which inhibit lactation (bromocriptine, cabergoline, ergotamine)
What are some strategies to minimize exposure to harmful drugs during lactation?
- Choose drug w/ favourable properties/kinetics
- Time doses right after breastfeeding
- Minimize dose and duration
- Monitor SE and drug levels
- Consider alternative drug or non-pharm measures
What is the cause of morning sickness?
- Unknown, some theories include:
- Hormonal changes (elevated hCG)
- Changes in GI motility (delayed gastric emptying and decreased esophageal sphincter tone)
- H. pylori infection
What is the course of N/V in pregnancy?
- Begins around 4-6 weeks
- Peaks between 7-12 weeks
- Lessens by 12-20 weeks
- Onset after 8-10 weeks rare (red flag)
What is hyperemesis gravidarum? What is the tx?
- Persistent, intractable vomiting
- May require hospitalization if dehydration occurs
What are some risk factors for N/V during pregnancy?
- Multiple pregnancy
- NVP in previous pregnancy
- Familial history
- Molar pregnancy
- History of GI problems
- History of migraines
What are some non-pharms for N/V in pregnancy?
- Eat small amounts of food every 1-2 h
- Separate solids and liquid by ~ 30 mins
- Minimize spicy, fried, or high-fat foods
- Maintain adequate fluid intake (2 litres/day)
- Avoid strong smells
What is pyridoxine? Is it safe to use for N/V in pregnancy?
- Vitamin B6
- May be useful for mild to moderate N/V
What are the ingredients of Diclectin? What are some SE?
- 10 mg of each doxylamine and pyridozine (1st gen antihistamine and vitamin B6)
- SE = sedation, anticholinergic
When would dimenhydrinate or diphenhydramine be used for N/V in pregnancy?
For breakthrough sx for women on Diclectin
When would metoclopramide be used for N/V in pregnancy?
Severe cases
When should N/V in pregnancy be referred?
- Unable to keep food/water down for more than 24 h
- Significant weight loss
- Signs of dehydration (increased thirst, decreased urination, dry mouth)
- Signs of infection
- Other sx inconsistent w/ N/V (neurlogical, hematemesis, abdominal pain)
- Onset after 10 weeks or return of sx
