Drug Use in Pregnancy and Lactation Flashcards
Maternal and fetal drug responses during pregnancy are
influenced by two factors:
1) Pregnancy induced physiologic changes.
2) The placental-fetal unit which affects:
lthe amount of drug that crosses the placenta.
lthe fraction of drug that is metabolized by the placenta
lthe distribution and elimination of the drug by the fetus.
Teratogens
Incidence of congenital manifestations is 3 – 5%
l 65 – 75% unknown cause
l 15 - 25% genetic causes
l 10% environmental causes
l Medication exposure is less than 1%
Factors That Can Influence Teratogenicity
l The embryonic stage at exposure
l Genotypes of the mother and the fetus
l The extent to which the drug crosses the placenta.
l Type of agent
l Dose
l Duration of exposure
l Simultaneous exposure to other drugs and environmental
agents
The difficult part of doing studies looking at drugs in pregnancy is that to be able to say that a drug causes this teratogenicity are some effect. The incidents in studies has to be higher than the incidence of just congenital manifestations.
So a drug has to show higher than three to 5% in a study or studies, multiple studies to say that that is transgenic.
Pregnancy trimesters fetal development review
from the time of the last menstrual period. Start with the last menstrual period. That would be the gestational age. 40 weeks. If you see 38 weeks, that’s embryonic age, right? So it’s the time of conception. So if you think last menstrual period, day 14, ovulation, hopefully, that’s when the pregnancy happens.
The first trimester. Obviously, if it’s gestational, is 012 weeks to 12 weeks, second trimester up to 28 weeks
eight to nine weeks of the the embryonic stage and then up to 12 weeks of gestational stage is where a lot of you, you’re seeing a lot of the development of the organs, right? You start, the CNS starts developing, the heart starts developing, you start see, ears and teeth and palate and external genitalia starts.
hen after that, there is still ongoing development, but it’s just getting bigger. Everything just seems to be getting bigger. And that’s why the biggest concern is that first trimester
The first two weeks is the time where you start seeing implantation. And this is where a lot of times that’s when we’ll see a spontaneous miscarriage happening. In this time. Majority of times we may not even know that someone has had a miscarriage there because that’s before even implantation
Placental Drug Transfer:
Can occur by simple diffusion (most common),
differential diffusion, active transport,
and pinocytosis
Transfer influenced by:
l molecular weight
l protein binding
l lipid solubility
l degree of ionization
l placental blood flow
l placental metabolism
l thickness of placental membrane
So smaller molecular weight, less than 500 da, e.g. molecular weight, not protein bound. You need free. Lipid-soluble, needs to be able to pass degree of ionization, not ionized.
Think about the placenta blood flow to the areas are good. Blood flow is their metabolism
Thicjbess of placenta
If thin, can increase drugs and toxins going thru system
Methods of Determining Safety of Drugs in
Pregnancy
Difficulty lies in how to evaluate the
evidence related to safety in pregnancy.
l Most RCTs will exclude pregnancy
l The overall risk of most teratogens is low.
l Will need a large number of exposures to
appreciate an increase in risk.
Most data is from case reports
that may not be generalized to
all women.
also retrospective cohort,
case-control
Evaluation of Data
Other issues:
l study sample size
l Most malformations occur rarely
l Many teratogens do not affect all fetuses
l contribution of maternal disease to fetal risk
l recall bias in retrospective studies
l unbalanced reporting: only reporting when adverse fetal outcome
versus uneventful ones
Usually the issue is that if usually people report something when something goes wrong, we’re not always capturing if something, if all the people that it was in, that, it went well in that. So that’s that’s why it’s like things like case-control can be good because then you can look at, in comparison to a control group, what did you see, right? But if you just look at cases, you’re not gonna be able to know or just say, Oh, I know about a case that they ended up with some kind of teratogenic effect and they took this drug.
l. So what about the effect on seizures? So a mother that has seizures and the effect of a seizure during pregnancy on the fetus versus the effect of the drug being taken at that time. So some of the, some some malformations can occur from having a seizure that can look like the same things that from certain drugs. Or what about being hypertensive during that time?
Need to look at mom’s conditions too
Pregnancy Registries:
- Post-marketing data
- Voluntary, recorded prospectively
Evaluation of Data
f/u of infants
l Follow-up of infants long term is also important.
l To assess the long term affects of teratogenic drugs on
neurobehavioral development:
l Drugs that can affect brain development: isotretinoin,
phenytoin, carbamazepine, valproic acid
But what about other effects like neurodevelopment? Like their personality and effects on or even things like ADHD and concentration and all of those effects where we’re finding out more and more now as we follow. But you have to follow these individuals a long term, right? And often we don’t do that adequately.
usually say no physical abnormalities and ok it.
? That’s what the first trimester is where you see a lot more of those physical effects, physical malformations. Later on that you start seeing some of those other effects that can happen on brain and brain development
The Old FDA Classifications of Drug-Use
During Pregnancy
Category Details
Category A Controlled studies in women fail to demonstrate
a risk to the fetus
Category B Animal studies show no risk + no controlled
human studies,
or show risk but human studies show no risk
Category C No animal studies or show risk but no human
studies
Category D Positive evidence of human fetal risk, but benefit
may outweigh risk
Category X Proven fetal risks, outweighs any benefit
We follow similar in Canada…
Changes:
Labeling involves 3 sections:
* Pregnancy
* Lactation
* Females/Males of Reproductive
Potential
Instead of the old labeling classification companies in
the U.S. must now include “risk summary”.
Proven Teratogens:
Few medications are proven teratogens
l Use of these agents does not guarantee a specific birth defect
will occur
l Avoid use during pregnancy!
l See table – examples.
Thalidomide Limb defects
Diethylstilbrestol (DES) Vaginal/cervical adenomacarcinoma, female
urogenital abnormalities
We don’t, we don’t use DES, which is diethylstilbestrol. No longer they actually used to use this. It was a synthetic estrogen that they actually used to use to prevent certain complications during pregnancy. I think maybe like with vaginal bleeding or things like that during the pregnancy if there’s effects on maintaining that pregnancy. So they used to actually use that during that time, but caused actually vaginal cancer and just affects your genital abnormalities in the female. The vaginal cancer came later.
Alcohol Craniofacial/limb defects, learning disorders
Isotretinoin Craniofacial, CNS, cardiac defects
Warfarin Skeletal & CNS defects
Methotrexate Neural tube, skull, and limb defects
Valproic Acid Neural tube, limb and cardiac defects
Androgens Masculinization of external female genitalia
Cocaine Neurodevelopment, low birth weighs
describe
thalidomide
Neural Tube Defects
Fetal Hydantoin Syndrome
Thalidomide was used for nausea in pregnancy
characteristics is the absence of these long bones as you can see. And this is called phocomelia actually handle absence of those long bones. And it happened in a third of pregnancies in the first trimester
They’ve had heart defects and they had issues with their ears.
neural tube defects
o folic acid is the deficiency
it can affect anywhere along from the brain down. The spinal cord, most commonly is down lower in the lower part of the back of the spinal cord. And it’s from drugs that affect folic acid may increase metabolism with that, including some of the anticonvulsants, phenytoin, valproic acid among others. And basically it’s the incomplete closure of this embryonic neural tube. Usually this closes before the end of the fourth week
portions of the spinal cord coming out of protruding from the bones
Fetal hydantoin syndrome
Phenytoin, carbamazepine (other anticonvulsants)
nasal bridge is quite broad. SThey can have effects in their heart as well. And and other issues that limb abnormalities
Seizure in preg can lead to it too
Cleft palate can happen too
Fetal Alcohol Spectrum Disorder
Who is at risk for having a child with
FASD?
l Alcohol use during pregnancy is associated with a range of
complications called “Fetal Alcohol Spectrum Disorder (FASD)”
l Alcohol easily crosses placenta
l Lifelong physical, behavioral and intellectual affects.
l Completely preventable by avoidance of alcohol during
pregnancy.
All women at child bearing age
FASD cuts across all social circles
I would say an individual with the uterus at childbearing age would be at risk for her child.
Alcohol affects in pregnancy…
l Amount of alcohol the mom drinks
l Timing of alcohol drinking:
l Can occur even before woman knows she is pregnant (days
19 – 21 most vulnerable)
l Pattern of drinking: binge worse
l Genetics
l Postnatal environment
There is no
safe amount
of alcohol
during
pregnancy
And need to consider BEFORE a woman gets
pregnant
The issue is that much of the effects of alcohol are in the early early time, especially that first four weeks of development, especially the first trimester, but especially that first four weeks before an individual knows that they’re pregnant.
fas
arnd
arbd
pFAS
FAS: most
severe
Physical, brain
damage,
neurodevelopment effects
pFAS: partial
physical
effects and
neurodevelopment effects
ARBD: many
birth defects ie
cardiac,
skeletal, renal`
etc
ARND: neurodevelopment
effects, no
physical evidence
fetal alcohol syndrome, that’s everything. They have some of the physical facts. They have neurodevelopment. They may have some brain issues and brain damage from the effects of alcohol
alcohol-related birth defects, then they have a lot of just those birth defects, maybe not as much on the development.
Alcohol-related neurodevelopment disorder is just based on neurodevelopment effects and there’s no physical effects. So you’ll see a lot of these individuals who don’t look like they have the spectrum in any way. But they have a lot of the neurodevelopment effects
Partial Fetal Alcohol Syndrome is just partial physical fx They don’t have the whole spectrum, but they may have components of bot
Fetal Alcohol Syndrome (FAS) Physical
Features
Also may have height/weight below the 10th percentile
Note: only 10% have the classic FAS characteristics!
low nasal bridge, short nose and flat midface, smooth philtrum, thick upper lip, micrognathia, microcephaly, epicanthal folds, short palpebral fissures, minor ear abnormalities
