FEATURES OF DRUGS ACTION DURING PREGNANCY

Drug use in pregnancy
Drugs can be harmful for the unborn child!!!
THE PLACENTA
Drugs pass placenta by passive diffusion
lipid barrier between maternal and embryonic/fetal circulations
slow process (used during caesarean section)
non-ionized drugs pass more rapidly
most drugs are small enough to passexceptions: growth hormone, conjugated steroids
cuts peak concentrations in maternal plasma

Drug use in pregnancy
effects of toxic drugs
• malformation
• growth retardation
• fetal death
• functional defects in newborn
• premature birth
Drugs should be used with caution during pregnancy

Drug use in pregnancy
Use of drugs in pregnancy is not always wrong
Some examples:
• High fever is harmful for the fetus in the first
months.
Use of paracetamol is better then no
treatment
• Diabetes during pregnancy needs intensive
therapy with insulin
• Folic acid protects against spina bifida
• Anti-epileptics are teratogenic. But an epileptic
insult may provoke harmful anoxia for the fetus.

Drug use in pregnancy
Toxic chemicals and irradiation can damage
Oocytes:
• all female germ cells develop prenatally. No
germ cells are formed after birth
• Oocytes are in situ and not multiplying.
• teratogenic effects can become apparent after
fertilization, maybe long after the presence of
damage
• EMEA does not allow women with childbearing
potential to take part in first in man studies

Drug use in pregnancy
Is damaged sperm teratogenic?
• Spermatozoa are continuously produced
• Damaged spermatozoa are slower and arrive late
when the oocytes is already fertilized → mostly not harmful?
• May lead to infertility
→ paternal teratogenicity cannot fully be excluded.
advice: use of condoms when the man is taking
products that are suspected to be harmful
termination of pregnancy because of paternal
teratogenicity is not justified

Drug use in pregnancy
The first trimester (day 8 – end of month 2)
Is the most important period for teratogenicity
Is period of formation of organs
3rd – 9th month
Less risk for malformations
except for urogenital tract and central nervous system
More functional effects
i.e. aminoglycosides nephro- & ototoxicity
salicylates increased risk of bleeding

Drug use in pregnancy
drugs have effects in newborn
• avoid CNS depressants
floppy infant syndrome
• avoid drugs with increased bleeding risk
like anticoagulants, salicylates
increased risk of cerebral hemorrhage during delivery
• NSAIDS and salicylates ↓ uterine contractility

Drug use in pregnancy
spontaneous malformations (=unknown origin)
2-4 %
Additional risk from drugs is small for most drugs
evidence for teratogenic effects
• golden standard is randomized controlled trial
(RCT). ethical objections
• epidemiologic studies cannot establish proven
causality
• large species differences in teratogenic effects
No drug is proven free from teratogenic effects

Drug use in pregnancy
Risk classification (FDA)
Category A:
Controlled studies in women fail to demonstrate
a risk to the fetus in the first trimester (and there
is no evidence of a risk in later trimesters), and
the possibility of fetal harm appears remote.

Drug use in pregnancy
Category B:
Either animal reproduction studies have not
demonstrated a fetal risk but there are no
controlled studies in pregnant women,
or
animal-reproduction studies have shown an
adverse effect (other than a decrease in fertility)
that was not confirmed in controlled studies in
women in the first trimester (and there is no
evidence of a risk in later trimesters).

Drug use in pregnancy
Category C:
Either studies in animals have revealed adverse
effects on the fetus (teratogenic or embryocidal
or other) and there are no controlled studies in
women,
or
studies in women and animals are not available.
Drugs should be given only if the potential
benefit justifies the potential risk to the fetus.

Drug use in pregnancy
Category D:
There is positive evidence of human fetal risk,
but the benefits from use in pregnant women
may be acceptable despite the risk (e.g., if the
drug is needed in a life-threatening situation or
for a serious disease for which safer drugs cannot be used or are ineffective).

Drug use in pregnancy
Category X:
Studies in animals or human beings have
demonstrated fetal abnormalities, or there is
evidence of fetal risk based on human experience
or both,
and
the risk of the use of the drug in pregnant women
clearly outweighs any possible benefit.
The drug is contraindicated in women who are or
may become pregnant.

Anti-infectives
Penicillins
Cephalosporins
Carbapenems
Fluoroquinolones
Macrolides
Aminoglycosides
Sulfonamides
Miscellaneous Antibiotics
Antivirals
Antiretrovirals
Antifungals

Penicillins
Category B in pregnancy
Cross the placenta easily and rapidly
Concentrations equal maternal levels
Lactation
Crosses in low concentrations
Compatible with breastfeeding

Cephalosporins
Category B in pregnancy
Cross the placenta during pregnancy
Some reports of increased anomalies with specific cephalosporins
(cefaclor, cephalexin, cephradrine)
Primarily cardiac and oral cleft defects
Lactation
Excreted into breastmilk in low concentrations
Considered compatible with breastfeeding

Carbapenems
(ertapenem, imipenem, meropenem)
Category B/C/B in pregnancy
Likely cross the placenta
Very little human data
Lactation
Excreted into breastmilk in low amounts
Unknown effects but likely low clinical significance

Fluoroquinolones
Pregnancy Category C
Not recommended in pregnancy
Cartilage damage in animals
Safer alternatives usually exist
Lactation
Excreted into breastmilk
Limited human data
AAP says compatible with breastfeeding

Macrolides
(azithromycin, clarithromycin, erythromycin)
Pregnancy Categories B/C/B
Cross the placenta in low amounts
Limited data with azithromycin and clarithromycin
Lactation
Erythromycin compatible
Others probably compatible

Aminoglycosides
(amikacin, gentamicin, tobramycin)
Pregnancy Category C
Rapidly cross placenta
Enter amniotic fluid through fetal circulation
Lactation
Compatible with breastfeeding
Not absorbed through GI tract

Sulfonamides
Pregnancy Category C
Readily cross the placenta
Concerns of use at term
Lactation
Excreted into breastmilk in low levels
Use should be avoided in premature infants

Tetracyclines
(doxycycline, minocycline, tetracycline)
Pregnancy Category D
Can cause problems with teeth and bone and other defects/effects
Have been linked to maternal liver toxicity
Lactation
Compatible with breastfeeding
Serum levels in infants undetectable

Miscellaneous Antibiotics
Aztreonam
Pregnancy Category B, likely safe in pregnancy, little human data
Lactation – Compatible per AAP
Clindamycin
Pregnancy Category B, commonly used
Lactation – Compatible per AAP

Miscellaneous Antibiotics
Linezolid
Pregnancy Category C, no human data available
Lactation – unknown, myelosuppression in animals
Metronidazole
Pregnancy Category B, carcinogenic in animals, avoid in 1st trimester if possible
Lactation – hold feeds for 12-24hrs afterward

Miscellaneous Antibiotics
Nitrofurantoin
Pregnancy Category B, possible hemolytic anemia with use at term
Lactation – Compatible, avoid with G-6-PD deficiency
Trimethoprim
Pregnancy Category C, potentially problematic early in pregnancy
Lactation – Compatible as combination drug

Miscellaneous Antibiotics
Vancomycin
Pregnancy Category B, compatible
Lactation – likely compatible, not absorbed

Antivirals
(acyclovir, famciclovir, valacyclovir)
Pregnancy Category B
Acyclovir and valacyclovir readily cross the placenta
Can be used for HSV treatment and suppression
Lactation
Acyclovir and valacyclovir are compatible
Famciclovir should be avoided

Antiretrovirals/NRTI
(abacavir, didanosine (ddI), emtricitabine (FTC))
Pregnancy Categories C/B/B
Maternal benefit usually outweighs fetal risk
Cross the placenta
Limited data with each do not show increased risk of anomalies
Didanosine has been associated with severe lactic acidosis w/ or w/o pancreatitis

Antiretrovirals/NRTI
(lamuvidine (3TC), stavudine (d4T))
Pregnancy Category C
Maternal benefit usually outweighs fetal risk
Cross the placenta by simple diffusion
Data with lamivudine show no increased risk of anomalies
Stavudine has been associated with severe lactic acidosis w/ or w/o pancreatitis
All NRTIs have been possibly linked to mitochondrial dysfunction postnatally

Antiretrovirals/NRTI
(tenofivir, zalcitabine (ddC), zidovudine (AZT))
Pregnancy Category B/C/C
Maternal benefit usually outweighs fetal risk
Cross the placenta by simple diffusion
Limited data with zalcitabine do not show increased risk of anomalies
Zidovudine is commonly used, but may cause neonatal anemia
Limited data with tenofivir show low risk of teratogenicity

Antiretrovirals/NNRTI
(delavirdine, efavirenz, nevirapine)
Pregnancy Category C
Maternal risk usually outweighs fetal risk
Likely cross into fetus (nevirapine readily)
Delavirdine has possible VSD risk, but limited human data
Efavirenz is associated with anomalies in monkeys, limited human data, possible NTD
Nevirapine can cause hepatotoxicity and rash
Nevirapine can be used as a single dose in labor to prevent HIV transmission

Antiretrovirals/PI
Pregnancy Category B/C
Maternal benefit usually outweighs fetal risk
Likely cross the placenta
All PIs can cause hyperglycemia
Atazanavir can cause hyperbilirubinemia
Indinavir can cause nephrolithiasis

Antiretrovirals/Fusion Inhibitor
(enfuvirtide)
Pregnancy Category B
Maternal benefit usually outweighs fetal risk
Very large molecule (4492 daltons), likely does not cross placenta
Animal data does not show risk
No human data available
Hold during first trimester if possible

Antifungals/Azoles
(fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)
Pregnancy Categories C/C/C/D/D
Likely cross placenta
Fluconazole > 400mg/day seems to be associated with cranio-facial abnormalities
Itraconazole appears to have low risk
Ketoconazole can impair testosterone and cortisol synthesis
No data in humans is available for voriconazole, increased risk in animals

Antifungals/Azoles
(fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)
Lactation
Fluconazole is compatible per AAP
Itraconazole could concentrate in milk and body tissues, not recommended
Ketoconazole is compatible per AAP
No data with voriconazole, not recommended

Antifungals/Echinocandins
(anidulofungin, caspofungin, micafungin)
Pregnancy Category C
No data with anidulofungin
No human data with caspofungin, single case at UVA, animal data suggests risk
Lactation
No human data, but probably compatible

Antifungals/Polyenes
Amphotericin B
Pregnancy Category B, compatible, lipid complexes also compatible
Lactation – no data available

Migraine Headache Therapy
Triptans
Ergots
Butalbital
Caffeine
Dichloralphenazone
Isometheptene

Triptans (5-HT1 agonists)
Pregnancy Category C
Limited human data exists, sumatriptan has been associated with VSDs in several cases
No data available in humans for almotriptan, eletriptan, frovatriptan, or zolmitriptan
Limited human data exists with naratriptan and rizatriptan, although animal data indicates moderate risks
Pregnancy registry available for exposures

Triptans (5-HT1 agonists)
Lactation
Cross into breastmilk and may concentrate
No reports of human lactation with almotriptan, frovotriptan, naratriptan, rizatriptan, or zolmitriptan
Sumatriptan is compatible per AAP
Eletriptan is likely compatible with low concentrations

Ergots
(Dihydroergotamine, ergotamine)
Pregnancy Category X
Oxytocic properties could cause IUGR by vascular disruption or increased uterine tone
Early exposure appears safe, not teratogens
Chronic exposure is contraindicated
Lactation
Contraindicated

Butalbital and Caffeine
Butalbital
Pregnancy Category C, can see neonatal withdrawal symptoms with long-term use
Lactation – not recommended
Caffeine
Pregnancy Category B, doses generally lower than that in coffee
Lactation – compatible

Dichloralphenazone and Isometheptene (Midrin)
Dichloralphenazone
Pregnancy Category B
Lactation – similar agent considered compatible
Isometheptene
Pregnancy Category C, extremely limited data
Lactation – potentially compatible

Safe Drug Administration in children
Administration of drugs during the first year of life can be a challenge due to rapid changes in body size, body composition, and organ function.

The Neonate – birth to 4 weeks

Neonate - Absorption
Two major factors affect the absorption of drugs
pH dependent passive diffusion
Gastric emptying

Gastric pH
Gastric pH (6-8) is directly related to the presence of amniotic fluid in the stomach
Postnatally, gastric acid secretory capacity appears after the first 24 to 48 hours and gastric acidity decreases during the first weeks of life
Adult values are achieved at about 3 months of life

Gastric pH in premature infant
In the premature infants, gastric pH may remain elevated due to immature acid secretion

Delayed Absorption in neonate
Prolonged emptying is seen in premature infant
In the neonatal period the emptying rate is variable and prolonged
Delayed absorption may also be a result of diminished pancreatic enzyme function and bile acid secretion.

Absorption from skin and muscle in neonate
Percutaneous absorption may be drastically increased due to immature epidermis and increased skin hydration
Absorption from intramuscular site may be unpredictable and decreased due to insufficient blood flow, poor muscle tone, and compromised muscle oxygenation

Distribution drugs in children
Distribution of drugs within the body is influenced by the amount and character of plasma proteins, and relative size of fluid, fat and tissue compartments of the body.
Total body water
Plasma proteins

Total Body Water
85 % in pre-term infant
78% in neonate
60% at 1 year
64 % in childhood (10 to 15 year old)
60% in adults
54% in elderly

Metabolism in infants
Hepatic enzyme activity and plasma / tissue esterase activity are both reduced during the neonatal period
The enzyme activity increases as the infant ages but can be compromised in cases of severely malnourished infants and children
Plasma half-life 2 to 3 times longer in neonates

Neonate Renal Excretion
Renal Excretion
At birth, glomerular function is more advanced that tubular function this persists until about 6 months of age.
This effects the efficiency at which the kidneys eliminate drugs.
This is especially important in the administration of aminoglycosides

Infant – 5 weeks to 1 year

Infant - Absorption
Low acidity in stomach until around 2 years of age
Gastric emptying still delayed
Percutaneous absorption: continue to be increased through childhood

Absorption - IM
Injected drugs are often erratically absorbed because of variability in muscle mass amount children and illness
IM generally avoided due to pain and possibility of tissue damage

Absorption - transdermal
May be enhanced in young children because the stratum corneum is thin and the ratio of surface area to weight is much greater than for older children and young adults
Skin disruptions (abrasions, burns, eczema) increase absorption

Absorption – transrectal
Transrectal is dependent on placement of the drug within the rectal cavity
Good for drugs such as acetaminophen (Tylenol)
Diazepam in status Epilepticus

Absorption - lungs
Varies less by physiologic parameters and more by reliability of the delivery device
Beta agonists may be used for asthma, pulmonary surfactant for hyaline membrane disease

Meds via mask

Infant - Distribution
Protein-binding capacity reaches adult values within 10 to 12 months
Higher doses (mg / kg) of water-soluble drugs are required in younger children due to higher percentage of their body weight in water

Infant – Hepatic Metabolism
Complete maturation of the liver develops by one year
Cytochrome P-450 enzyme system in the small bowel and liver are the most important factor in drug metabolism

Infant – Renal Excretion
Renal elimination depends on plasma protein binding, renal blood flow, GFR and tubular secretion all are altered in the first two years of life.

Drug Dosing
Dosing in children less than 12 years is always of function of age, body weight or both
When very accurate levels dosing in needed, dose adjustments should be based on plasma drug concentration

Child – 1 to 12 years