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The risks attending drug use

during pregnancy & lactation

Critical factors affecting placental drug transfer and drug effects on the fetus
Drugs in Pregnancy and include the following:

the physicochemical properties of the drug; (1)

Lactation Periods the rate at which the drug crosses the placenta and the amount of drug (2)
reaching the fetus;
the duration of exposure to the drug; (3)
distribution characteristics in different fetal tissues; (4)
the stage of placental and fetal development at the time of exposure to the (5)
Eti Nurwening Sholikhah drug; and
the effects of drugs used in combination (6)
Department of Pharmacology & Therapy
Faculty of Medicine
Universitas Gadjah Mada
Yogyakarta

Drug Category In Pregnancy - FDA Classification

A: No risk to the fetus Objectives
B: No risk to the fetus But there are no adequate and well-
controlled studies in pregnant women
C: Adverse effect on the fetus on animals, but there are no
adequate and well-controlled studies in humans. 1. Recognize factors which determine drug
Consider Potential benefits v. potential risks
passage across the placenta and into
D: Positive evidence of human fetal risk based on adverse
reaction data from investigational or marketing experience breast milk.
or studies in humans. 2. Identify aspects of medications that
Consider Potential benefits v. potential risks determine safety during lactation.
X: Studies in humans or animals have demonstrated fetal
abnormalities and/or there is positive evidence of human 3. Review anti-infectives and migraine meds
fetal risk based on adverse reaction data from in pregnancy and lactation
investigational or marketing experience, and the risks
involved in use of the agent in pregnant women clearly
outweigh the potential benefits.

Teratogens Teratogenic Factors

A substance, organism, physical agents or Timing of exposure

deficiency state capable of inducing Developmental stage during exposure
abnormal structure or function such as: Maternal dose and duration
Gross structural abnormalities Maternal pharmacokinetics
Functional deficiencies Genetic factors/phenotypes
Intrauterine growth restriction Interactions between agents
Behavioral aberrations
Demise

Dicke, JM. Med Clin North Am 1989;73:567-81.

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FDA Pregnancy Categories

FDA Pregnancy Categories
Major problems exist
Category not required if:
Drug not absorbed systemically Established in 1979
AND Lack of data in humans
No potential for indirect fetal harm
What does a C drug really mean
Otherwise, in addition to the pregnancy Difficult to assign an A to any drug
category, information on teratogenicity, effects
on reproduction, and when available, effects Does not address lactation safety
on later growth, development and functional
maturation of the child should be included

FDA Labeling Changes Drug Transfer to the Fetus

3 categories fertility, pregnancy, and Placental transfer may occur by:

lactation Passive diffusion
Clinical considerations provides risks
Facilitated diffusion
and possible alternatives
Summary risk assessment evaluates Active transport
human and animal data Placental surface area
Discussion of underlying data used to Placental metabolism
formulate risk

Drug Passage into Breast Milk Drug Transfer

Diffusion from maternal plasma into Into Breast Milk

milk Molecular weight

Higher maternal plasma levels mean Across Placenta Lipid solubility

higher breast milk concentrations Molecular weight Ionization

Lipid solubility Protein binding
Equilibrium will be established with
Ionization Drug
most drugs between milk and plasma
Proteinbinding concentration
Chemical Drug equilibrium
Structure

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Other Factors Fetal Drug Disposition

Into Breast Milk

Size < 200 60 80% passes through liver, the rest
Across Placenta daltons travels through ductus venosus to heart
Size < 400 Drug pKa and brain
daltons Equilibration
Hepatic drug metabolism
High blood speed
concentration High blood
Adrenal gland metabolism
Similar concentration Recirculation through amniotic fluid
configuration

Drug Concentration in Breast Milk Calculating Drug Exposure

Milk consumption 150 ml/kg/d

Lower pH than serum Milk concentration either Cpmax or
Varying degrees of fat random sample
concentrations Maximum exposure will be at Cpmax
Foremilk Relative infant dose - < 10% better
Hindmilk Infant dose/maternal dose using mg/kg/d
Milk/Plasma ratio

Neonatal Factors Infant Adverse Effects

Volume of milk consumed

Higher gastric pH
Differences in GI flora
GI transit time
Higher concentrations of free drug
Higher percentage of body water
Lower rates of metabolism and excretion
GI diarrhea, constipation, vomiting,
feeding intolerance, hypoglycemia
CNS lethargy, sedation, poor suckling,
muscle hypotonia, tremors,
restlessness, withdrawal upon
discontinuation
Other possible sensitization or allergic
reaction, culture results if needed may
be difficult to interpret

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Anti-infectives Penicillins

Penicillins Sulfonamides Category B in pregnancy

Cephalosporins Miscellaneous Cross the placenta easily and rapidly
Antibiotics Concentrations equal maternal levels
Carbapenems
Fluoroquinolones Antivirals
Macrolides Antiretrovirals
Antifungals
Lactation
Aminoglycosides
Crosses in low concentrations
Compatible with breastfeeding

Carbapenems
Cephalosporins (ertapenem, imipenem, meropenem)

Category B in pregnancy
Category B/C/B in pregnancy
Cross the placenta during pregnancy
Some reports of increased anomalies with Likely cross the placenta
specific cephalosporins (cefaclor, Very little human data
cephalexin, cephradrine)
Primarily cardiac and oral cleft defects
Lactation
Lactation
Excreted intobreastmilk in low amounts
Excreted intobreastmilk in low
concentrations Unknown effects but likely low clinical
Considered compatible with breastfeeding significance

Fluoroquinolones Macrolides
(floxins) (azithromycin, clarithromycin, erythromycin)

Pregnancy Category C Pregnancy Categories B/C/B

Not recommended in pregnancy Cross theplacenta in low amounts
Cartilage damage in animals
Limited datawith azithromycin and
Safer alternatives usually exist clarithromycin
Lactation
Excreted into
breastmilk Lactation
Limited human data Erythromycin compatible

AAP says compatible with breastfeeding Others probably compatible

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Aminoglycosides
(amikacin, gentamicin, tobramycin) Sulfonamides

Pregnancy Category C Pregnancy Category C

Rapidly cross placenta Readily cross the placenta
Enter amniotic fluid through fetal Concerns of use at term
circulation
Lactation
Lactation
Excreted intobreastmilk in low levels
Compatible with breastfeeding
Use should be avoided in premature
Not absorbed through GI tract
infants

Tetracyclines
(doxycycline, minocycline, tetracycline) Miscellaneous Antibiotics

Pregnancy Category D Aztreonam

Can cause problems with teeth and bone Pregnancy Category B, likely safe in
and other defects/effects pregnancy, little human data
Have been linked to maternal liver toxicity Lactation Compatible per AAP

Clindamycin
Lactation
Pregnancy Category B, commonly used
Compatible with breastfeeding
Lactation Compatible per AAP
Serum levels in infants undetectable

Miscellaneous Antibiotics Miscellaneous Antibiotics

Linezolid Nitrofurantoin
Pregnancy Category C, no human data Pregnancy Category B, possible hemolytic
available anemia with use at term
Lactation unknown, myelosuppression in Lactation Compatible, avoid with G-6-
animals PD deficiency
Metronidazole Trimethoprim
Pregnancy Category B, carcinogenic in Pregnancy Category C, potentially
animals, avoid in 1st trimester if possible problematic early in pregnancy
Lactation hold feeds for 12-24hrs Lactation Compatible as combination
afterward drug

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Antivirals
Miscellaneous Antibiotics (acyclovir, famciclovir, valacyclovir)

Vancomycin Pregnancy Category B

Pregnancy Category B, compatible Acyclovir and valacyclovir readily cross
Lactation likely compatible, not absorbed the placenta
Can be used for HSV treatment and
suppression
Lactation
Acyclovir and valacyclovir are compatible
Famciclovir should be avoided

Antiretrovirals/NRTI
Antiretrovirals/NRTI (lamuvidine (3TC), stavudine (d4T))
(abacavir, didanosine (ddI), emtricitabine (FTC))

Pregnancy Categories C/B/B Pregnancy Category C

Maternal benefit usually outweighs fetal Maternal benefit usually outweighs fetal risk
risk Cross the placenta by simple diffusion
Data with lamivudine show no increased risk of anomalies
Cross the placenta
Stavudine has been associated with severe lactic acidosis w/ or
Limited data with each do not show w/o pancreatitis
increased risk of anomalies All NRTIs have been possibly linked to mitochondrial
dysfunction postnatally
Didanosine has been associated with
severe lactic acidosis w/ or w/o
pancreatitis

Antiretrovirals/NNRTI
Antiretrovirals/NRTI (delavirdine, efavirenz, nevirapine)
(tenofivir, zalcitabine (ddC), zidovudine (AZT))

Pregnancy Category B/C/C Pregnancy Category 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
Maternal risk usually outweighs fetal risk
Likely cross intofetus (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

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Antiretrovirals/Fusion Inhibitor
Antiretrovirals/PI (enfuvirtide)

Pregnancy Category B/C Pregnancy Category B

Maternal benefit usually outweighs fetal Maternal benefit usually outweighs fetal
risk risk
Likely cross the placenta Very large molecule (4492 daltons), likely

All PIs can cause hyperglycemia ( GDM?) does not cross placenta
Atazanavir can cause hyperbilirubinemia Animal data does not show risk

Indinavir can cause nephrolithiasis No human data available

Hold during first trimester if possible

Antifungals/Azoles
Antiretroviral Combinations (fluconazole, itraconazole, ketoconazole,
posaconazole, voriconazole)
Atripla (1 tab daily)
Pregnancy Categories C/C/C/D
Efavirenz, emtricitabine, tenofovir
Likely cross placenta
Trizivir (1 tab BID)
Fluconazole > 400mg/day seems to be associated with cranio-
Abacavir, lamivudine, zidovudine
facial abnormalities
Combivir (1 tab BID)
Itraconazole appears to have low risk
Lamivudine, zidovudine
Truvada (1 tab daily) Ketoconazole can impair testosterone and cortisol synthesis
Emtricitabine, tenofovir No data in humans is available for voriconazole, increased risk
in animals
Epzicom (1 tab daily)
Abacavir, lamivudine

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
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

No data with voriconazole, not Lactation

recommended No human data, but probably compatible

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Avoid by All Means (Category D)

Antifungals/Polyenes

Amphotericin B * Tetracyclines * Quinolones

* ACE-Inhibitors * ARB s
Pregnancy Category B, compatible, lipid
* Warfarin
complexes also compatible
* Statin * Alcohol
Lactation no data available
* Valproic Acid * Phenytoin
* Lithium Salts * Vitamin - A

Folic Acid Supplementation in Pregnancy Anti-emetic Drugs in Pregnancy

Prevents Neural tube defects Doxylamine (Doxinate- Doxylamine + Pyridoxine)

Decrease in homocystinemia (and heart disease)
SAFE - More than 30 million women took Bendectin
-------------------------------------------------------------------------------------------- from 1956 to 1983. At least 25 epidemiological studies and 2
---------------------------------------------------------------------------------------- meta-analyses have been performed regarding its use during
---------- pregnancy, making it the worlds most studied drug in
* Neural tube defects develop in the first 28 days
pregnancy. Also one of the most talked about
after conception.
Litogen
* "Once you know you're pregnant it's too late to do
anything about [them]," Promethazine , Chlorpromazine,
* Half of all pregnancies are unplanned
Diphenhydramine, Dimenhydrinate and Cyclizine
* The incidence of neural tube defects might be 45% are safe but better avoided near term
Ondansetron and Metoclopramide should be used
with caution, particularly during the first trimester

Analgesics & Anti-inflammatory Drugs in Pregnancy

Antihistaminics In Pregnancy
Drugs/WkS. 0-12 12-24 24-Term Comments
--------------------------------------------------------------
First-generation (e.g. chlorpheniramine) and second-
hepatic/renal tox. S S Paracetamol S
generation (e.g. cetirizine) antihistamines have not been
closure of D.A.in N C C Aspirin
incriminated as human teratogens. utero

No controlled trials with loratadine and fexofenadine in human ---do--- N C NSAID S

N N N - Ketorolac
pregnancy
-
* H1 blockers do not increase the teratogenic risk in humans and
withdrawl sympt. - C Pethidine/ Dextrpropo/ -
may, in fact, be associated with a protective effect. By preventing Codeine/Pentazocine
vomiting, antihistamines may ensure better metabolic
conditions to the fetus and thus may reduce some. * S = Safe C = Cautious use N = Not to use
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

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NSAIDs In Pregnancy : COX 2 Inhibitors Anxiolytic,Sedative & Hypnotic Drugs In Pregnancy

Benzodiazepine Drugs e.g.

In humans, an incidence of oligohydramnios Diazepam / Alprazolam - Category D
has been observed in women who consumed Buspirone - Category B
significant amounts of aspirin, non-selective COX Zolpidem - Category B
inhibitors
or selective COX 2 inhibitors during the third trimester Antidepressants in Pregnancy
of pregnancy.
COX 2 inhibitors have been found to be nephrotoxic Fluoxetine Category B * Amitryptiline Category C
particularly during nephrogenesis (during last part Sertraline Category B * Doxepin Category C
of pregnancy and early neonatal period) Citalopram Category B * Imipramine Category C
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

* Lithium Category D

U.T.I. in pregnancy
Antibiotics In Pregnancy

During pregnancy ureters are dilated and kinked because of :

Antibiotic Category Antibiotic Category
- increased progesterone relax smooth muscle
B Tetracyclines D Ampicillin - obstruction of the lower ureters in late pregnancy
B Quinolones D Amoxycillin This encourages :
Azithromycin B Cephalosporines stasis and reflux of infected urine up the ureter and kidney
B bladder volume and bladder tone

C Clarithromycin ureteral tone, contribute to urinary stasis and

ureterovesical reflux
Aminoglycosides B Clindamycin
C Amikacin
C Gentamycin
Strepto./Kana C*

U T I in Pregnancy : Diagnosis of U T I :

Asymptomatic bacteriuria ( colony count< 105) : 1) Urine Analysis

Untreated , can lead to cystitis in 30% Significant bacteriuria has been defined as finding more
& pyelonephritis in 50% than 105 colony-forming units per mL of urine
Acute cystitis : dysuria, urgency, frequency
2) Urine culture should be used as a routine screening
Acute pyelonephritis: fever, chills, nausea, vomiting
procedure at the first prenatal visit or between 12 to 16
and flank pain.
weeks of gestation.
-------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------
Organisms : Escherichia coli -- 80 to 90 % of infections.
Treating Asymptomatic Bacteriuria with Antibiotics Pr. mirabilis and Kleb. pneumoniae seen
* clears bacteriuria occasionally.
* incidence of Pyleonephritis Gram-positive organisms e.g. B streptococcus
* incidence of premature delivery and Staphy. saprophyticus are less common
* incidence of low birth weight baby

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Malaria In Pregnancy
U.T.I. in pregnancy
to malaria Immuno suppression and loss of acquired immunity
Amoxicillin 500 mg. tds 7 days or
development of Placenta is the preferred site of sequestration and
Cephalaxin 500 mg. tds 7 days or
malarial parasite.
Nitrofurantoin 100 mg. tds 7 days or
atypical in presentation Hypoglycemia
2nd / 3rd generation cephalosporins and Amoxy / Clavulinate can be - Acute pulmonary oedema
given - Acute renal failure
- Anaemia
Avoid Aminoglycosides / Quinolones - Convulsions / Coma

Drugs For Malaria In Pregnancy

Malaria In Pregnancy - Fetal complications

Spontaneous abortion
First trimester : Quinine + Clindamycin
Pre mature birth, still birth
Placental insufficiency
2nd / 3rd trimester : above + Artemisin +
I.U.G.R. (temporary / chronic) Mefloquine,
Low birth weight Pyrimethamine / sulfadoxine
Fetal distress (as required)
Trans placental spread of the infection to the
fetus can result in congenital malaria.

Contra indicated : Tetracycline; Doxycycline;

Primaquine; Halofantrine

Antiepileptic drugs (AED) in pregnancy Pregnancy , Epilepsy &

Anti -Epileptic Drugs (AED)

Optimise AED before conception .1

Monotherapy as far as possible .2
Discuss Teratogenic potential of AED &
risk of major & minor birth defects
Pre- pregnancy & Pregnancy Folic acid
(0.5 mg. daily) supplementation
Vit. K supplementation (10mg. Daily) or .5
Inj. Vit. K as soon as after onset of labor
Congenital abnormalities if mothers taking AED :
.3 * hare lip or cleft palate,
* malformation of the limbs , heart, face, eyes and ears
.4 * neural tube defects .
The risk of neural tube defects is
0.2 - 0.5 %. in the general population
1 % risk with carbamazepine
1 - 2 % with sodium valproate

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Pregnancy , HIV & ART

Antifungal Drugs In Pregnancy

Use of combination ART during pregnancy both to safeguard maternal

Imidazoles - safe as topical therapy for fungal skin infections .
health and to reduce the risk of vertical transmission of HIV-1 infection
is advocated . Nystatin is minimally absorbed and is effective for vaginal therapy
Amphotericin B - no reports of teratogenesis
The cohort comprised 2123 women who received ART during
pregnancy (monotherapy in 1590, combination therapy without PI in Fluconazole - exhibits dose-dependent teratogenic effects; safe at
396, and combination therapy PI in 137) and 1143 women who did not lower doses (150 mg/day)
receive antiretroviral therapy
Ketoconazole, flucytosine, and griseofulvin - teratogenic
Conclusions : As compared with no ART or monotherapy, and/or embryotoxic in animals
combination therapy for HIV-1 infection in pregnant women is not
associated with rates of premature delivery or with low birth weight,
low Apgar scores, or stillbirth in their infants. The association between
combination therapy with PI and an risk of very low birth weight
requires confirmation.
-----------------------------------------------------------------------------------------------

Toxoplasmosis In Pregnancy Toxoplasmosis In Pregnancy

Pregnant lady presenting with :- SPIRAMYCIN from the first trimester until delivery
* fever, chills, and sore throat, the risk of fetal infection by 60%.
* enlargement of the posterior cervical lymph nodes, Presently, this drug is not known to have a
* malaise, fatigue, headaches, muscle aches, teratogenic effect
* who is seronegative for mononucleosis, Dose : 6 to 9 miu / day in divided doses.
should be tested for toxoplasmosis infection [Rovamycin forte - 1tab.(3miu)]
Toxo - IgM & IgG should be ordered Infection in fetus ( if confirmed) -

Add pyrimethamine +
leucovarin + sulfadiazine

Antirheumatic drug therapy in pregnancy

Rx of Bronchial Asthma in Pregnancy
Aspirin C Methotrexate X
D in III trimester Gold C Short acting agonist inhaler - safe
NSAIDs B Long acting agonist inhaler - not studied
Cyclosporin A C
D in III trimester
Azathioprine D Inhaled Beclomethasone & Budesonide - safe
Corticosteroids
Prednisone B Chlorambucil D Other inhaled steroids not tested
Dexamethasone C
Cyclophosphamide D Oral Prednisolone safe to fetus, maternal complications
---------------------------------------
Hydroxychloroquine C D-penicillamine D Emergency Rx - regular dose of agonist inhaler at
Sulfasalazine B 15 - 20 minutes for 3 to 4 doses
D if near term
Add Ipratropium Inhalation

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Drug effects on the unborn fall into two basic categories:

1. Predictable effects that derive from the known .1

pharmacological drug properties.

Examples are:
masculinization of the female fetus -
by androgenic hormones;
brain hemorrhage due to oral anticoagulants; -
bradycardia due to -blockers. -

2. Effects that specifically affect the developing

However the low concentration of drug in breast milk, may result in organism and that cannot be predicted on the basis
unwanted effect in child if continous happen. of the known pharmacological activity profile.

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