IMMUNOSUPPRESSAN

TS IN PREGNANCY

MODERATOR: DR.SURENDRA KUMAR THALOR SIR

PRESENTER: DR.GAURAV KAUSHIK
• IMMUNOSUPPRESSION :
Immunosuppression is defined as “ A state of
temporary or permanent dysfunction of immune
response resulting from insults to the immune system
and leading to increased susceptibility to disease”
• Drug exposure of the embryo/fetus depends on the
permeability of the blood–placenta barrier.
• The predominant mechanism by which substances
cross the human placenta is simple passive
diffusion.
• Lipophilic molecules, low protein binding, low
degree of ionization, molecular weights < 600 Da -
>permeate easily across placenta
Risk related to time of drug consumption
• Before conception
Physicians prescribing a drug for women of childbearing potential
should have several concerns:
1. Contraceptive failure because of medication interactions;
2. Potential risk to mother and fetus caused by the drug, should
pregnancy occur;
3. Possible interference with conception;
4. Potential risk of spontaneous abortion
5. Preserving fertility.
● First trimester

Very early pregnancy ( first 2 to 2.5 weeks of gestation )

1. All the cells are undifferentiated and will respond similarly to

drug exposure.

2. So there could be spontaneous abortion because of death of

all of the cells
or
death of only a few cells and remaining undifferentiated cells
divide to recover without defects
Organogenesis phase (weeks 2 to 8 of gestation)

1. Differentiating cells may be affected and result in congenital

anomalies.

2. All medications known to have possible teratogenic effects should be

avoided.
US FDA PREGNANCY DRUG RISK CATEGORIES
A – Controlled studies show no fetal risk
B – No risk to human fetus,despite possible animal risk Or, no risk in animal
studies and human studies have not been done
C – Risk cannot be ruled out- human studies are lacking
Animal studies may or may not show risk
Potential benefits may justify potential risk
D - Positive evidence for risk to human fetus
However,benefits may outweigh risks of the drug
X- Contraindicated in pregnancy
There is no reason to risk use of the drug in pregnancy
Unrated - No pregnancy category assigned.
 Immunosuppressants and Immunomodulators in
pregnancy are listed below:
1. Systematic & topical corticosteroids
2. Azathioprine
3. Cyclosporine
4. Hydroxychloroquine
5. Intravenous immunoglobulin
6. Methotrexate
7. Mycophenolate mofetil
8. Rituximab
9. Tofacitinib
10. Cyclophosphamide
Systematic and topical
corticosteroids
Systemic corticosteroids:
o Glucocorticoids may exert their activities by two
main mechanisms of action

o The classic genomic effects, that require the

translocation to the nucleus of the complex
glucocorticoid-glucocorticoid receptor, and
secondary nongenomic effects, that are probably
mediated by plasma membrane receptors
• In pregnant women glucocorticoids may cause a
predisposition to hypertension and preeclampsia when used
at high doses.
• These agents easily cross the placenta , but 90% of the
maternal dose of glucocorticoids is metabolized within the
placenta by 11β-hydroxysteroid dehydrogenase-2 (11β-
HSD2) which converts cortisol, prednisone, and
methylprednisolone into inactive products while
dexamethasone and betamethasone are less well
metabolized
• There has been concern about a possible
increase of oral-facial clefts in newborns from
mothers receiving glucocorticoids
• Cortisol exposure at earlier gestations can
influence fetal growth
• Exogenous glucocorticoids may result in dysfunction
of the fetal hypothalamic–pituitary–adrenal axis (HPA)
with permanent changes in physiology, structure and
metabolism that might cause a number of chronic
diseases in later life

• Pregnancy summary rating = Moderate-high risk

• FDA historic rating= C( D in 1st trimester)

 Mild/moderate topical corticosteroids :

• Pregnancy summary rating – Probably compatible

• FDA historic rating- C

• Adverse effects: No association was found with oral

clefts,fatal growth restriction,preterm delivery,or fatal
death in 2 large studies
Potent/Very potent topical corticosteroids:
• Pregnancy summary rating:Moderate-high risk

• FDA historic rating: C

• Adverse effects: High doses potent/very potent topical

corticosteroids were associated with fatal growth
restriction, 3% increased risk for every 30 g tube used
• In pregnancy consider short acting
prednisone,prednisolone or methylprednisolone,
which are effectively metabolized by the placenta
and reach lower concentration in fetus than the
longer acting dexamethasone and betamethasone
• Avoid > 20mg/day when possible
Systemic Immunomodulators:

Azathioprine:After oral administration, azathioprine

is rapidly transformed into 6-mercaptopurine by
hepatic and erythrocyte glutathione

• Mercaptopurine is bio-transformed into

mercaptopurine nucleotides (thioinosine
monophosphate, thioguanine and 6-thioguanine
nucleotides) that inhibit the synthesis and utilization
of precursors of RNA and DNA, so halting the
proliferation of activated lymphocytes
• Thioguanine nucleotides are incorporated into human bone
marrow cells
• Pregnancy summary rating-Low risk in 1st trimester while
Moderate-high risk in 3rd trimester
• FDA historic rating-“D”
• Adverse effects:Teratogenic in some animal models,but no
clear association in humans
• Risk of infant immunosuppression when used in 3rd
trimester
• Azathioprine is considered safer than other
drugs, such as mycophenolate or alkylating
agents, and can be used to replace them in
pregnant women with autoimmune diseases
• Azathioprine crosses the placenta, however the
fetal liver lacks inosinate pyrophosphorylase,
which converts azathioprine to active
metabolites.
• This protects the fetus from adverse effects of
azathioprine early in pregnancy
Cyclosporine :Cyclosporine is very lipid-soluble drug,
is extensively distributed in the body, and is highly
metabolized.
• High concentrations of cyclosporine metabolites in the
placenta can be observed, indicating the presence of
cyclosporine metabolizing enzymes in the placenta.
• The maternal–fetal trans-placental passage of
cyclosporine can be influenced by the functional
activity of P-glycoprotein.
 •In an experimental model, it was demonstrated that P-
glycoprotein pumps cyclosporine out of the trophoblast cells
of the rat placenta in the ATP-dependent manner and restricts
the passage of cyclosporine across the placental barrier. The
drug does not appear to be teratogenic

• Pregnancy summary rating – Probably compatible

• FDA Historic Rating- “C”
• Adverse effects:Breastfed infants should be
monitored with serum level if there is a concern for
toxicity
 Hydroxychloroquine: HCQ is the hydroxylated analogue
of chloroquine
• The drug has been initially used as an antimalarial agent,
since it may inhibit the plasmodial heme polymerase
• HCQ is not classified among immunosuppressive drugs.
However, HCQ can cause expansion and vacuolization of
lysosomes and inhibition of their functions
• These changes can interfere with the function of the
immunocompetent cells and cause downregulation of the
immune response against auto-antigenic peptides

 Intravenous immunoglobulins:
• Pregnancy summary rating- compatible
• FDA Historic Rating- “C”
 • Pregnancy summary rating- Probably compatible
• FDA Historic Rating- “C”
• First line therapy for pregnant mothers with lupus

• Adverse effects:Can be associated with neurological

disturbances and interference with hearing, balance, and
vision in the fetus.
 Methotrexate : Methotrexate competitively
inhibits dihydrofolate reductase, an enzyme that
catalyzes the conversion of dihydrofolate to the
active tetrahydrofolate.
• Folic acid is needed for the de novo synthesis of
the nucleoside thymidine, required for DNA
synthesis.
• folate is essential for purine and pyrimidine base
biosynthesis, so synthesis will be inhibited.
• Methotrexate, therefore, inhibits the synthesis of
DNA, RNA, thymidylates, and proteins
 • Pregnancy summary rating- “Contraindicated”
• FDA Historic Rating- “X”
• Risk of miscarriage and multiple fatal
malformations,highest at 8-10 weeks gestation,and
increased with higher doses
•Advice:
Test for pregnancy before initiation
oUse adequate contraception during treatment and
for one ovulatory cycle after discontinuation
oAdvise men with female sexual partners to use
effective contraception during therapy and for 3
months after discontinuation
Mycophenolate mofetil: It is a prodrug that release
mycophenolic acid (MPA), an inhibitor of inosine-5′-
monophosphate dehydrogenase, an enzyme essential
for de novo purine synthesis
• Mycophenolate mofetil particularly affects T and B
lymphocytes since they rely almost exclusively on de
novo purine synthesis
 •Pregnancy summary rating-Moderate-high risk
•FDA historic rating-“D”
•Adverse effects: Risk of miscarriage and multiple fatal
malformations
o Decreases blood level of oral contraceptives
Rituximab : It is a chimeric monoclonal antibody that binds
to CD 20 on the surface of CD 20+ B cells and induce their
depletion.Rituximab depletes B cells through three
mechanisms
(1)Antibody dependent cellular cytotoxicity
(2) Complement mediated cytolysis
(3) Signaling induced cell death

•
 •Pregnancy summary rating-low risk
• FDA historic rating-“C”
•Adverse effects: Some infants born with depleted B
lymphocytes,recovered by 6 months
o Manufacturer advises contraception for 12
months after treatment
Tofacitinib :

• Pregnancy summary -low risk

• FDA historic rating- N/A

• Adverse effects: Malformations in animal

studies
Cyclophosphamide: This drug is converted by the
enzymes of cytochrome P450 system to 4-
hydroxycyclophosphamide which is in equilibrium with
its tautomer aldophosphamide
• This is oxidized by aldehyde dehydrogenase to inactive
carboxycyclophosphamide, but some amount of
aldophosphamide escapes the effects of aldehyde
dehydrogenase and is cleaved to two toxic metabolites:
the alkylating phosphoramide mustard and the
teratogenic acrolein which inhibits DNA replication and
causes cell death.
•Miscarriages and pre-term deliveries have been
reported in mothers taking cyclophosphamide
•Cases of malformation have been described in
newborns of mothers who received
cyclophosphamide in the first months of
pregnancy
•US FDA historic rating-“D”
Psoriasis Therapy (Systemic and topical)
Acitretin:Acitretin has anti-inflammatory and anti-proliferative
effects. It normalizes keratinocyte differentiation in the
epithelium. It also hinders the expression of proinflammatory
cytokines like interleukin-6 (IL-6), migration inhibitory factor-
related protein-8 (MRP-8), and interferon-gamma.

• Pregnancy summary rating-“ Contraindicated”

• FDA historic rating-“X”
• Advice :Effective contraception must be used for 1 month
before and 3 months after use

Adalimumab:
• Pregnancy summary report: Probably compatible
• FDA historic rating-“B”
Apremilast:
Pregnancy summary rating-“Moderate-high risk”
FDA historic rating-“C”
Brodalumab:
Pregnancy summary rating- No data available
FDA historic rating-N/A
Adverse effects:Animal studies without adverse effects
Etanercept:
Pregnancy summary rating- Low risk
FDA historic rating-“B”
Adverse effects: IgG1 Fc fusion protein with low
transplacental transport
Brodalumab:
Pregnancy summary rating- No data available
FDA historic rating-N/A
Adverse effects: Animal studies without adverse effects
Infliximab:
Pregnancy summary rating- Low risk
FDA historic rating-“B”
Adverse effects:Live vaccines are not recommended to
infliximab- exposed infants for 6 months after birth
Ixekizumab:
Pregnancy summary rating- No data available
FDA historic rating-N/A
Adverse effects: Animal studies without adverse effects
Secukinumab:
• Pregnancy summary rating-Low risk
• FDA historic rating-N/A
• Adverse effects: Animal studies without adverse effects
Tildrakizumab:
• Pregnancy summary rating- No data
• FDA historic rating-N/A
• Adverse effects: Animal studies without adverse effects
Ustekinumab:
• Pregnancy summary rating- Low risk
• FDA historic rating- “B”
• Adverse effects: Animal studies without adverse effects
• Atopic Dermatitis Therapies (Systemic and topical)
Crisaborole:
• Pregnancy summary rating- No data available
• FDA historic rating-N/A
• Adverse effects:Animal studies with fetal toxicity only at
maternally toxic doses
Dupilumab:
• Pregnancy summary rating- No data available
• FDA historic rating-N/A
• Adverse effects:Animal studies without adverse effect
Calcineurin Inhibitors (CNIs)
•CNI exert their actions through the inhibition of a calcium-
dependent serum threonine phosphatase, called calcineurin

• As a consequence of calcineurin inhibition the proliferation

and differentiation of cytotoxic and other effector T cells are
inhibited
 Pimecrolimus:
•Pregnancy summary rating- Low risk
• FDA historic rating- “C”

Tacrolimus:
•Pregnancy summary rating- Low risk
• FDA historic rating- “C”
•Note: In topical formulations,these drugs undergoes minimal
systemic absorption resulting in peak blood level ranging from
undetectable to 20ng/ml
Miscellaneous Drugs:

Dapsone:
• 1)Inhibition of neutrophil myeloperoxidase
• (2)Inhibition of eosinophils myeloperoxidase
• (3) Inhibition of neutrophil adhesion to vascular endothelial
integrity
• (4) Inhibition of chemotaxis
• (5) Inhibition of LTB4 binding
• (6) Inhibition of dihydropteroate synthetase
 *Pregnancy summary rating-“Probably compatible ”
*FDA historic rating-“C”
*Adverse effects:Not associated with fetal malformation
but may cause maternal and fetal hemolytic anemia
during pregnancy and lactation

Fluorouracil:
*Pregnancy summary rating-“Contraindicated”
*FDA historic rating-“X”
Thank you