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Received: 22 August 2016    Accepted: 17 October 2016

DOI: 10.1111/aji.12601

REVIEW ARTICLE

Management of pemphigus disease in pregnancy

Soheil Tavakolpour1,2 | Hajar Sadat Mirsafaei2 | Saeid Delshad3

1
Skin Research Center, Shahid Beheshti
University of Medical Sciences, Tehran, Iran
2
Immunology Research Center, Tehran
University of Medical Sciences, Tehran, Iran
3
Medical biology Research Center,
Kermanshah University of Medical Sciences,
Kermanshah, Iran
Correspondence
Soheil Tavakolpour, Skin Research Center,
Shahid Beheshti University of Medical
Sciences, Tehran, Iran.
Email: soheil.tavakolpour@gmail.com
Pemphigus can cause complications during pregnancy and may cause serious harm to
a fetus. For this study, a comprehensive review of common treatments of pemphigus
and their adverse effects associated with pregnancy and male fertility was conducted.
We concluded that a period of remission with minimal or no therapy before concep-
tion could significantly reduce the risk of the disease flaring up, at least in the first tri-
mester. The period of remission causes a delay in the flare-up of the disease, which
means lower cumulative doses and the prevention of possible congenital abnormali-
ties caused by corticosteroid or immunosuppressant treatments. All common treat-
ments of pemphigus—azathioprine, mycophenolate mofetil, and methotrexate—should
be avoided during pregnancy. However, it appears that systemic corticosteroids in a
safe dose with a topical form of corticosteroids may be used without serious risk. Due
to the lack of data associated with rituximab therapy, it is recommended that this drug
be avoided 12 months before conception. It appears that the safest treatment of pem-
phigus is intravenous immunoglobulin (IVIg), which may be more effective when used
with topical corticosteroids. Due to the delayed effect of IVIg, it should be used some
months prior to conception.

KEYWORDS
autoimmunity, corticosteroids, intravenous immunoglobulin, pemphigus, pregnancy

1 | INTRODUCTION pemphigus can be exacerbated during pregnancy or even appear for

Pemphigus is an autoimmune intra-epidermal blistering disease, which
may be fatal in the absence of effective treatment. In pemphigus, the
production of autoantibodies against adhesion molecules causes the
appearance of blisters in skin and/or mucous membranes. It can appear
with no clear reason and can flare up or go into remission in different
circumstances. During the disease, autoantigens are targeted by au-
toantibodies, which could result in the loss of intercellular adhesion.
Some high-risk groups have been recognized over the years. Middle-
aged or older, as well as people of Jewish ancestry, are at greater risk
1–3
than others of developing pemphigus. As Th2 cells are dominant
during pregnancy and pemphigus is a Th2-dominant autoimmune dis-
ease, pregnant women have an increased incidence of pemphigus.4–6
The exacerbation of pemphigus in pregnant women has also been re-
7,8
ported in multiple studies. This can cause serious problems for both
mother and fetus.
Because the fetus’s chance of survival strongly depends on the
mother’s health, it is vital to keep the mother healthy. Unfortunately,
the first time during pregnancy. In these cases, aberrant maternal au-
toantibodies are usually transmitted to the neonate, which leads to the
development of blisters upon birth.6,9 Fortunately, the neonate will be
lesion-free within 1-4 weeks after the birth, either spontaneously or
with mild topical corticosteroids treatment.10 Depending on the se-
verity of the disease, both mother and fetus may be in danger. As the
immune responses are deeply involved in pemphigus, it is vital to in-
vestigate any change in immunity in pregnancy and its association with
pemphigus development or progression. Another important issue that
should be considered is the type of therapies that may be safely used
by pregnant women with pemphigus. Systemic corticosteroids are
considered to be the first-line therapy in the majority of autoimmune
diseases. This type of drug is also frequently used in patients with
pemphigus, regardless of the pregnancy status of the patients. There
are also other treatments, including azathioprine (AZA), mycopheno-
late mofetil (MMF), methotrexate (MTX), rituximab (RTX), intravenous
immunoglobulin (IVIg), and topical forms of corticosteroids, the usage
of which in pregnancy should be carefully evaluated.

Am J Reprod Immunol 2017; 77: e12601; wileyonlinelibrary.com/journal/aji © 2016 John Wiley & Sons A/S.  |  1 of 9
DOI: 10.1111/aji.12601 Published by John Wiley & Sons Ltd
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2 of 9       TAVAKOLPOUR eT AL.
Being able to observe the pemphigus phases prior to, during, and
after the pregnancy period could help to manage this disease better.
Based on the reports, and taking into account the effects of commonly
used drugs in pemphigus or any other associated autoimmune dis-
eases, some recommendations could be employed to prevent, or at
least minimize, the adverse effects of those drugs. In this study, a con-
clusion was sought as to how pregnant women with pemphigus might
be best managed.
2 | MAJOR IMMUNE SYSTEM
ALT ER ATIO NS DURING PREGNANCY
A pregnant woman’s immune system should be able to protect both
mother and fetus from foreign antigens, as well as tolerate a semial-
logeneic fetus. Thus, some alteration is needed to balance the immune
system players. It is generally accepted that T cells are critical players
in the immune system and whose functions may lead to a successful
pregnancy, pregnancy failure, or preimplantation embryo develop-
ment.11 There is much evidence to show that the Th1:Th2 balance be-
comes skewed toward production of the latter (Th2) throughout the
12,13
period of gestation. This could significantly affect the remission
or relapse of various autoimmune diseases.14 Indeed, during a normal
pregnancy and after delivery, Th2-associated cytokines are dominant
compared to Th1-associated cytokines, whereas women with recur-
rent spontaneous abortions show a near-normal Th1:Th2 balance,
indicating promotion of Th1-associated responses.15 Surprisingly, Th2
dominance was also reported in recurrent abortions by some authors,
which highlights the role of other cells in immune alteration.16
As Th17 is another emerged T helper with a critical role in immune
responses, it has attracted much attention during the last decade.
There is no consensus yet concerning Th17 cell alterations in healthy
17,18
pregnancy. It seems that the Th17 cell population is closely re-
lated to regulatory T cells (Tregs). In fact, the Th17/Treg paradigm is
important in healthy pregnancies or recurrent spontaneous abortions.
The function of effector T cells, including Th1, Th2, and Th17, is reg-
ulated via Tregs (CD4+Foxp3+ Treg and type 1 regulatory T cells). It
has been demonstrated that these cells also play an important role
in a successful pregnancy. An association between the decrease in
19 20
Tregs and unexplained infertility was suggested. Wang et al. found
that Th17 populations increase, while Treg populations decrease in
unexplained recurrent pregnancy loss. Concisely, the Th17:Treg ratio
during a healthy pregnancy shifts in favor of the Tregs, while, in spe-
cific pregnancy disorders, the Th17:Treg ratio decreases.21 Natural
killer (NK) cells also change during pregnancy. In early pregnancy, an
increase and decrease in NK cells and cytotoxic T cells, respectively,
were reported.22 Decrease of CD5+ B cells was also reported during
pregnancy.22,23 Lima et al.24 reported a significantly lower number of
B cells during the third trimester of pregnancy and on delivery day.
hi hi
Interestingly, naïve B cells and CD24 CD38 regulatory B-cell pop-
ulation alteration showed the reverse trend. Indeed, these cells were
significantly increased in the third trimester and on delivery day. This
may be due to the lower B-cell activating factor of the TNF family,
which was observed in the serum of pregnant mice.25 Theoretically,
patients with pemphigus benefit from a decrease in Th17:Treg ratio,
as well as an increase in regulatory B-cell population. However, there
is no evidence of improvement of pemphigus during pregnancy. This
highlights the critical role of Th2 cells, which increase during a preg-
nancy. Indeed, stimulatory effect of Th2 dominancy in the induction
of pemphigus may overcome the inhibitory effects of other cells’ al-
terations. Due to the lack of knowledge about the role of NK cells and
cytotoxic T cells in pemphigus, it cannot be determined that changing
the levels of these cells is in favor of patients with pemphigus or not.
3 | THE IMMUNE SYSTEM IN PEMPHIGUS
Analogous to the other autoimmune diseases, several immune cells,
including T cells, B cells, macrophages, mast cells, and eosinophils, are
deeply involved in the development of pemphigus.26–30 Although there
is a lack of information about the exact roles of these cells, different
studies have shown how different subtypes of T cells and B cells con-
tribute to the development and initiation of pemphigus. The majority
of studies unanimously concluded that both immunoglobulin G (IgG)1
and IgG4 are predominant subclasses of autoantibodies against the
desmosomal glycoprotein, Dsg1 and Dsg3 in pemphigus.31,32 These
autoantibodies are promoted in the presence of Th2-associated cy-
tokines, including interleukin (IL)-4, IL-6, IL-10, and IL-13.27 It is wor-
thy of note that IL-10 is considered to be a double-edged sword in
pemphigus, something which has recently been well-discussed.33
Although there is not enough evidence to show the contribution of
mast cells in pemphigus, it seems that an increased number of this
type of cell may be involved in the development of pemphigus.28
Interestingly, during pregnancy, the numbers of mast cells increase.
This may lead to the exacerbation of pemphigus during pregnancy.34
T cells, which change significantly during pregnancy, are one of the
most important players in pemphigus.35,36 It is generally accepted that
the Th1:Th2 ratio shifts toward Th2 dominancy during pregnancy.15,19
As has been previously shown, naïve T cells differentiate into Th2 cells,
which resulted in the increased production of Th2-associated cyto-
kines. Some of these cytokines induce specific isotype switching to-
ward IgE and IgG4.37,38 Considering the dominance of Th2 cells in the
active form of pemphigus, it is expected that shifting the Th1:Th2 bal-
ance toward Th2 in pregnancy will cause the disease to flare up.39,40
There are multiple reports of pemphigus initiation or exacerbation
during pregnancy.6,9 This may be explained by an increase in Th2 cells,
which is followed by IgG isotype switching. It seems that Th2 cells play
a more important role than the Th17:Treg ratio or regulatory B cells.
Th2-associated cytokines cause IgG isotype switching in addition to
an initiation of a positive feedback loop toward more Th2 differentia-
tion. Although there is, to date, no study to compare the effects of Th2
cells, Tregs, and effector and regulatory B cells, we believe that Th2
cells contribute more in the development and progression of pemphi-
gus. This opinion can be supported by an increase in regulatory B cells,
as well as a decrease in Th17:Treg ratio, which cannot overcome the
progressive effects of Th2 dominancy.
TAVAKOLPOUR eT AL.
4 | PEMPHIGUS DISEASE AND
PREGNANCY
As pemphigus is basically caused by immunologic factors and its out-
come is associated with skin and mucous membranes, it has become
a complicated disease.41 During a pregnancy, this disease becomes
even more complicated and needs more attention for it to be well-
managed. In order to manage this condition better, it is essential to
consider immunologic changes during pregnancy, the safety and effi-
ciency of common treatments, and also prenatal and postpartum care
for patients with pemphigus.
The management of pemphigus during pregnancy can be divided
into different parts. Pemphigus may initially appear before the preg-
nancy. In these circumstances, the pregnancy will be categorized as
a high-risk pregnancy, which will require the close monitoring of both
mother and fetus. Due to abnormal immune responses, some specific
pregnancy disorders, including preterm birth, pre-eclampsia, and un-
expected recurrent pregnancy loss, may interfere with a healthy preg-
nancy. Moreover, pemphigus may appear during the pregnancy for the
first time. There are different reported cases of pemphigus develop-
ment during pregnancy.8 These cases should be controlled with low-
risk treatments until the delivery.
Because pemphigus usually flares up during pregnancy,8,14 those
patients who are of childbearing age should be advised to avoid preg-
nancy when they have recently experienced a relapse or are using
certain drugs, such as MTX or MMF. These drugs will be discussed in
the remainder of this study. Some patients with pemphigus may stop
treatment when they learn that they are pregnant. Both a review of
the literature and our own observations revealed that it is not ben-
eficial and may even cause more serious and irrecoverable problems
to mother and fetus. In fact, it may cause an activation of the disease
and lead to unwanted outcomes associated with the neonate. Disease
activity during conception relates to a lower chance of a successful
delivery. It may lead to stillbirth, spontaneous abortion, or neonate
pemphigus.8,10 All these events may be explained by abnormal im-
mune responses due to pemphigus.
Selecting the best therapies, based on the stage of pregnancy, the
severity of the disease, and the patient’s history of treatment, is the
best solution for managing a pregnancy during pemphigus. It seems
that a complete serological and clinical remission some months before
conception could significantly reduce the risk of pemphigus activation
during the pregnancy, or at least delay the flare-up.42 It was shown
that patients with systemic lupus erythematosus (SLE), who were in
the remission phase before conception, had a higher rate of live birth
and full-term delivery and a lower rate of disease flare-up.43 In other
words, a pregnancy should be planned to occur when the patient is in
her remission phase.
In women with pemphigus, some contraindicated medications, in-
cluding MMF, MTX, and AZA, should be stopped and replaced prior
to conception with safe and effective ones, such as topical corticoste-
roids, the low-dose systemic corticosteroids, as well as IVIg. It is rec-
ommended that individuals who develop pemphigus for the first time
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during pregnancy should avoid using high-risk treatments, including
MTX, MMF, and AZA. Because RTX is a relatively new treatment and
a lack of B cells may lead to serious problems in pregnant women, it
is not recommended during pregnancy. Although low-dose systemic
corticosteroids are not high-risk treatments during pregnancy, using
these as the first-line therapy in pemphigus is not recommended.
Topical corticosteroids, on the other hand, are completely safe during
pregnancy.44 Thus, the latter may be considered as the safest choice in
mild-to-moderate pemphigus. Low-dose systemic corticosteroids and
the initiation of IVIg therapy are also recommended when the disease
is progressive.
Previous studies have shown that pemphigus foliaceus (PF) during
pregnancy does not lead to serious harm to the fetus compared to
pemphigus vulgaris (PV). Additionally, neonatal PF is considerably
lower than neonatal PV. This may be explained by the different dis-
tribution of desmoglein (Dsg)1 and desmoglein (Dsg)3 in fetuses and
adults. For example, in a study involving 19 mother–neonate pairs di-
agnosed with PF, no skin lesion was observed in newborn neonates.45
However, there are some reports of neonatal PF.46,47
Although pemphigus is not a contagious disease and a mother can-
not transfer it to her child, newborns may show symptoms of pemphi-
gus. Neonate pemphigus was first described by Ruocco et al.48 more
than 40 years ago. Subsequently, several reports were published which
described different abnormal pregnancy outcomes in patients with
pemphigus. These outcomes included stillbirth, spontaneous abortion,
preterm pregnancy, low birthweight, and craniofacial malformations.
Although a correlation between the severity of the disease in preg-
nant women and neonatal pemphigus seems probable,49,50 there is no
strong correlation between the severity of the disease and pregnancy
outcomes. Some studies reported the birth of a lesion-free baby from a
mother with an active disease.51,52 In contrast, there were some reports
of neonatal pemphigus born from clinically asymptomatic mothers.53,54
5 | MEDICATION
Among the commonly used drugs in pemphigus, MTX and MMF are
contraindicated during pregnancy.55–58 The results regarding the
safety of AZA in pregnant women are contradictory.59,60 Considering
the risk of congenital abnormalities, AZA is not recommended.
Patients with pemphigus during pregnancy should be treated in a
similar way as patients in normal conditions. However, some safety
concerns should be considered concerning unwanted outcomes as-
sociated with the fetus. Drugs should be chosen based on the severity
of the disease and the stage of pregnancy. It is necessary to avoid self-
cessation of treatment when pregnancy is revealed. This could cause
a flare-up, which might be followed by several serious problems for
both mother and fetus. Except in some reported cases, it was shown
that mothers with a disease of mild severity have a higher chance of a
successful pregnancy and delivery compared to those with an active
disease. Thus, a smart choice of treatment should be preferred to ces-
sation of therapy.
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Systemic corticosteroids, including prednisolone, prednisone,
and methylprednisolone, are frequently used as the first-line ther-
apy in pemphigus. There is no doubt about the efficiency of these
treatments, while their adverse effects, especially during pregnancy,
have been a controversial issue over the years. Despite their possi-
ble and accepted adverse effects during pregnancy, systemic corti-
costeroids are still widely used. MMF is an immunosuppressant that
is used in pemphigus, in addition to its main usage in preventing
organ rejection. MMF was found as a potentially useful agent in pa-
tients with mild or moderate pemphigus vulgaris (PV).61 However, it
should not be used during pregnancy because of its serious and irre-
vocable outcomes. There are some serious concerns associated with
paternal exposure to MMF and pregnancy outcomes before and
58
during conception. AZA is another commonly used treatment in
pemphigus, which is usually used in a steroid-sparing fashion. There
has been some concern about congenital abnormalities as a result of
AZA therapy in pregnant women, and this has limited the use of AZA
therapy during pregnancy. Similar to MMF, MTX is categorized as a
D-class drug by the Food and Drug Administration (FDA). Various
warnings exist about the danger of MTX therapy in pregnancy.
A further option for controlling blisters is topical corticosteroids,
which are safe in pregnancy.44 Highly potent topical corticosteroids
can be systematically absorbed, especially when used in thin lay-
ers of the skin. This may lead to some mild adverse effects due to
the systematic absorption of steroids. The majority of studies have
found no association between maternal exposure to topical corti-
costeroids of any potency and pregnancy outcomes. Indeed, reports
of adverse effects associated with mild to medium potency do not
exist. Nevertheless, there is the risk of low birthweight in maternal
44
use of potent, or very potent, topical corticosteroids. There are lim-
ited studies on the safety and efficiency of rituximab in pregnancy.
Rituximab has been categorized as a C-class drug. Administration of
this biological drug is not recommended 12 months before any at-
62
tempts to conceive. Using rituximab in pregnant women causes an
abnormality in the neonate’s B cells, while B-cell recoveries without
infectious complications were reported in entire cases. Additionally,
no abnormality associated with the response to vaccination was
observed.63
IVIg is another option for treating pemphigus. The safety of using
this treatment in pregnant women with SLE was previously reported.64
T A B L E   1   Summary of key information associated with commonly used treatments in patients with pemphigus during pregnancy
Drug name FDA pregnancy category Safety
Systemic corticosteroids C Relatively
Azathioprine D No
Mycophenolate mofetil D No
Methotrexate X No
Topical corticosteroids C Yes
Rituximab C Insufficient
data
Intravenous immunoglobulin C Yes
Unfortunately, there is only one study of IVIg therapy in pregnant
women with pemphigus.65 It was introduced as an effective and com-
pletely safe therapy. Taken together, the usage of IVIg in different
autoimmune diseases, such as SLE or multiple sclerosis (MS) during
pregnancy, may be considered as a safe drug.64,66 Table 1 summarizes
the key information about the safety and major concerns associated
with discussed treatments.
5.1 | Systemic Corticosteroids
Using systemic corticosteroids, especially prednisone and predniso-
lone, in cases of pemphigus could lead to remission of pemphigus
most of the time. There is no difference between the treatments
of pregnant patients and non-pregnant ones, except the safety as-
sociated with the fetus. Because this treatment at a low dose is
relatively safe during pregnancy, it could be the golden key to mini-
mizing the disease severity in pregnant patients with pemphigus.
There is no evidence of significant association between the systemic
corticosteroids and early and late miscarriage.67 Although some re-
ports of cleft lip are available, there are no other major congenital
abnormalities associated with systemic corticosteroids.68 There are
also some observations that corticosteroids may not lead to oral
cleft.69 Preterm delivery and lower birthweight are other possible
outcomes of exposure to corticosteroids.68 Overall, it seems that
systemic corticosteroids are a relatively safe and efficient option
for pregnant patients who need to control the disease during preg-
nancy. It is better that the dose of these drugs be reduced as much
as is possible, depending on the severity of the disease and other
used drugs.
5.2 | Azathioprine
Azathioprine, which is widely used as a steroid-sparing agent in
pemphigus, may cause some serious problems during pregnancy.
Increased risks of premature birth and congenital abnormalities have
been reported as unwanted effects of using azathioprine in pregnant
patients.70 In contrast, Goldstein et al.71 found that there is no asso-
ciation between birth defects and exposure to azathioprine. However,
analogous to the previous reports, an association with lower birth-
weight, gestational age, and prematurity was reported.
Serious concerns Breastfeeding safety
Cleft abnormalities Relatively
Congenital abnormalities No
Congenital abnormalities No
Congenital abnormalities; abortifacient No
Lower birthweight Yes
Hematologic abnormalities; infection; No
prematurity; spontaneous abortion
No concern Yes
TAVAKOLPOUR eT AL.
5.3 | Mycophenolate Mofetil
MMF manipulates DNA synthesis, which leads to the inhibition of B
cells, as well as a proliferation of T cells. It also causes a reduction in
the synthesis of antibodies in addition to the induction of T-cell ap-
72
optosis. As it has been found to be a teratogenic agent in rats and
rabbits, it is necessary to evaluate its genetic effects in humans. As a
result of some evidence of harm caused in animals and a lack of knowl-
edge of its effects in humans, it was classified as a C-class drug by the
FDA. Discovery of the teratogenic effects of MMF in humans led to its
reclassification as a D-class drug. A review of the literature revealed
that MMF can also lead to preterm delivery as well as spontaneous
abortion. Craniofacial malformations were reported in the majority of
73
cases treated with MMF. Surprisingly, there seems to be no correla-
tion between the administration of MMF and phenotype severity.73
Recently, a warning about the high risk of MMF consumption be-
fore and during pregnancy in women with pemphigus who are of child-
bearing age was released.58 Patients should be aware that MMF can
theoretically reduce the effectiveness of contraceptive drugs. Thus, it
is necessary to use more than one birth-control method. Highly effec-
tive contraception was strongly suggested in order for patients to avoid
conception during the period of MMF therapy. Additionally, a negative
pregnancy test is necessary before a patient can start MMF therapy.
Contraceptive use is essential up until 3 weeks after the last dose
of MMF in women patients. Men should also be carefully monitored
when being treated with MMF. It was warned that, until 90 days after
the last dose of MMF in men, condoms should be used to avoid possi-
ble pregnancy. The partner also should use a contraceptive method.58
5.4 | Methotrexate
Although this drug is not widely used in pemphigus, it should be
declared that MTX therapy for pregnant patients should be com-
pletely avoided. It is considered as pregnancy category X by the
FDA, which means the presence of positive evidence of human
fetal risk. MTX is considered as an effective abortifacient, as well as
a congenital abnormalities inducer.56,74 However, Lewden et al.75
conclude that no strong teratogenic risk is associated with a low
dose of MTX.
Considering the high risk of MTX exposure during pregnancy in
patients of childbearing age, strict contraception is advised. Because
of a lack of data to enable a definitive conclusion, or to confirm the
exact safe timing after MTX treatment, cessation of MTX 3 months
before conception is recommended.76 In an unwanted pregnancy,
immediate cessation of MTX, in addition to close monitoring for any
possible congenital abnormalities, is needed. Despite concerns about
adverse pregnancy outcomes among men exposed to methotrexate
before conception, no increased risk has been found so far.77–79
5.5 | Topical Corticosteroids
Topical corticosteroids are considered to be a necessary part of
the treatment of skin conditions. They are also widely used to heal
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pemphigus-associated lesions, usually with systemic corticosteroids.
They have fewer adverse effects than systemic corticosteroids, which
leads to the common usage of them in those patients who cannot tol-
erate systemic corticosteroids. Because of their high levels of safety
compared to the systemic corticosteroids or immunosuppressant
drugs, they can be an effective and safe option for pregnant women
with mild-to-moderate pemphigus who suffer from blisters on their
skin. This type of treatment is classified as FDA pregnancy class C.
Although topical corticosteroids are relatively safe, they can be sys-
tematically absorbed, and can, especially when potent or very potent,
be used on the thin skin of the eyelids, genitals, and skin creases. As
topical corticosteroids are absorbed in significantly lower amounts
compared to systemic ones, they could be used in a steroid-sparing
fashion relative to systemic corticosteroids. Although there are some
concerns about lower birthweight, published studies on the associa-
tion between pregnancy outcomes and topical corticosteroids had
shown no serious risk for this type of treatment in pregnant women.80
In general, there is no concern about birth defects, preterm delivery,
and fetal death when topical corticosteroids are used during preg-
nancy.81 All together, these results encourage the use of topical corti-
costeroids in cases with mild blisters on the skin or as a steroid-sparing
agent.
5.6 | Rituximab
RTX is increasingly used in patients with refractory pemphigus, or
those who do not respond to corticosteroids or do not tolerate them.
Prematurity and spontaneous abortion are possible adverse effects
of RTX administration.62 However, congenital abnormality is rare.
Considering other reports of RTX administration during pregnancy,
it seems that the majority of cases could tolerate RTX without any
serious adverse effect.82,83 Because RTX effects can persist for up to
12 months, it is advised to avoid becoming pregnant in this period in
order to minimize hematologic side-effects.
5.7 | Intravenous Immunoglobulin
The precise mechanisms by which IVIg functions as an anti-
inflammatory agent remain debatable. It possibly affects the func-
tions and cytokine production of T cells and B cells. It may also act
through a mediated Fc receptor blockade on macrophages or modu-
lating cell migration.84 Moreover, it may provide negative feedback
to the pathogenic plasma cells, which results in a reduction in the
production of autoantibodies. Unlike immunosuppressive therapy,
IVIg does not increase the risk of infection, which makes it more
reliable during pregnancy. IVIg is increasingly used in several auto-
immune diseases. It is usually administrated at the dose of 1-2 g/
kg in divided doses over 2-5 days, which is repeated at monthly
intervals on the basis of antibody clearance rates.85 This therapy
is considered a safe and effective treatment compared to several
other therapies, including corticosteroids and immunosuppressant
drugs. Its effectiveness in patients with pemphigus and patients
with pemphigoid has also been reported in several studies.86–88
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Additionally, the efficacy of IVIg in the prevention of blister for-
89
mation in an experimental model of PV was confirmed. IVIg was
also introduced as an effective treatment to control autoantibody-
mediated diseases.85 However, its high cost may be considered a
barrier to its use as a first-line therapy during pregnancy in patients
with pemphigus.
Theoretically, this treatment may not harm the fetus or mother
during pregnancy. There is only one study associated with the use of
IVIg for pemphigus during pregnancy.65 That study concluded that IVIg
65
can be useful and safe in treating pregnant patients with pemphigus.
There are several other studies on different autoimmune diseases that
reported the safety of IVIg in pregnant women.64,66 There is also some
evidence that IVIg therapy is beneficial in preventing immunologic
abortion.90,91 IVIg therapy may help to protect the fetus from any pos-
sible infection, which may be increased during immunosuppressants
or many biological treatments. Interestingly, IVIg led to the birth of
lesion-free neonates in patients with pemphigus vulgaris.65 According
to these findings and comparisons with other types of therapies, IVIg
is likely to be an excellent choice of therapy for pemphigus during
pregnancy.
6 | EFFECT OF TREATMENTS
ON BREASTFEEDING
Generally, corticosteroids pass into breast milk and may lead to some
problems for the infant. However, the amounts of two of the most
commonly used oral corticosteroids, prednisone and prednisolone,
in breast milk are very low. No adverse effects have been reported
associated with the maternal use of oral corticosteroids and breast-
fed infants. Avoiding breastfeeding for 4 hours after the last dose of
systemic corticosteroids in those patients under treatment with sys-
temic corticosteroids is recommended to minimize possible adverse
effects on the infant.92 There are controversial results associated
with using AZA and breastfeeding safely. In one study, AZA was not
compatible with breastfeeding.93 In contrast, Sau et al.94 concluded
that breastfeeding should not be withheld from infants of mothers
receiving AZA. Although mild-to-moderate topical corticosteroids
are considered safe, potent or very potent dosages while breastfeed-
ing are not recommended. Stopping MTX, MMF, and RTX therapy is
recommended while breastfeeding. There is some evidence that IVIg
may appear in the breast milk, but it may not be hazardous for the
infant.66,95
7 | CONCERNS ABOUT NEONATES
Autoantibodies can be transferred from the mother to neonates dur-
ing pemphigus. It is expected that neonates born to mothers with re-
fractory pemphigus experience more severe neonate pemphigus than
those born to mothers with milder conditions. There is no report of
neonatal pemphigus persisting beyond the neonatal period and pro-
gressing to the adult disease. This is because of the replacement of
new normal antibodies with aberrant maternal autoantibodies. In live
births with blisters due to the transferred autoantibodies, the disease
will be resolved within 1-4 weeks with no treatment. Sometimes, in
cases with more serious blisters, it is better that mild corticosteroid
(topical or oral) be used to prevent any possible infection. Considering
its non-progressive manner, which means that no new vesicles or bul-
lae develop in the newborn after birth, neonate pemphigus is not a
real threat for the newborn baby. Interestingly, mothers diagnosed
with PF rarely bore a baby with lesions.
8 | MANAGEMENT OF PEMPHIGUS
DURING PREGNANCY AND AFTER DELIVERY
Considering previous reports of pemphigus severity during preg-
nancy, it seems that pregnant women with pemphigus are at some
serious risks, including exacerbation of the disease, fetal loss, preterm
birth, and neonate pemphigus. Thus, in patients with previously de-
veloped pemphigus, treatment some months before the pregnancy
should be planned to reduce these risks. This condition could be man-
aged by a suitable treatment that does not harm the fetus and which
controls the disease well. Additionally, the disease should go through
the remission phase before a decision regarding the pregnancy is
made. This will possibly help to reduce the risk of flare-ups. Therefore,
conception during the stable remission of the disease with minimal
or no therapy is recommended. Cayirli et al.42 presented a case of a
pregnant woman diagnosed with PV who experienced no exacerba-
tion of disease during the pregnancy. This could be explained by the
occurrence of conception during a remission period.
The management of disease is not limited to the pre-conception
period. Indeed, disease may also flare up after termination of a preg-
nancy, which highlights the role of drug choice during pregnancy to
control a possible relapse in the postpartum period. Although it is es-
sential to control the disease during pregnancy, it is also necessary to
keep steroids to a minimum as this could control the disease. Indeed,
higher doses of steroids in pregnant women may lead to some extra
problems, such as diabetes, hypertension, and premature rupture,
which will make the pregnancy more complicated.55 Pemphigus could
be developed in pregnant women for the first time. In this case, topical
corticosteroids are the best choice as the first-line therapy. In cases
of progressive diseases, low-dose systemic corticosteroids as well as
IVIg could be employed. These therapies will significantly reduce the
risk of specific pregnancy disorders as well as control the disease until
the delivery. After the delivery, other types of adjuvants, such as MMF,
AZA, or RTX, could be added to control the disease better. There is a
chance of disease remission some months after childbirth.
9 | CONCLUSION
Patients with pemphigus who have decided to become pregnant are
in danger of the disease flaring up. Although not always the case, this
could cause serious outcomes for both mother and fetus. It is not
TAVAKOLPOUR eT AL.
possible for women of childbearing age to avoid pregnancy just be-
cause of the fear of the disease flaring up. Thus, it is essential to find
a solution to manage this condition. This review found that a disease
remission at least 6 months before conception with no therapy or
minimal therapy could significantly reduce the risk of disease flare-
up. In this circumstance, even if there was the risk of a flare-up, it
will be delayed, which will mean starting treatment after the first tri-
mester. Thus, the risk of congenital abnormalities could significantly
be decreased. It was also found that treatment during pregnancy
should be well planned to reduce the risk of any unwanted outcome.
Patients, who experience pemphigus for the first time during preg-
nancy, should be managed with low-dose systemic corticosteroids,
topical corticosteroids, and IVIg. Among the common therapies,
the use of IVIg with topical corticosteroids is the safest and most
effective treatment in patients with pemphigus during pregnancy.
According to FDA warnings and also previously reported cases, AZA,
MMF, and MTX should be completely avoided during pregnancy.
Despite the risk of systemic corticosteroids, they could be used in
those who cannot be treated with the recommended treatments.
Due to the delayed effect of IVIg, it is recommended that it be used
some months prior to conception.
CO NFLICT OF INTEREST
None.
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How to cite this article: Tavakolpour, S., Mirsafaei, H. S. and
Delshad, S. (2017), Management of pemphigus disease in pregnancy.
American Journal of Reproductive Immunology, 77: e12601.
doi: 10.1111/aji.12601
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