ORIGINAL ARTICLE—ALIMENTARY TRACT
Expert consensus on vaccination in patients with inflammatory
bowel disease in Japan
Takashi Ishige
1
?
Toshiaki Shimizu
2
?
Kenji Watanabe
3
?
Katsuhiro Arai
4
?
Koichi Kamei
5
?
Takahiro Kudo
6
?
Reiko Kunisaki
7
?
Daisuke Tokuhara
8
?
Makoto Naganuma
9
?
Tatsuki Mizuochi
10
?
Atsuko Murashima
11
?
Yuta Inoki
5
?
Naomi Iwata
12
?
Itaru Iwama
13
?
Sachi Koinuma
14
?
Hirotaka Shimizu
4
?
Keisuke Jimbo
6
?
Yugo Takaki
15
?
Shohei Takahashi
16
?
Yuki Cho
17
?
Ryusuke Nambu
13
?
Daisuke Nishida
7
?
Shin-ichiro Hagiwara
18
?
Norikatsu Hikita
17
?
Hiroki Fujikawa
4
?
Kenji Hosoi
19
?
Shuhei Hosomi
20
?
Yohei Mikami
21
?
Jun Miyoshi
22
?
Ryusuke Yagi
1
?
Yoko Yokoyama
23
?
Tadakazu Hisamatsu
22
Received: 30 July 2022 / Accepted: 28 December 2022
C211 Japanese Society of Gastroenterology 2023
Abstract Immunosuppressive therapies can affect the
immune response to or safety of vaccination in patients
with inflammatory bowel disease (IBD). The appropriate-
ness of vaccination should be assessed prior to the initia-
tion of IBD treatment because patients with IBD frequently
undergo continuous treatment with immunosuppressive
drugs. This consensus was developed to support the
decision-making process regarding appropriate vaccination
for pediatric and adult patients with IBD and physicians by
providing critical information according to the published
literature and expert consensus about vaccine-pre-
ventable diseases (VPDs) [excluding cervical cancer and
coronavirus disease 2019 (COVID-19)] in Japan. This
consensus includes 19 important clinical questions (CQs)
& Takashi Ishige
ishiget@gunma-u.ac.jp
1
Department of Pediatrics, Gunma University Graduate
School of Medicine, 3-39-22, Showa-Machi, Maebashi,
Gunma 371-8511, Japan
2
Department of Pediatrics and Adolescent Medicine, Juntendo
University Graduate School of Medicine, Tokyo, Japan
3
Division of Gastroenterology and Hepatology, Department of
Internal Medicine, Hyogo Medical University, Nishinomiya,
Japan
4
Division of Gastroenterology, Center for Pediatric
Inflammatory Bowel Disease, National Center for Child
Health and Development, Tokyo, Japan
5
Division of Nephrology and Rheumatology, National Center
for Child Health and Development, Tokyo, Japan
6
Department of Pediatrics, Juntendo University Faculty of
Medicine, Tokyo, Japan
7
Inflammatory Bowel Disease Center, Yokohama City
University Medical Center, Yokohama, Japan
8
Department of Pediatrics, Wakayama Medical University,
Wakayama, Japan
9
Department of Gastroenterology and Hepatology, Kansai
Medical University, Osaka, Japan
10
Department of Pediatrics and Child Health, Kurume
University School of Medicine, Kurume, Fukuoka, Japan
11
Center for Maternal-Fetal, Neonatal and Reproductive
Medicine, National Center of Child Health and Development,
Tokyo, Japan
12
Department of Infection and Immunology, Aichi Children’s
Health and Medical Center, Obu, Japan
13
Division of Gastroenterology and Hepatology, Saitama
Children’s Medical Center, Saitama, Japan
14
Japan Drug Information Institute in Pregnancy, National
Center of Child Health and Development, Tokyo, Japan
15
Department of Pediatrics, Japanese Red Cross Kumamoto
Hospital, Kumamoto, Japan
16
Department of Pediatrics, Kyorin University School of
Medicine, Tokyo, Japan
17
Department of Pediatrics, Osaka Metropolitan University
Graduate School of Medicine, Osaka, Japan
18
Department of Pediatric Gastroenterology, Nutrition and
Endocrinology, Osaka Women’s and Children’s Hospital,
Osaka, Japan
19
Division of Gastroenterology, Tokyo Metro Children’s
Medical Center, Tokyo, Japan
20
Department of Gastroenterology, Osaka Metropolitan
University Graduate School of Medicine, Osaka, Japan
123
J Gastroenterol
https://doi.org/10.1007/s00535-022-01953-w
on the following 4 topics: VPDs (6 CQs), live attenuated
vaccines (2 CQs), inactivated vaccines (6 CQs), and vac-
cination for pregnancy, childbirth, and breastfeeding (5
CQs). These topics and CQs were selected under unified
consensus by the members of a committee on
intractable diseases with support by a Health and Labour
Sciences Research Grant. Physicians should provide nec-
essary information on VPDs to their patients with IBD and
carefully manage these patients’ IBD if various risk factors
for the development or worsening of VPDs are present.
This consensus will facilitate informed and shared deci-
sion-making in daily IBD clinical practice.
Keywords Ulcerative colitis C1 Crohn’s disease C1
Immunization C1 Vaccine-preventable disease
Introduction
Vaccination protects vaccinated persons and those around
them who are vulnerable to disease, reducing the risk of
disease spread among family members, colleagues, and
other people in the community. The recent progress in the
treatment of inflammatory bowel disease (IBD) has
allowed more patients to receive immunosuppressive
treatments (Table 1) than in the past. Because immuno-
suppressants often affect the safety and immunogenicity of
vaccination and are often difficult to discontinue, the
necessity of vaccination should be evaluated immediately
after the diagnosis of IBD. This consensus was established
to provide critical information required for clinicians to
plan appropriate preventive care for patients with IBD. The
information in the consensus is based on a literature review
and the opinions of experts in IBD and vaccination.
Because of the lack of sufficient data, most of the previous
guidelines on vaccination of patients with IBD considered
only limited evidence of vaccine safety and effectiveness in
IBD populations. In addition, evidence from individual
countries is needed because routine vaccine schedules and
sanitation measures vary from country to country; however,
such evidence is scarce. Because close attention is essential
to avoid vaccine-related adverse events [e.g., infection by the
vaccine virus after administration of a live attenuated vac-
cine (LAV)], these consensus statements are based on
reviews of manuscripts, accumulation of evidence, and
discussion among members; however, they are not based on
assessment of the certainty of the evidence. This consensus
consists of the following sections: vaccine-preventable dis-
eases (VPDs), LAVs, inactivated vaccines, and vaccination
during pregnancy and breastfeeding. Information about
severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) vaccination is provided elsewhere. Likewise, human
papilloma virus vaccination is not described in this consen-
sus because at the time of this writing, the recommendation
for the vaccine had been temporarily suspended until Octo-
ber 2021.
Although this consensus is based on the infectious dis-
ease status, vaccination policy, and health insurance system
in Japan, it will facilitate informed and shared decision-
making in daily IBD clinical practice.
Methods
A Health and Labour Sciences Research Grant for Research
on Intractable Diseases from the Ministry of Health, Labour,
and Welfare of Japan was obtained to support the develop-
ment of a task force for establishment of an expert consensus
on vaccination in patients with IBD. First, a steering com-
mittee comprising seven pediatric gastroenterologists, four
21
Division of Gastroenterology and Hepatology, Department of
Internal Medicine, Keio University School of Medicine,
Tokyo, Japan
22
Department of Gastroenterology and Hepatology, Kyorin
University School of Medicine, Tokyo, Japan
23
Department of Intestinal Inflammation Research, Hyogo
College of Medicine, Nishinomiya, Hyogo, Japan
Table 1 List of immunosuppressive and non-immunosuppressive
treatments defined in this consensus
Immunosuppressive agents
Corticosteroids (prednisolone, methylprednisolone, budesonide)
Azathioprine
6-Mercaptopurine
Tacrolimus
Cyclosporine
Infliximab (including biosimilar)
Adalimumab (including biosimilar)
Golimumab
Ustekinumab
Tofacitinib
Non-immunosuppressive agents
5-ASA
Sulfasalazine
Enteral nutrition formula
Granulocyte and monocyte adsorption apheresis/
leukocytapheresis
Darvadstrocel
Vedolizumab
a
5-ASA 5-aminosalicylic acid
a
Vedolizumab is not included among the immunosuppressive agents
because its effect is gut-selective, whereas specific consideration for
opportunistic infections is recommended
123
J Gastroenterol
physician gastroenterologists, and one expert in women’s
health and medication during pregnancy was formed. The
committee was charged to develop questions for a systematic
literature search. The literature review team then performed
the systematic literature search using PubMed and Ichushi
(www.jamas.or.jp). Gray literature, including alerts from the
government or statistical data from the National Institute of
Infectious Diseases, was included. The review team com-
prised 20 physicians, including pediatric gastroenterologists,
physician gastroenterologists, and women’s health experts.
The review team was divided into four sections; vaccine-
preventable diseases (VPDs), LAVs, inactivated vaccines,
and vaccination during pregnancy and breastfeeding and
made drafts of commentaries. The commentaries were dis-
cussed with the steering committee members, who were also
divided into those sections, and statements were established.
A Web meeting attended by all the committee members was
then conducted to establish a consensus among the members.
After a few corrections were made based on the discussion at
the meeting, agreement among all the committee members
was confirmed electronically. The manuscript was made
available to all the intractable diseases grant members for
commenting before submission. However, the strength of the
recommendations was not adjudicated in this consensus.
Vaccine-preventable diseases
VPDs are diseases that are preventable by vaccination.
Table 2 and Fig. 1 show the currently available vaccines and
the recommended schedule of vaccination in Japan. Infants
and people of advanced age are susceptible to VPDs and tend
to have more severe outcomes of VPDs compared with
healthy adults. Patients with IBD also have an increased risk
of the development or worsening of VPDs than do healthy
individuals; therefore, physicians should provide necessary
information on VPDs to their patients with IBD and carefully
manage these patients if various risk factors for the devel-
opment or worsening of VPDs are present (e.g., advanced
age or current treatment with immunosuppressive therapies).
Before deciding to vaccinate a patient with IBD, it is nec-
essary to obtain the patient’s vaccination record and history
of VPDs. Antibody testing should then be taken into con-
sideration, especially for hepatitis B, measles, rubella,
mumps, and varicella, although such testing is not covered
by health insurance in Japan.
Q1. Are patients with IBD at increased risk for
VPDs?
[Statement]
(1) Patients with IBD have an increased risk of
the development or worsening of VPDs
compared with healthy individuals.
(2) Particularly among patients with IBD, the
risk of VPDs is higher in advanced-age
populations; undernourished patients; patients
with comorbidities such as chronic diseases
(e.g., diabetes and kidney disease), primary
immunodeficiencies, and HIV infection; and
patients receiving immunosuppressive
therapies.
Table 2 Vaccines available in Japan
Routine vaccination
Live attenuated vaccine
Bacille Calmette-Guerin (BCG)
Measles (or measles-rubella combined)
Rubella
Varicella rotavirus
Inactivated vaccine
Diphtheria, pertussis, tetanus, and polio (DPT-IPV)
Diphtheria, pertussis, tetanus (DPT)
Polio
Diphtheria-tetanus (DT)
Japanese encephalitis
Human influenza type b (Hib)
Hepatitis B
Human papilloma virus (2- and 4-valent vaccines)
Influenza
Pneumococcus (13- and 23-valent vaccines)
COVID-19 (mRNA and viral vector vaccines)
Voluntary vaccination
Live attenuated vaccine
Mumps
Yellow fever
Shingles (live attenuated varicella)
Inactivated vaccine
Tetanus
Diphtheria
Hepatitis A
Meningococcus
Rabies
Shingles (recombinant zoster)
Human papilloma virus (9-valent vaccine)
J Gastroenterol
123
[Commentary]
Among patients with IBD, the risk of opportunistic
infections is higher in advanced-age populations;
undernourished patients; patients with comorbidities such
as chronic diseases (e.g., diabetes and kidney disease),
primary immunodeficiency, and HIV infection; and
patients receiving immunosuppressive therapy [1–3]. In
particular, immunosuppressive therapy increases the risk of
opportunistic infections, and the immunosuppressive ther-
apy-mediated risk of infection is known to be even higher
in patients receiving combination therapies (e.g., thiopuri-
nes plus steroids or thiopurines plus steroids plus inflix-
imab) [1–3]. In addition, individuals of advanced age
sometimes do not know their vaccination record in spite of
their increased risk of infection; thus, it is very important to
prevent older patients with IBD from developing VPDs of
an infectious nature.
In a systematic review, the pooled incidence of
invasive pneumococcal disease was 65/100,000 person-
years in patients with chronic inflammatory diseases
(including IBD) compared with 10/100,000 in healthy
controls [4]. In terms of Haemophilus influenzae type b
(Hib), a cohort study showed no significant difference in
the Hib-mediated mortality rate between IBD and non-
IBD groups, but hospitalizations due to Hib infection
were significantly higher in patients with than without
IBD with an adjusted odds ratio of 1.34 [95% confidence
interval (CI) 1.16–1.55] [5]. In terms of herpes zoster,
which has been preventable by recombinant herpes zoster
vaccine for populations of advanced age (C 50 years)
since January 2020 in Japan, a cohort study demon-
strated that the prevalence of herpes zoster in patients
with IBD was significantly higher than that of healthy
subjects [6, 7]. With respect to human papillomavirus
disease, a systematic review of five cohort studies and
Fig. 1 Standard vaccine schedule for children in Japan (as of October 2020). These recommendations are derived from the Japan Pediatric
Society
J Gastroenterol
123
three case–control studies clarified that patients with IBD
on immunosuppressive therapy had an increased risk of
cervical high-grade dysplasia/cancer compared with the
general population [8]. In a comparative study, the long-
term hospitalization rate due to seasonal influenza was
significantly higher in patients with than without IBD
(5.40% vs. 1.85%, respectively; P\0.001) [9]. Several
studies of hepatitis B virus (HBV) revealed a higher risk
of HBV infection in patients with IBD than in healthy
individuals [10, 11], whereas other studies showed no
significant difference in HBV infection between indi-
viduals with and without IBD [12, 13]. The Japan
Society of Hepatology guidelines for the management of
HBV infection cautions clinicians about the risk of HBV
reactivation in HBV carrier patients receiving immuno-
suppressive therapy; the guidelines thus recommend
testing patients for HBV antibody prior to immunosup-
pressive therapy [14]. There is no evidence indicating a
higher risk of diphtheria, tetanus, pertussis, or polio in
patients with IBD than in healthy populations, possibly
because of the low prevalence of these diseases or
uneven distribution of cases [1].
No studies have analyzed the risks of measles, rubella,
and mumps between patients with IBD and healthy
individuals, but one study revealed a higher risk of
severe measles infection in immunocompromised patients
than in healthy individuals [15]. In terms of varicella
zoster virus (VZV), one report revealed 5 deaths among
20 patients with IBD (16 adults and 4 children) receiving
immunosuppressive therapy [16]. In a retrospective study
of pediatric patients with IBD, the rate of hospitalization
following a primary VZV infection was higher in
patients with than without IBD [17]. A Japanese
nationwide study that collected data on episodes of
measles, rubella, varicella, and mumps in pediatric
patients receiving immunosuppressive therapy for kidney
disease, rheumatoid arthritis, gastrointestinal disease, or
post-organ transplantation showed that 4 of 47 hospital-
ized pediatric patients (43 with VZV and 4 with mumps)
receiving immunosuppressive therapy died of dissemi-
nated VZV infection [18]. This finding indicated a risk
of worsening VZV infection in patients with IBD
receiving immunosuppressive therapy. In terms of rota-
virus, no study has analyzed the risks and severity of
rotavirus infection between patients with IBD and heal-
thy individuals. However, a case–control study of 4584
patients with rotavirus infection showed that immuno-
compromised patients had a 7.4-fold higher risk of
hospitalization than the general population [19].
Q2. Which patients with IBD are at increased
risk for VPDs?
[Statement]
(1) Patients who have IBD with primary
immunodeficiencies are at increased risk for
VPDs and LAV-induced infections.
Particularly, 7–10% of pediatric patients who
are diagnosed with IBD before the age of
6 years have monogenic IBD, and most of them
have associated immunodeficiencies; therefore,
these patients should be referred to specialists
for vaccination decisions in addition to IBD
management.
(2) Advanced-age patients with IBD tend to
have impaired immune function and associated
comorbidities and complications; they are thus
at increased risk for infectious diseases. These
patients are recommended to receive necessary
vaccinations at appropriate time points.
[Commentary]
Patients who have IBD with primary immunodefi-
ciency and advanced-age patients with IBD are at high
risk for VPDs. Primary immunodeficiency is a broad
category of diseases in which immune resistance to
pathogens is impaired at birth, and more than 400 dif-
ferent types of primary immunodeficiencies have been
identified [20]. IBD caused by monogenic germline
mutations (i.e., monogenic IBD) was recently found to
be present in approximately 7–10% of patients with IBD
diagnosed before the age of 6 years, and most of these
cases of monogenic IBD were found to be comorbid
with primary immunodeficiency disease [21]. In one
systematic review, 44.7% of 750 patients with mono-
genic IBD had severe or atypical infections [22]. In
Japan, targeted genetic panel tests for certain causative
genes have been covered by national health insurance
since 2018, making genetic diagnosis possible.
Vaccination programs for patients with IBD vary
widely depending on the primary immunodeficiency
disease. For example, LAVs are contraindicated in
patients with primary immunodeficiency diseases affect-
ing cellular immunity (such as severe combined
immunodeficiency and Wiskott–Aldrich syndrome)
because of the risk of life-threatening vaccine-induced
J Gastroenterol
123
illness. However, inactivated vaccines can be adminis-
tered to patients with primary immunodeficiency,
although the antibody levels after vaccination vary
depending on the etiology of the primary immunodefi-
ciency [23]. In patients with chronic granulomatous
disease, Bacille Calmette-Gue′rin (BCG) is contraindi-
cated because BCG vaccination may lead to the devel-
opment of disseminated BCG disease, resulting in severe
outcomes [24].
Therefore, if patients with IBD are suspected to have
monogenic germline mutations or primary immunodefi-
ciency because of very early onset (\6 years of age), a
family history of IBD or primary immunodeficiency,
refractory anal lesions, or strong resistance to conventional
IBD treatment, referral of these patients to specialized
facilities for appropriate vaccination programs and sched-
ules is recommended.
Advanced-age patients with IBD are at higher risk for
VPDs than younger patients with IBD and healthy
advanced-age individuals because of their reduced
immunity and higher prevalence of comorbidities/com-
plications such as diabetes, renal impairment, and low
nutritional status [25]. Generally, individuals C 65 years
of age are at increased risk for invasive pneumococcal
infection and seasonal influenza virus, and those C 50
years of age are at increased risk for reactivation of
VZV [26–28]. Immunosuppressive therapy has been
shown to increase the risk of severe infections in indi-
viduals of advanced age. One study demonstrated that
advanced-age patients with IBD receiving infliximab and
adalimumab had a 20-fold higher incidence of severe
infections than did patients of the same age with IBD
but without infliximab and adalimumab therapy [29]. In
terms of herpes zoster as an adverse event associated
with tofacitinib therapy, tofacitinib-treated patients of
advanced age (C 65 years) with ulcerative colitis have
been shown to have higher rates of herpes zoster with an
odds ratio of 9.55 (95% CI 4.77–17.08) than tofacitinib-
treated younger patients (\65 years of age) [30]. In
particular, physicians should be aware of the risk of
VPDs, including opportunistic infections, and should take
into consideration appropriate vaccination planning in
patients with refractory IBD receiving combinations of
steroids, thiopurines, and biologic agents.
Q3. Should physicians obtain vaccination
records and the history of VPDs in patients with
IBD at the time of IBD diagnosis?
[Statement]
At the time of IBD diagnosis, physicians should
obtain the patient’s vaccination records and
history of VPDs, such as measles, rubella,
varicella (herpes zoster, especially in adults
aged ≥ 50 years), mumps, hepatitis B, and
pneumococcal infection.
[Commentary]
Patients with IBD are at risk of developing opportunistic
infections and aggravating VPDs during treatment
depending on age, nutritional status, and immunosuppres-
sive therapy [31–36]. Nevertheless, evaluation of immunity
to VPDs seems to be insufficient in patients with IBD
[37, 38].
To the extent possible, LAVs against VPDs (e.g.,
measles, rubella, varicella, and mumps) should be given
before starting immunosuppressive therapy in patients with
IBD [1]. For this purpose, it is necessary to confirm the
vaccination records and history of VPDs at the time of IBD
diagnosis. In particular, knowing the history of varicella or
herpes zoster is important to determine the risk of devel-
oping herpes zoster while receiving immunosuppressive
therapy. To prevent herpes zoster in patients of advanced
age, recombinant herpes zoster vaccine has been available
to adults aged C 50 years since 2020 in Japan. Thus, it is
also important to confirm the vaccination history of herpes
zoster vaccine in advanced-age patients with IBD.
A program for HBV as a routine vaccination in infants
has been in place since 2016 in Japan; thus, there remains a
substantial HBV-unvaccinated population at risk of sexu-
ally transmitted HBV at or after adolescence. Patients
receiving immunosuppressive therapy are at risk of HBV
reactivation and aggravation of HBV infection [39, 40],
and it is, therefore, necessary to obtain the HBV vaccina-
tion history and provide appropriate information to patients
at the time of IBD diagnosis. In addition to HBV, it is
appropriate to obtain all of the patient’s vaccination history
to fully understand the risk of aggravation of other VPDs.
J Gastroenterol
123
Q4. Should physicians perform antibody tests
to determine the patient’s immunity to VPDs?
[Statement]
(1) Hepatitis B screening is recommended for
all patients with IBD at the time of diagnosis of
IBD.
(2) In terms of VPDs (varicella, herpes zoster,
measles, rubella, and mumps) other than
hepatitis B, antibody testing should be taken
into consideration to assess immunity against
these VPDs in patients with IBD without a
history of or vaccination records for these
VPDs.
(3) Even if hepatitis B screening and antibody
testing for VPDs are not performed at the time
of IBD diagnosis, physicians should take these
screening and antibody tests into consideration
before or after the initiation of
immunosuppressive therapies.
[Commentary]
Several cohort studies worldwide have indicated that
the prevalence of HBV and hepatitis C virus (HCV) in
patients with IBD is similar to that in the general pop-
ulation [2, 41, 42]. Reactivation of HBV is a well-known
complication of immunosuppression, and an increased
incidence of liver failure due to viral reactivation has
been described in patients with IBD under immunosup-
pression [39, 40]. The European Crohn’s and Colitis
Organisation (ECCO) guideline recommends serological
HBV screening for all patients at diagnosis of IBD [2],
and Pittet et al. [43] recommended serological HBV
screening including hepatitis B surface (HBs) antigen,
anti-HBs immunoglobulin G (IgG), and anti-hepatitis B
core IgG for adults with IBD in Switzerland. Although
HCV is not a VPD, the guidelines recommend serolog-
ical screening for HCV using antibody testing in patients
with IBD at diagnosis. If possible, HCV-RNA testing
should be taken into consideration for HCV screening
[2, 44].
Patients with IBD who are undergoing immunosup-
pressive therapy and seronegative for VZV IgG are at
risk of severe varicella and thus require prompt post-
exposure prophylaxis in the event of exposure. At
diagnosis of IBD, patients should be screened for their
susceptibility to primary varicella infection by obtaining
a thorough history. We suggest anti-herpes zoster IgG
antibody testing for patients without a clear history of
varicella, herpes zoster, or receipt of varicella vaccine
[2]. We also suggest testing for antibodies to measles,
rubella, mumps, and VZV at diagnosis of IBD at least
once, although as of 2021, insurance coverage of anti-
body testing is not approved for patients other than those
who are suspected to have infection in Japan [43].
At diagnosis of IBD, or at least prior to commence-
ment of immunosuppressive therapy including vedolizu-
mab, we suggest testing for antibodies to HBV, VZV,
measles, rubella, and mumps. For seronegative patients
with IBD, we suggest administration of the course of
vaccines.
Q5. Should physicians give vaccination or
additional booster shots to patients with IBD
who have low antibody titers?
[Statement]
When the serum titers of antibody to hepatitis
B, measles, rubella, mumps, or varicella are
low, vaccination or additional booster shots to
acquire protection against these VPDs need to
be taken into consideration at the proper time
point in patients with IBD.
[Commentary]
Patients with IBD have increased risks of oppor-
tunistic infections and development or worsening of
VPDs according to their age (e.g., advanced age),
nutritional status, and immunosuppressive therapies.
Therefore, maintaining protective immunity in patients
with IBD by vaccination is critical to optimize these
patients’ outcomes [1, 2, 25, 38, 43, 45–49]. For patients
with IBD not on immunosuppressive therapy, we suggest
administration of live and inactivated vaccines. For
patients on immunosuppressive therapy, LAVs are not
recommended [1, 45]. In terms of HBV vaccine for
patients with IBD, we suggest administration of a three-
dose vaccination series (at 0, 1, and 6 months) when the
anti-HBs antibody titer declines to\10 mIU/mL. When
the anti-HBs antibody titer is still\10 mIU/mL at
1–2 months after a three-dose vaccination series in
J Gastroenterol
123
patients with IBD, we suggest administration of an
additional three-dose vaccination series. For patients with
an immune response to HBV vaccine (anti-HBs antibody
titer of C 10 mIU/mL), we suggest no further antibody
testing and no booster shots [14, 50]. The test sensitivity
and the cut-offs for protective immunity to measles,
rubella, and VZV vary among the techniques used, such
as enzyme immunoassays [enzyme immunoassay (EIA)
and enzyme-linked immunosorbent assay (ELISA)],
hemagglutination inhibition assays, particle agglutination
assays, and neutralization tests [50]. Based on an
understanding of these problems, we suggest using the
antibody titers necessary to consider the need for vac-
cinations that are documented in several domestic
guidelines for vaccination of patients with IBD. For
example, based on a guideline for vaccination from the
Japan Society for Hematopoietic Cell Transplantation,
the ELISA IgG antibody titers necessary to consider the
need for vaccinations against measles, rubella, and
varicella are B 4.0, B 5.0, and B 5.0 IU/mL, respec-
tively [51]. In another study and guideline, the EIA IgG
antibody titer necessary to consider the need for vacci-
nations against measles, rubella, mumps, and varicella
was B 4.0 for all [52]. The United States Centers for
Disease Control and Prevention (CDC) stated that the
sensitivity of ELISA to detect antibody to VZV varies
according to the antigens used and that ELISA is,
therefore, not accurate enough for evaluation of immu-
nity against VZV. The CDC recommends purified gly-
coprotein ELISA as a more sensitive method; however,
testing with purified glycoprotein ELISA is not com-
mercially available. Thus, it is necessary to appropriately
interpret the examined VZV antibody titers based on an
understanding of these problems raised by commercial
assays.
Although the sensitivities and cut-off points of anti-
body titers vary according to the testing methods, we
suggest administration of vaccination or booster shots to
patients with IBD when the ELISA (or EIA) IgG anti-
body titers are\4–5 against measles, rubella, mumps,
and varicella. In terms of the Hib vaccine, herpes zoster
vaccine (recombinant vaccine), influenza vaccine, Strep-
tococcus pneumoniae vaccine, meningococcal vaccine,
human papillomavirus vaccine, and diphtheria, tetanus,
and pertussis vaccine combined with inactivated polio-
virus (DTaP-IPV) vaccine, we suggest that vaccination is
based not on the antibody titers but instead on the pre-
vious vaccination records [45, 49, 51].
Q6. Should physicians perform antibody testing
after vaccination in patients with IBD?
[Statement]
(1) In addition to humoral immunity, cellular
and mucosal immunity play crucial roles in
protection against VPDs. Therefore, serum
antibody titers cannot explain all aspects of
protective immunity, and antibody testing has
resultant limitations in the assessment of
vaccine-mediated immunity.
(2) Anti-HBs antibody testing is useful for
assessing hepatitis B vaccine-mediated
immunity and making decisions regarding
additional booster shots.
(3) Antibody tests for measles, rubella, mumps,
and VZV are useful for decision-making
regarding vaccination, but these tests are
limited in the assessment of vaccine-mediated
immunity.
[Commentary]
Not only humoral immunity with antibodies but also
physical barriers (e.g., mucus and epithelial cells) at the
site of infection of pathogenic microorganisms and various
immune cells involved in mucosal immunity are important
in the prevention of infection. In other words, it is difficult
to predict the severity of the infection or whether it can be
prevented based only on antibody titers [53], therefore;
evaluation of the immune status after vaccination should be
judged comprehensively based on each patient’s age,
nutritional status, and administration of drugs such as
immunosuppressive agents. Measuring antibody titers after
vaccination or during the course of IBD treatment is rela-
tively easy and objective and can be used to make decisions
on additional vaccination. Notably, however, the sensitivity
of antibody measurement and the optimal cutoff value of
the antibody for prevention of infection vary depending on
the measurement technique.
Regarding HBV, the Canadian Association of Gas-
troenterology and the ECCO recommend that all patients
with IBD receive a three-dose series of HBV vaccinations
and that the anti-HBs IgG antibody titer be measured
4–12 weeks after the third vaccination to achieve an anti-
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123
HBs antibody level of[10 IU/L [2, 45]. HBV vaccination
of all infants has been routine in Japan since 2016 to pre-
vent horizontal transmission, but people born before that
date (excluding those born to HBs antigen-positive moth-
ers) are unlikely to have HBV immunity. It is thus
important to confirm patients’ birth year and vaccination
records. The vaccination guideline for healthcare workers
issued by the Japanese Society for Infection Prevention and
Control also recommends confirmation of the anti-HBs IgG
antibody titer after a three-dose series of HBV vaccination
and, if necessary, consideration of an additional booster to
achieve an anti-HBs antibody level of C 10 IU/L [50].
Regarding measles, rubella, and mumps, the CDC does
not recommend serologic testing pre- and post-vaccination
because of the low sensitivity of such testing to detect
antibodies [54]. There is reportedly no difference in anti-
body levels after vaccination for measles, rubella, and
mumps viruses between patients with IBD on immuno-
suppressive therapy and healthy controls [55]. Conse-
quently, measuring antibody titers after vaccination in
these patients might be useful to determine primary vaccine
failure, in which a person does not develop protective
immunity after vaccination, or secondary vaccine failure,
in which a person loses an initially acquired immunity [56].
However, the usefulness of routine antibody titer mea-
surement is limited because the rate of antibody acquisition
after vaccination is generally very high.
With regards to VZV, the CDC does not recommend
pre- and post-vaccination serologic testing because of the
low sensitivity of antibody detection after vaccination [57].
Because no correlations between the viral antibody titer
and the risk of developing herpes zoster or the severity of
herpes zoster/postherpetic neuralgia have been reported
[58, 59], the usefulness of antibody titer measurement after
vaccination is low.
Live attenuated vaccines
LAVs are made of pathogenic viruses or bacteria with
reduced toxicity. Because they contain pathogenic organ-
isms, the risk of infection due to the vaccine strain cannot
be eliminated. As a rule, therefore, immunocompromised
or immunosuppressed patients and pregnant woman should
not receive LAVs because of safety concerns.
In this section, immunosuppressive treatment that
requires attention with respect to the concomitant use of
LAVs will be explored. Furthermore, the recommended
duration between the last LAV and introduction of
immunosuppressive treatment as well as the duration
between the cessation of immunosuppressive treatment and
LAV administration will be discussed.
LAVs for pregnant women will be discussed in another
section. Yellow fever vaccine, which is administered to
individuals who travel to endemic areas, will not be dis-
cussed; its risks and benefits should be considered in the
clinical setting as needed.
Although live varicella vaccine is approved for the
prevention of herpes zoster in people aged C 50 years, the
recently approved inactivated herpes zoster vaccine can be
used when an LAV is contraindicated.
Vaccinating family members and surrounding individ-
uals could decrease the risk of infection in patients who
should not receive LAVs.
Q7. Can patients on immunosuppressive
treatment receive LAVs?
[Statement]
In principle, LAVs should not be administered
to patients receiving immunosuppressive
treatment.
[Commentary]
Effectiveness of LAVs in patients receiving immuno-
suppressive treatment
Clinical data regarding the efficacy of LAVs in patients
receiving immunosuppressive treatment are limited [1, 2].
However, several prospective interventional studies have
focused on the resultant antibody elevation after LAV
administration in patients who have undergone organ
transplantation and in those receiving immunosuppressive
treatments, including biologics.
In a Japanese study, the seroconversion rate for measles,
rubella, varicella, and mumps vaccines was 80.0%, 100%,
59.1%, and 62.9%, respectively, in children and young
adults receiving immunosuppressants for IBD or other
conditions if their immunological condition met the criteria
of a CD4 cell count of C 500/mm
3
, stimulation index of
phytohemagglutinin-induced lymphocyte proliferation of
C 101.6, and serum IgG level of C 300 mg/dL. Among 32
patients, only one 5-year-old boy with Crohn’s disease
receiving azathioprine developed a breakthrough varicella
infection [52]. Another study revealed the probable effi-
cacy of live varicella vaccines for adults with IBD
receiving azathioprine [60].
A large prospective randomized controlled study
(VERVE trial) of the efficacy of live varicella vaccine in
patients receiving anti-tumor necrosis factor (anti-TNF)
agents is ongoing in the United States.
J Gastroenterol
123
Accumulation of further evidence for the efficacy of
LAVs in patients receiving immunosuppressive treatment
is expected.
Safety of LAVs in patients receiving immunosuppres-
sive treatment
Administration of LAVs to patients with IBD receiv-
ing immunosuppressive treatment in Japan should follow
the package insert of each drug (Table 3) as well as the
‘‘Immunization guideline for children post-organ trans-
plantation and under immunosuppressive treatment
2014’’ [61]. Thus, in principle, LAVs are not recom-
mended for patients receiving immunosuppressive treat-
ments other than vedolizumab. However, clinical
research on the use of LAVs in patients receiving
Table 3 Description of vaccination in the package insert for the treatment of inflammatory bowel disease
Trade name Generic name Prescribing information
Steroids
PREDONINE Prednisolone
Prednisolone
Sodium succinate
Important precautions: do not administer live vaccines to patients receiving long-term or high-
dose steroids or within 6 months after discontinuation
PREDONEMA
Enema
Prednisolone
Sodium phosphate
STERONEMA Betamethasone
Sodium phosphate
RINDERON
suppositories
Betamethasone
Solu-medrol for
intravenous use
Methylprednisolone
Sodium succinate
Contraindications: do not administer live vaccines or attenuated live vaccines to patients
receiving immunosuppressive therapy of this medicine
RECTABUL rectal
foam
Budesonide Important precautions: when administering a live vaccine to a patient receiving this medicine,
the patient’s immunological condition should be examined, and extreme caution should be
exercised
Zentacoat Budesonide None stated
Immunomodulators
IMURAN/AZANIN Azathioprine Contraindications for co-administration: there is a risk of breakthrough infection in
immunosuppressed patients who receive live vaccines. The live vaccine may increase and
become pathogenic if administered to
LEUKERIN Mercaptopurine
Hydrate
Immunosuppressants
Prograf Tacrolimus Hydrate Contraindications for co-administration: do not inoculate live vaccines
Sandimmun Ciclosporin
METHOTREXATE Methotrexate Important precautions: do not inoculate live vaccines while receiving this medicine
Biological products
REMICADE Infliximab Important precautions: do not inoculate live vaccines while receiving this medicine
Pregnant women: caution should be exercised when live vaccines are administered to infants
born to patients who have received this medicine
HUMIRA Adalimumab Important precautions: do not inoculate live vaccines
Pregnant women: caution should be exercised when live vaccines are administered to infants
born to patients who have received this medicine
Simponi Golimumab Important precautions: do not inoculate live vaccines while receiving this medicine
Pregnant women: caution should be exercised when live vaccines are administered to infants
born to patients who have received this medicine
Stelara Ustekinumab Important precautions: do not inoculate live vaccines while receiving this medicine
ENTYVIO Vedolizumab Precautions for co-administration: if symptoms based on the live vaccine appear after
vaccination, appropriate measures should be taken. The possibility of infection caused by live
vaccines cannot be ruled out
XELJANZ Tofacitinib citrate Important precautions: do not inoculate live vaccines while receiving this medicine
J Gastroenterol
123
immunosuppressive treatment has been conducted in
several countries, including Japan, and a consensus and
social system to support the use of LAVs in patients
who may benefit from them are needed.
In principle, LAVs are not recommended for patients
with immunosuppressive conditions, particularly cellular
immune deficiency, because of the risk of lethal viral
infection by the vaccine strain. Therefore, LAVs are
contraindicated in patients undergoing immunosuppres-
sive treatment. Some lethal events after administration of
LAVs, including yellow fever and BCG vaccines, have
been reported in this population [62, 63].
Although a few reports have addressed the safety of
LAVs for patients with IBD receiving immunosuppres-
sants, the safety of measles, rubella, varicella, and
mumps was discussed in a large systematic review and
other reports [52, 60, 64–66]. The BCG and rotavirus
vaccines are supposed to be given before 1 year of age.
Patients with infantile-onset IBD receiving immunosup-
pressive treatment and infants born of mothers receiving
immunosuppressive treatment require special attention.
Primary immunodeficiency should be ruled out in
patients with infantile-onset IBD, and in principle, LAVs
should not be administered in this high-risk population
[61]. The ‘‘Pregnancy and delivery’’ section addresses
the care of infants born of mothers receiving immuno-
suppressive treatment. No reports have described the
administration of BCG and rotavirus vaccine to infants
with IBD receiving immunosuppressive treatment.
Patients with IBD are thought to be at high risk of VPDs
[67, 68]. Patients with very-early-onset IBD under
immunosuppressive treatment are at particularly high risk
if they miss or receive an insufficient number of immu-
nizations. They may not receive contraindicated vaccines,
such as LAVs.
In general, patients receiving immunosuppressive ther-
apy are at high risk of serious infection [31], and preven-
tion of VPDs should be emphasized; however, LAVs
cannot be administered if the instructions in the package
inserts are followed. To change this situation, an ongoing
study is evaluating the safety and efficacy of LAVs in
patients under immunosuppressive treatment [52].
Although the acceptable immunological condition for safe
LAV administration in patients under immunosuppressive
treatment requires further evaluation, studies have sug-
gested that LAVs can be safely administered if these
patients’ cellular and humoral immunological parameters
are within normal levels.
Q8-1. Are LAVs prioritized over treatment of
underlying diseases?
Q8-2. What is the recommended duration
between administration of LAVs and
introduction of immunosuppressive treatment?
Q8-3. What is the recommended duration
between cessation of immunosuppressive
treatment and administration of LAVs?
[Statement]
(A8-1) Disease control should be prioritized
over LAV administration.
(A8-2) Immunosuppressive treatment should
be initiated at least 3 weeks after LAV
administration.
(A8-3) LAVs should be administered at least
3 months after the cessation of
immunosuppressive treatment.
[Commentary]
LAVs for patients without prior administration and
without detectable antibody should be discussed on an
individual-patient basis considering the disease activity and
importance of vaccination. Ideally, LAVs should be
administered before the introduction of immunosuppres-
sive treatment [2, 61]. However, some patients with IBD
require immunosuppressive treatment before completion of
LAVs. Disease control should be prioritized in those
requiring early immunosuppressive treatment, and admin-
istration of LAVs should be considered once immunosup-
pressive treatments are discontinued in the disease course
[1, 69]. LAVs should be administered once disease
remission has been induced without immunosuppressants.
Immunosuppressants should be initiated at least
1 month after LAV administration according to the ECCO
guideline and at least 3 weeks after LAV administration
according to the ‘‘Immunization guideline for children
undergoing organ transplantation and immunocompro-
mised condition’’ (Fig. 2)[2].
For patients under immunosuppressive treatment, LAVs
can be administered at least 3 months after immunosup-
pressive treatment is discontinued as written in the
domestic guideline (Fig. 2)[61]. Those taking high-dose
corticosteroids should not receive LAVs for 6 months after
the discontinuation of steroids according to the package
J Gastroenterol
123
inserts. The ECCO guideline recommends a 1-month
duration between the cessation of immunosuppressive
treatments (corticosteroids, methotrexate, tofacitinib,
cyclosporine, and tacrolimus) and LAV administration
based on the half-life of these immunosuppressants. The
package insert of each LAV does not clearly indicate the
duration between cessation of immunosuppressants and
LAV administration.
Although infection by the vaccine virus of an LAV
could occur in patients under immunosuppressive treat-
ment, there are few reports of lethal or serious infection
except for patients receiving BCG [63]. Therefore, the risks
and benefits of LAV administration in high-risk patients
should be considered on an individual-patient basis.
Inactivated vaccines
Inactivated vaccines are made by isolating and purifying
disease-causing pathogens, such as bacteria and viruses,
and inactivating them with formalin, phenol, heat treat-
ment, or ultraviolet irradiation to eliminate their infectivity
and pathogenicity without affecting their protective anti-
gens. Therefore, serious adverse reactions are unlikely to
occur. However, compared with LAVs, immunity is more
difficult to acquire and is shorter-lasting. Therefore, repe-
ated vaccinations are required to maintain immunity, fol-
lowed by additional immunizations after a certain period of
time. A toxoid is a vaccine in which bacterial toxins are
treated with formalin or other agents to eliminate toxicity.
These vaccines require repeated inoculations similar to
inactivated vaccines. Table 2 shows a list of inactivated
vaccines and toxoids that can be provided in Japan.
In daily medical practice, inactivated vaccines and
toxoids are often collectively referred to as inactivated
vaccines; thus, the term ‘‘inactivated vaccines’’ is used in
this section to refer to both types.
Inactivated vaccines for patients with IBD are consid-
ered effective except in cases of severe disease or use of
high-dose steroids. Furthermore, inactivated vaccines can
be administered during immunosuppressive therapy.
Notably, the possibility of a low antibody acquisition rate
should be considered.
This section describes the relevance of inactivated
vaccines to IBD.
Q9. Is inactivated vaccination recommended
for patients with IBD on immunosuppressive
therapy?
[Statement]
(1) Inactivated vaccination is considered
effective even during immunosuppressive
therapy. However, it is necessary to consider
that the antibody acquisition rate may decrease
during immunosuppressive therapy.
(2) There have been no reports of serious
adverse reactions such as infections associated
with vaccination, and the vaccine can be safely
administered according to the normal schedule.
[Commentary]
Several reports have described inactivated vaccination
of patients with IBD on immunosuppressive therapy,
including reviews [70, 71]. Large numbers of patients have
acquired antibodies, and the safety of this practice has been
deemed adequate.
Fig. 2 Duration between
immunosuppressive treatment
and live attenuated vaccine
administration [61]
J Gastroenterol
123
Influenza virus vaccines can reportedly reduce the rate
of immune acquisition in patients treated with thiopurines
or anti-TNF agents [72, 73].
In patients receiving the hepatitis B vaccine,
immunomodulatory drugs such as azathioprine and
methotrexate did not decrease the antibody acquisition rate;
the acquisition rate reportedly decreased only in patients
with IBD using anti-TNF agents [74]. In addition, one
study showed that older age is associated with a lower
antibody acquisition rate [75].
Patients with IBD have a high incidence of cervical and
oral cancer, and patients with anal lesions are at high risk of
human papillomavirus-related anal cancer. Therefore, anti-
body acquisition by human papillomavirus vaccination is
important. In a report of the human papillomavirus tetrava-
lent vaccine in 33 pediatric patients with IBD on immuno-
suppressive therapy, 100% of the patients acquired
antibodies to types 6, 11, and 16 and 96% acquired antibodies
to type 18 [76]. These rates were comparable to the antibody
acquisition rate in healthy women, and there were no serious
adverse reactions related to vaccination [76].
In one study, the median seroprotection rate against the
pneumococcal 13-valent diphtheria conjugate vaccine
(PCV13) significantly increased from 43.9% at inclusion to
90.4% (P\0.001) after vaccination. Patients receiving
anti-TNF agents achieved a slightly lower seroprotection
rate (from 44.5 to 86.6%) than patients treated with other
types of immunosuppressive therapy [77]. Furthermore,
patients administered infliximab or combination immuno-
suppressive therapy had significantly lower response rates
against the 23-valent pneumococcal polysaccharide vac-
cine (PPSV23) (57.6% and 62.5%, respectively) compared
with the group on mesalamine (88.6%; P\0.05 for both
comparisons) [78]. Additionally, both PCV13 and PSSV23
were generally safe and well tolerated.
Regarding the safety of the vaccine, a systematic review
of pediatric patients with IBD revealed no infections
caused by the vaccine strain, indicating that the vaccine can
be safely administered [71].
Inactivated vaccines can be safely administered to
patients with IBD on immunosuppressive therapy according
to the normal schedule, with most patients acquiring
antibody.
Q10. In what situations should inactivated
vaccination be avoided?
[Statement]
There are no conditions or situations in which
inactivated vaccination should be obviously
avoided in patients with IBD. Inactivated
vaccination is considered to be beneficial
regardless of the patient’s immunosuppressive
status, but the clinician should consider that the
rate of antibody production may be reduced
during immunosuppressive therapy.
[Commentary]
Inactivated vaccines can be administered to patients
with IBD who are not receiving immunosuppressive ther-
apy, with the same safety considerations as for healthy
patients. However, a systematic review of pediatric patients
with IBD showed that even those on immunosuppressive
therapy can be safely vaccinated without developing
infections caused by vaccine strains [71]. The same results
were reported in a systematic review of pediatric rheumatic
disorders, not IBD [79]. Immunosuppressive therapy cau-
ses a decrease in both cellular (T-cell) and humoral (B-cell)
immunity. In the latter case, both live and inactivated
vaccines are available. In the former case, LAVs are con-
traindicated in principle, and inactivated vaccines may
cause a reduction in antibody production because the
helper T cells may not be able to reproduce the antibody-
producing function of B cells.
A decrease in the immune response due to immuno-
suppressive therapy can reportedly occur when pred-
nisolone is administered at a dose of C 2 mg/kg/day
(C 20 mg/day for 10 kg) for longer than 14 days at a body
weight of\10 kg or when thiopurines or biologic agents
are used [80]. However, the same judgment cannot be
made to every patients because the mechanism of action
and concomitant conditions of the drugs used, immuno-
logical characteristics of individual patients, nutritional
status, and other factors also affect the results.
J Gastroenterol
123
Several reports have described a reduction in inactivated
vaccine-acquired antibody titers during immunosuppres-
sive therapy. In a study of influenza virus vaccines, the
seroconversion rate was lower in pediatric patients with
IBD treated with thiopurines and infliximab than in healthy
subjects [81].
Conversely, a retrospective cohort study of the vaccine
in pediatric patients and a randomized controlled study in
adult patients showed that a sufficient antibody production
rate was obtained even during immunosuppressive therapy
in pediatric patients [82], whereas a sufficient antibody
production rate was observed in adult patients other than
those using anti-TNF agents [73]. In addition, research has
suggested that the efficacy of HBV and pneumococcal
vaccines may be attenuated during the acute phase of the
disease and during immunosuppressive therapy [83].
Q11. Should the influenza vaccine be provided
every year? Should the vaccine be given twice?
[Statement]
High-risk individuals, who are prone to severe
influenza infection, are eligible for regular
influenza vaccination based on the
Immunization Law. In principle, a single
influenza vaccination is sufficient for patients
with IBD aged ≥ 13 years.
[Commentary]
Influenza is an acute febrile infectious disease caused by
the influenza virus. The symptoms are often associated
with high fever, regardless of the vaccination status; the
severity of the disease is often mild to moderate; and the
prognosis is generally relatively good. The disease often
resolves spontaneously with a fatality rate of\0.1%.
Although the effectiveness of the vaccine varies among
seasons, vaccination is recommended by the Japanese
Association for Infectious Diseases for patients at high risk
of complications from influenza (Table 4). In patients with
IBD receiving immunosuppressive therapy, active vacci-
nation is recommended because such patients are consid-
ered to be at high risk of complications.
Guidelines from the Japanese Association for Infectious
Diseases and from the United States recommend that
influenza vaccination be administered by the end of
October [84]. The prevalent influenza strains vary each
year. In addition, the vaccine’s effectiveness in prevention
of the disease is strongest after vaccination and decreases
by approximately 8–9% each subsequent month. Therefore,
annual influenza vaccination is recommended.
In individuals aged C 65 years, the benefit of the vac-
cine is decreased at 30 days post-vaccination. One study
showed that the rate of reduced efficacy in patients of this
age was 10.8% (95% CI 2.6–23.8%) for influenza A
(H3N2), 9.6% (95% CI - 3.3 to 32.7%) for influenza A
(H1N1), and 10.8% (95% CI 1.4–33.9%) for influenza
B/Yamagata. Notably, antibody titers are more likely to
decrease in patients of advanced age because of the slightly
faster rate of reduction than in the overall population of
patients aged C 18 years [84]. Not only patients of
advanced age but also pregnant women, children under
5 years of age, and patients with underlying medical con-
ditions should be cautious because of the possibility of
influenza complications [85].
A randomized comparative study of the influenza vac-
cine in adults with IBD undergoing anti-TNF therapy or
thiopurine therapy was conducted by dividing the patients
into two groups: those who received a single dose and
those who received an additional dose. There was no dif-
ference in the immune response after additional vaccina-
tion with the influenza vaccine, and no additional
vaccination was required [86].
The Japanese Association for Infectious Diseases rec-
ommends a single dose of influenza vaccine for people
aged C 13 years and two doses for children
aged B 12 years.
Table 4 Patients at high risk of complications during influenza
infection
6-Month-old or more and under 5-year-old
65 Years of age or older
Chronic respiratory diseases (bronchial asthma, COPD, etc.)
Cardiovascular disease (excluding hypertension alone)
Chronic kidney, liver, blood, metabolic diseases (diabetes, etc.)
Neuromuscular disease (including motor paralysis, convulsions,
dysphagia)
Immunosuppressive state (including those caused by HIV and
drugs)
Pregnancy
Residents of long-term medical treatment facilities
Significant obesity
Patients receiving long-term aspirin
Cancer-bearing patients
COPD chronic obstructive pulmonary disease, HIV human immun-
odeficiency virus
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123
Q12. Is the inactivated herpes zoster vaccine
effective in patients with IBD?
[Statement]
The inactivated herpes zoster vaccine is
approved for prevention of herpes zoster in
individuals aged > 50 years. However, data
regarding vaccination in patients with IBD and
receiving immunosuppressive therapy are
insufficient.
[Commentary]
Herpes zoster is a skin disease caused by VZV reacti-
vation. It is characterized by erythema and neuralgia that
usually develop eccentrically. Postherpetic neuralgia is
characterized by hyperalgesia and allodynia that persist
even after herpes zoster has resolved, and many cases of
intractable chronic pain have been recorded. Consequently,
patients’ quality of life markedly decreases.
The only way to prevent herpes zoster and postherpetic
neuralgia is inoculation with the vaccine [87–89]. In Japan,
in addition to the dry attenuated live varicella vaccine,
recombinant herpes zoster vaccine (an inactivated vaccine)
can be used in adults aged[50 years. This inactivated
vaccine has a preventive effect of C 90% against herpes
zoster and postherpetic neuralgia with two doses at an
interval of 2–6 months, and[85% of cases can be pre-
vented for 4 years after vaccination [90, 91]. Therefore, the
inactivated herpes zoster vaccine is recommended to prevent
complications associated with herpes zoster in immunized
adults aged[50 years regardless of their history of live
vaccination or herpes zoster occurrence. This inactivated
vaccine is also preferable to the LAVs for the prevention of
herpes zoster and related complications.
Notably, the concomitant use of LAVs with steroids and
thiopurines is contraindicated, and LAVs are not recom-
mended for patients treated with biologics that affect the
immune system. Instead, the inactivated herpes zoster vac-
cine is prescribed for these patients. The inactivated vaccine
has been approved for adults aged[50 years, but its effi-
cacy is not fully confirmed in patients with IBD, especially
those receiving immunosuppressive therapy [92]. Because
inoculation with the inactivated herpes zoster vaccine is paid
for by the patients themselves, it will be economically
burdensome.
Q13. Should the pneumococcal vaccine be
provided to advanced-age patients with IBD?
[Statement]
Pneumococcal vaccination is recommended for
aged patients, particularly those
aged > 65 years.
[Commentary]
In 2019 in Japan, the ‘‘Concept of Streptococcus pneu-
moniae vaccine for adults aged 65 and over’’ (3rd edition)
was presented by the joint committee of the Japanese Res-
piratory Society and the Japanese Society of Infectious
Diseases. In March 2021, the ‘‘Concept of pneumococcal
vaccination for high-risk persons aged 6 to 64’’ was pre-
sented by the joint committee of the Japanese Respiratory
Society, the Japanese Society of Infectious Diseases, and the
Japanese Society of Vaccination.
Pneumococcal vaccines include PPSV23 and PCV13.
PPSV23 is a routine vaccine for adults aged C 65 years.
Currently, PCV13 inoculation followed by a series of
PPSV23 inoculation (regular or voluntary inoculation) can
be administered. In Japan, the effect of the vaccine within
5 years after PPSV23 inoculation is 27.4% for all types of
pneumococcal pneumonia and 33.5% for serum-type pneu-
mococcal pneumonia [93]. According to a report targeting
invasive pneumococcal disease in patients aged C 15 years
in Japan, the effect of vaccination against invasive pneu-
mococcal disease caused by the serotypes included in the
PPSV23 vaccine is 45%. Age-stratified analysis revealed
that the efficacy of the PPSV23 vaccine serotype is 75% in
individuals aged 15–64 years and 39% in individuals
aged[65 years. Based on this evidence, an improvement in
the PPSV23 inoculation rate in adults aged C 65 years has
been expected; nevertheless, vaccination for individuals
with underlying diseases has not been investigated. Addi-
tionally, pneumococcal vaccines for high-risk persons (such
as patients with rheumatoid arthritis and collagenous dis-
eases) aged 6–64 years have been presented by the joint
committee, indicating the need to recognize attenuation of
immunogenicity of the pneumococcal vaccine in patients
undergoing thiopurine therapy.
Although clear evidence on whether IBD increases the
risk of pneumococcal infection has not been provided [45],
the pneumococcal vaccine is recommended for adult
patients with IBD who are considered to be at a high risk of
pneumococcal infection or who are receiving immuno-
suppressive therapy. This vaccine should also be adminis-
tered before immunosuppressants are given. However,
studies have yet to verify whether pneumococcal vaccina-
tion is recommended for patients with IBD if
J Gastroenterol
123
immunosuppressive treatment is not performed or for
patients with fewer risk factors for pneumococcal infection.
Data are also insufficient to propose the most appropriate
type of vaccine and administration schedule.
Age is considered a risk factor for pneumococcal
infection; thus, pneumococcal vaccination is beneficial for
older patients with IBD, especially those aged C 65 years,
unless they have contraindications for vaccination.
Q14. When inactivated vaccines are provided to
patients with IBD being treated with anti-TNF
agents, should the timing of anti-TNF therapy
and inactivated vaccination be considered?
[Statement]
Inactivated vaccines can be administered on the
same day of anti-TNF therapy.
[Commentary]
Several studies have revealed the efficacy of inactivated
vaccination for patients who have IBD, rheumatoid
arthritis, and other collagenous diseases receiving anti-TNF
agents. Although the antibody acquisition rate of the vac-
cine is slightly reduced in patients using anti-TNF agents
[81, 94], sufficient antibody titers have been obtained, and
inoculation can be safely conducted. These findings show
that the benefits of inactivated vaccination outweigh its
disadvantages. Therefore, inactivated vaccines can be
administered to patients with IBD even when they are
using anti-TNF agents.
Few studies have described the appropriate timing of
inactivated vaccination after anti-TNF agents are given. In a
study of patients with rheumatoid arthritis and ankylosing
spondylitis being treated with infliximab, the antibody
acquisition rates were compared between patients inoculated
with influenza vaccine on the day of infliximab administra-
tion (n = 22) and patients inoculated 3 weeks after inflix-
imab administration (n = 16). The results indicated no
difference in the antibody acquisition rates between the two
groups [95]. Interestingly, in patients with rheumatoid
arthritis, a higher immune response to vaccination against
the H1N1 strain was achieved in the group inoculated on the
day of infliximab administration than in the group inoculated
3 weeks after infliximab administration.
A randomized controlled trial of patients with IBD was
conducted to compare patients inoculated on the day of
infliximab administration (n = 69) with those inoculated
between two doses of infliximab administration (n = 68).
All patients received influenza vaccines [A/California/7/
2009 (H1N1), A/Victoria/361/2011 (H3N2), B/Wisconsin/
1/2010] while undergoing infliximab maintenance therapy.
The proportions of patients with sufficient antibody titers to
prevent influenza infection (hemagglutination inhibition
antibody titer of C 1:40) were 67% versus 66% (P = 0.8)
for H1N1, 43% versus 49% (P = 0.5) for H3N2, and 69%
versus 79% (P = 0.2) for B/Wisconsin/1/2010, respec-
tively. In addition, no significant differences in the exac-
erbation of the current disease or in the incidence of
adverse reactions were observed between the two groups,
and no serious adverse events were observed in either
group [82].
Research on influenza vaccines for patients taking
infliximab is limited. However, some studies have indi-
cated that there is no evidence showing that the schedule of
inactivated vaccination should be staggered in patients
receiving anti-TNF agents. Therefore, inactivated vaccines
can be administered on the same day as anti-TNF agents.
Pregnancy, lactation, and vaccination
Special consideration is required for pregnant and lactating
patients with IBD. Vaccination and infection control are
key issues during these periods. Because VPDs often affect
pregnancy outcomes, vaccination should be appropriately
received before pregnancy if possible. If a patient diag-
nosed with IBD wishes to become pregnant, vaccination
should be administered at the time of IBD diagnosis.
The benefits and risks of vaccination during pregnancy
must be carefully explained to patients. Inactivated vacci-
nes are considered safe during pregnancy. For patients who
are worried about vaccines, accurate information including
the incidence of congenital malformations or spontaneous
abortion among typical births should be provided. The
indication for vaccines for infants born to mothers with
IBD should be considered based on the duration, types, and
placental transfer of immunosuppressive agents used dur-
ing pregnancy.
J Gastroenterol
123
Q15. Which vaccines are recommended for
women with IBD who wish to become
pregnant?
[Statement]
(1) To avoid congenital rubella syndrome,
patients with a low rubella-specific antibody
titer are encouraged to be vaccinated for rubella
before pregnancy.
(2) Varicella and measles vaccination are
recommended before pregnancy if the patient is
confirmed to have no history of vaccination or
infection.
[Commentary]
A rubella epidemic occurred in Japan from 2012 to
2013, resulting in a high incidence of congenital rubella
syndrome. The cause of this epidemic is considered to be
the high rate of lack of sensitization to rubella among men
in their 30 s and 40 s and young pregnant women at that
time. A rubella epidemic and an outbreak of congenital
rubella syndrome were also reported from 2018 to 2019
[96]. Infection with rubella in the first trimester of preg-
nancy can cause congenital rubella syndrome, potentially
resulting in cataracts, glaucoma, congenital heart disease,
and sensorineural hearing loss. Congenital rubella syn-
drome due to reinfection also may occur even if the mother
has been previously vaccinated, although this is rare. In
Japan, rubella vaccination is recommended to prevent the
development of congenital rubella syndrome for women
who wish to become pregnant if their rubella-specific
antibody titer (hemagglutination inhibition method)
is B 1:16.
Because of the risk of severe disease if varicella or
measles is contracted during pregnancy, women with IBD
who have no history or vaccination of these diseases and
wish to become pregnant should be considered for these
vaccines. Because rubella vaccine, measles vaccine,
measles-rubella vaccine, and varicella vaccine are LAVs,
other sections of this document should be consulted to
determine the vaccination plan for patients who are
receiving and/or planning scheduled immunosuppressive
treatment.
Because these vaccines are contraindicated during
pregnancy, patients should be instructed to use contracep-
tion for 2 months after vaccination. If rubella or measles
vaccines are administered to a patient who is unaware that
she is pregnant or when pregnancy occurs within 2 months
of vaccination, the CDC and the Japan Society of Obstet-
rics and Gynecology guidelines indicate that there is no
need to interrupt the pregnancy because no clinically sig-
nificant risk to the fetus has been demonstrated in previous
research [97].
Voluntary rubella vaccination is recommended for
partners of pregnant women, their children, and their other
family members living together who have no history of
rubella or vaccination. To prevent rubella transmission to
the female partner, rubella vaccination is recommended for
men with IBD who have no history or vaccination of
rubella.
Q16. Can pregnant women with IBD be
vaccinated?
[Statement]
Inactivated vaccines can be used for pregnant
women.
[Commentary]
In principle, inoculation of pregnant women using LAVs
should be avoided because of concerns about the possi-
bility of transfer of the vaccine component virus to the
fetus, resulting in infection (see Q15). Vaccines other than
LAVs (e.g., inactivated vaccines) do not cause infection in
the fetus and can be administered as necessary.
Patients with IBD are considered at risk for severe
influenza infection, and annual influenza vaccination is
recommended in both Europe and the United States [2, 80].
Increased risks of the following have been reported in
pregnant women who contract influenza: hospitalization,
maternal mortality, spontaneous abortion, preterm birth,
low birth weight, small for gestational age, and fetal death
[98–101]. The influenza vaccine used in Japan is an inac-
tivated vaccine, which theoretically poses no risk to preg-
nant women or fetuses. Many studies have revealed the
safety of influenza vaccination during pregnancy, showing
that it is not associated with adverse birth events and can
improve pregnancy outcomes [102, 103]. Influenza vacci-
nation of pregnant and postpartum women reduces the
incidence of influenza in infants up to 6 months of age. In
the United States, inactivated influenza vaccination of
pregnant women is recommended during influenza epi-
demics because it is the most effective technique for pre-
venting severe cases of influenza [104].
Based on the above, it is recommended that pregnant
women with IBD, who are considered to be more suscep-
tible to severe influenza, receive inactivated influenza
vaccine when they desire vaccination.
J Gastroenterol
123
Q17. Can an infant born of a woman with IBD
who received immunosuppressive treatment
during pregnancy be vaccinated?
[Statement]
(1) If the mother received a biologic medication
during the second or third trimester, then LAVs
are not recommended until the age of 6 months.
(2) Infants born to mothers with IBD who
received steroids and thiopurines during
pregnancy are recommended to follow the
standard vaccination schedule.
[Commentary]
Currently, four types of inactivated vaccines (Hib,
pneumococcal vaccine, hepatitis B vaccine, and DTaP-IPV
vaccine) and two LAVs (BCG and rotavirus) are recom-
mended for standard vaccination at\1 year of age in
Japan (Fig. 1).
For many biologics, drug concentrations in cord blood
are reportedly higher than those in maternal plasma (in-
fliximab, about 1.6 times; adalimumab, about 1.5 times;
vedolizumab, about 0.8 times; and ustekinumab, about 1.8
times) [105–107]. Because of the long plasma disappear-
ance half-life of biologics, these drugs were still
detectable in the blood at 3–6 months of age in infants born
to mothers with IBD who had received infliximab and
adalimumab in the third trimester of pregnancy [105, 108].
In a single case report describing a child of a mother
exposed to infliximab during pregnancy, the child received
a BCG vaccination at 3 months of age and then died of
disseminated BCG infection at 4.5 months of age [63].
Although some reports have indicated that no major
problems were observed in the children [109, 110],
national and international professional guidelines recom-
mend that infants of mothers who received biologics during
the second or third trimester of pregnancy should avoid
LAVs and BCG vaccination for at least 6 months after
birth [61, 111–113].
Administration of the rotavirus vaccine is recommended
by 14 weeks 6 days after birth to avoid vaccination at
6 months to 2 years of age, which is a susceptible period
for the development of vaccination-associated intussus-
ception. Therefore, it is difficult to actively recommend
vaccination of infants born to mothers with IBD who
received immunosuppressive treatment during pregnancy.
Some reports have indicated no apparent increase in
adverse reactions after rotavirus vaccination by 6 months
of age in infants born to mothers with IBD who had
received biologic agents (infliximab, adalimumab, ustek-
inumab, or vedolizumab) during pregnancy [114, 115].
Administration of inactivated vaccines should follow a
standard vaccination schedule. Several reports have
described an adequate immune response with no adverse
events after inactivated vaccines were given to infants born
to mothers with IBD who had received immunosuppressive
treatment during pregnancy [110, 114, 116].
Placental transfer has been measured for prednisolone
[117], thiopurines [118, 119], and immunosuppressive
drugs (tacrolimus and cyclosporine) [120, 121], and the
cord blood concentrations of all were reportedly lower than
those in maternal plasma. Because the plasma elimination
half-life of these drugs is shorter than that of biologics, the
use of any of these agents until delivery is not considered to
adversely affect either live or inactivated vaccines given
according to the standard vaccination schedule in Japan
[122].
One report described B-cell hypofunction in the cord
blood of an infant born to a mother who had continued
azathioprine during pregnancy, but the infant’s immune
function was normal at 1 month of age [123]. Other reports
have described blood cell abnormalities and decreased
immune function in infants born to mothers who had
continued azathioprine during pregnancy, and all of these
abnormalities normalized within about 2 months
[124, 125].
Q18. Can breastfeeding women with IBD be
vaccinated?
[Statement]
Mothers with IBD can be vaccinated while breastfeeding.
[Commentary]
In Japan, vaccination is considered to have no adverse
effect on the safety of breast milk when live or inactivated
vaccines are administered to nursing women [126].
Although components of the rubella vaccine are reportedly
secreted into breast milk and transient asymptomatic
infection has been observed in infants [127], most infants
did not show clinical symptoms, and the rubella vaccina-
tion of the children was not affected [128, 129].
The yellow fever vaccine is rarely administered in
Japan; however, some reports have described yellow fever
vaccine-associated encephalitis and neurological disorders
in infants after the vaccine was administered to lactating
mothers [130, 131]. The CDC states that lactating mothers
should be vaccinated only if travel to a yellow fever-en-
demic area is unavoidable [126].
J Gastroenterol
123
Q19. Can breastfed infants of women with IBD receiving
immunosuppressive therapy be vaccinated?
[Statement]
(1) Breastfed infants of mothers with IBD
receiving biologics are recommended to be
vaccinated according to the standard schedule.
(2) Breastfed infants of mothers with IBD
receiving steroids and thiopurines are also
recommended to be vaccinated according to the
standard schedule.
[Commentary]
Factors that enhance drug transfer to breast milk include
low blood protein binding, basic drugs, high lipophilicity,
and small molecular weight.
Biologics have very high molecular weights, which
limits their transfer to breast milk. Infliximab and adali-
mumab have been detected in very small amounts by
sensitive assays, but no reports have described adverse
events in breasted infants [132–134]. Because the oral
bioavailability of biologics is extremely low, even if a
small amount of a drug is ingested orally by an infant
through breast milk, it is hardly absorbed and thus poses no
problem for the infant’s vaccination.
Prednisolone and thiopurines have been measured in the
milk of breastfeeding women who are orally receiving
these drugs, and the amount of drug ingested by fully
lactating infants from breast milk is estimated to be about
1–5% of the infant’s therapeutic dose; additionally, the
estimated rate of adverse events in lactating infants is low
[135, 136]. Expert guidelines in North America and Europe
consider prednisolone and thiopurines to be safe for use
during breastfeeding [111, 112, 137–140]. Because of the
low likelihood of affecting the infant’s immune function,
general vaccination of infants is not considered
problematic.
During steroid pulse therapy, the amount of drug
ingested by the infant via breast milk increases with the
dose of medication; therefore, the clinician must carefully
consider whether breastfeeding should be performed. If a
breastfed infant shows symptoms that suggest an adverse
event caused by a drug transferred to breast milk, the
infant’s drug blood level should be measured and immune
function evaluated before vaccination.
Acknowledgements This work was supported in part by a Health
and Labour Sciences Research Grant for Research on
Intractable Diseases from the Ministry of Health, Labour and Welfare
of Japan (Hisamatsu 20316729). The authors thank Angela Morben,
DVM, ELS, from Edanz (https://jp.edanz.com/ac), for editing a draft
of this manuscript.
Declarations
Conflict of interest Any financial relationships with enterprises,
businesses, or academic institutions in the subject matter or materials
discussed in the manuscript are listed as follows. (1) Those from
which the authors or the authors’ spouse, partner, or immediate rel-
atives have individually received any income, honoraria, or any other
types of remuneration: AbbVie, Astellas Pharma, Celgene, Chugai
Pharmaceutical, EA Pharma, Janssen Pharmaceutical, JIMRO, Kissei
Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma,
Mochida Pharmaceutical, Nichi-Iko Pharmaceutical, Nobel Pharma,
Pfizer, Takeda Pharmaceutical, and UCB Japan. (2) Those from
which the authors have received scholarship/research grants: AbbVie,
Alfresa Pharma, AstraZeneca, Chugai Pharmaceutical, Daiichi-San-
kyo, EA Pharma, EP-CRSU, Janssen Pharmaceutical, JIMRO, Kyorin
Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceuti-
cal, Nippon Kayaku, Pfizer, Taiju Life Social Welfare Foundation,
Takeda Pharmaceutical, TERUMO, Vaccination Research Center,
and ZERIA Pharmaceutical. (3) Those from which the authors have
individually received an endowed chair: AbbVie, EA Pharma, Mit-
subishi Tanabe Pharma, and ZERIA Pharmaceutical.
References
1. Benchimol EI, Tse F, Carroll MW, et al. Canadian Association
of Gastroenterology clinical practice guideline for immuniza-
tions in patients with inflammatory bowel disease (IBD)—part
1: live vaccines. Gastroenterology. 2021;161:669–80.
2. Kucharzik T, Ellul P, Greuter T, et al. ECCO guidelines on the
prevention, diagnosis, and management of infections in
inflammatory bowel disease. J Crohn’s Colitis.
2021;15:879–913.
3. Toruner M, Loftus EV, Harmsen WS, et al. Risk factors for
opportunistic infections in patients with inflammatory bowel
disease. Gastroenterology. 2008;134:929–36.
4. van Aalst M, Lo¨tsch F, Spijker R, et al. Incidence of invasive
pneumococcal disease in immunocompromised patients: a sys-
tematic review and meta-analysis. Travel Med Infect Dis.
2018;24:89–100.
5. Stobaugh DJ, Deepak P, Ehrenpreis ED. Hospitalizations for
vaccine preventable pneumonias in patients with inflammatory
bowel disease: a 6-year analysis of the nationwide inpatient
sample. Clin Exp Gastroenterol. 2013;6:43–9.
6. Nugent Z, Singh H, Targownik LE, et al. Herpes zoster infection
and herpes zoster vaccination in a population-based sample of
persons with IBD: is there still an unmet need? Inflamm Bowel
Dis. 2019;25:532–40.
7. Tsai SY, Yang TY, Lin CL, et al. Increased risk of varicella
zoster virus infection in inflammatory bowel disease in an Asian
population: a nationwide population-based cohort study. Int J
Clin Pract. 2015;69:228–34.
8. Allegretti JR, Barnes EL, Cameron A. Are patients with
inflammatory bowel disease on chronic immunosuppressive
therapy at increased risk of cervical high-grade dys-
plasia/cancer? A meta-analysis. Inflamm Bowel Dis.
2015;21:1089–97.
9. Tinsley A, Navabi S, Williams ED, et al. Increased risk of
influenza and influenza-related complications among 140,480
patients with inflammatory bowel disease. Inflamm Bowel Dis.
2019;25:369–76.
10. Chen D, Luo S, Ben Q, et al. Prevalence of hepatitis B and C and
factors for infection and nonimmune in inflammatory bowel
disease patients in China. Eur J Gastroenterol Hepatol.
2017;29:509–15.
J Gastroenterol
123
11. Tolentino YFM, Fogac?a HS, Zaltman C, et al. Hepatitis B virus
prevalence and transmission risk factors in inflammatory bowel
disease patients at Clementino Fraga Filho university hospital.
World J Gastroenterol. 2008;14:3201–6.
12. Ardesia M, Costantino G, Mondello P, et al. Serology of viral
infections and tuberculosis screening in an IBD population
referred to a tertiary centre of Southern Italy. Gastroenterol Res
Pract. 2017;2017:4139656.
13. Chevaux JB, Nani A, Oussalah A, et al. Prevalence of hepatitis
B and C and risk factors for nonvaccination in inflammatory
bowel disease patients in Northeast France. Inflamm Bowel Dis.
2010;16:916–24.
14. Drafting Committee for Hepatitis Management Guidelines, the
Japan Society of Hepatology. Japan Society of Hepatology
guidelines for the management of hepatitis B virus infection:
2019 update. Hepatol Res. 2020;50:791–816.
15. Permar SR, Griffin DE, Letvin NL. Immune containment and
consequences of measles virus infection in healthy and
immunocompromised individuals. Clin Vaccine Immunol.
2006;13:437–43.
16. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus
infection in inflammatory bowel disease. Inflamm Bowel Dis.
2012;18:2392–403.
17. Adams DJ, Nylund CM. Hospitalization for varicella and zoster
in children with inflammatory bowel disease. J Pediatr.
2016;171:140–5.
18. Kamei K, Miyairi I, Ishikura K, et al. Prospective study of live
attenuated vaccines for patients with nephrotic syndrome
receiving immunosuppressive agents. J Pediatr.
2018;196:217–22.
19. Bruijning-Verhagen P, Nipshagen MD, de Graaf H, et al.
Rotavirus disease course among immunocompromised patients;
5-year observations from a tertiary care medical centre. J Infect.
2017;75:448–54.
20. Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors
of immunity: 2019 update on the classification from the Inter-
national Union of Immunological Societies Expert Committee.
J Clin Immunol. 2020;40:24–64.
21. Pazmandi J, Kalinichenko A, Ardy RC, et al. Early-onset
inflammatory bowel disease as a model disease to identify key
regulators of immune homeostasis mechanisms. Immunol Rev.
2019;287:162–85.
22. Nambu R, Warner N, Mulder DJ, et al. A systematic review of
monogenic inflammatory bowel disease. Clin Gastroenterol
Hepatol. 2022;20:e653–63.
23. Sobh A, Bonilla FA. Vaccination in primary immunodeficiency
disorders. J Allergy Clin Immunol Pract. 2016;4:1066–75.
24. Kawashima H, Hasegawa D, Nakamura M, et al. Hazards of
early BCG vaccination: BCGitis in a patient with chronic
granulomatous disease. Pediatr Int. 2007;49:418–9.
25. Nakase H, Uchino M, Shinzaki S, et al. Evidence-based clinical
practice guidelines for inflammatory bowel disease 2020.
J Gastroenterol. 2021;56:489–526.
26. Pneumococcal vaccination: who and when to vaccinate. In:
Centers for Disease Control and Prevention (CDC). https://
www.cdc.gov/vaccines/vpd/pneumo/hcp/who-when-to-vacci
nate.html. Accessed 8 June 2022.
27. Demicheli V, Jefferson T, Di Pietrantonj C, et al. Vaccines for
preventing influenza in the elderly. Cochrane Database Syst
Rev. 2018;2:CD004876.
28. Gupta G, Lautenbach E, Lewis JD. Incidence and risk factors for
herpes zoster among patients with inflammatory bowel disease.
Clin Gastroenterol Hepatol. 2006;4:1483–90.
29. Cottone M, Kohn A, Daperno M, et al. Advanced age is an
independent risk factor for severe infections and mortality in
patients given anti-tumor necrosis factor therapy for inflamma-
tory bowel disease. Clin Gastroenterol Hepatol. 2011;9:30–5.
30. Winthrop KL, Melmed GY, Vermeire S, et al. Herpes zoster
infection in patients with ulcerative colitis receiving tofacitinib.
Inflamm Bowel Dis. 2018;24:2258–65.
31. Leung VS, Nguyen MT, Bush TM. Disseminated primary
varicella after initiation of infliximab for Crohn’s disease. Am J
Gastroenterol. 2004;99:2503–4.
32. Ritz MA, Jost R. Severe pneumococcal pneumonia following
treatment with infliximab for Crohn’s disease. Inflamm Bowel
Dis. 2001;7:327.
33. Long MD, Martin C, Sandler RS, et al. Increased risk of
pneumonia among patients with inflammatory bowel disease.
Am J Gastroenterol. 2013;108:240–8.
34. Millonig G, Kern M, Ludwiczek O, et al. Subfulminant hepatitis
B after infliximab in Crohn’s disease: need for HBV-screening?
World J Gastroenterol. 2006;12:974–6.
35. Culver E, Travis S. How to manage the infectious risk under
anti-TNF in inflammatory bowel disease. Curr Drug Targets.
2010;11:198–218.
36. Viget N, Vernier-Massouille G, Salmon-Ceron D, et al.
Opportunistic infections in patients with inflammatory bowel
disease: prevention and diagnosis. Gut. 2008;57:549–58.
37. Selby L, Hoellein A, Wilson JF. Are primary care providers
uncomfortable providing routine preventive care for inflamma-
tory bowel disease patients? Dig Dis Sci. 2011;56:819–24.
38. Crawford NW, Catto-Smith AG, Oliver MR, et al. An Australian
audit of vaccination status in children and adolescents with
inflammatory bowel disease. BMC Gastroenterol. 2011;11:87.
39. Loras C, Gisbert JP, M?′nguez M, et al. Liver dysfunction related
to hepatitis B and C in patients with inflammatory bowel disease
treated with immunosuppressive therapy. Gut. 2010;59:1340–6.
40. Park SH, Yang SK, Lim YS, et al. Clinical courses of chronic
hepatitis B virus infection and inflammatory bowel disease in
patients with both diseases. Inflamm Bowel Dis.
2012;18:2004–10.
41. Huang ML, Xu XT, Shen J, et al. Prevalence and factors related
to hepatitis B and C infection in inflammatory bowel disease
patients in China: a retrospective study. J Crohns Colitis.
2014;8:282–7.
42. Harsh P, Gupta V, Kedia S, et al. Prevalence of hepatitis B,
hepatitis C and human immunodeficiency viral infections in
patients with inflammatory bowel disease in north India. Intest
Res. 2017;15:97–102.
43. Pittet LF, Verolet CM, Michetti P, et al. Risk of vaccine-pre-
ventable infections in Swiss adults with inflammatory bowel
disease. Digestion. 2021;102:956–64.
44. Rahier JF, Magro F, Abreu C, et al. Second European evidence-
based consensus on the prevention, diagnosis and management
of opportunistic infections in inflammatory bowel disease.
J Crohn’s Colitis. 2014;8:443–68.
45. Jones JL, Tse F, Carroll MW, et al. Canadian Association of
Gastroenterology clinical practice guideline for immunizations
in patients with inflammatory bowel disease (IBD)-part 2:
inactivated vaccines. Gastroenterology. 2021;161:681–700.
46. Mir FA, Kane SV. Health maintenance in inflammatory bowel
disease. Curr Gastroenterol Rep. 2018;20:23.
47. Vinsard DG, Wakefield D, Vaziri H, et al. Vaccine-pre-
ventable diseases in hospitalized patients with inflammatory
bowel disease: a nationwide cohort analysis. Inflamm Bowel
Dis. 2019;25:1966–73.
48. Ning L, Liu R, Li S, et al. Increased risk of herpes zoster
infection in patients with inflammatory bowel disease: a meta-
analysis of cohort studies. Eur J Clin Microbiol Infect Dis.
2020;39:219–27.
J Gastroenterol
123
49. Gidengil C, Chen C, Parker AM, et al. Beliefs around childhood
vaccines in the United States: a systematic review. Vaccine.
2019;37:6793–802.
50. Mikamo H, Taya K, Ishiguro N, et al. Vaccine guidelines for
healthcare professionals Ver.3. Jpn J Environ Infect.
2020;35:S1–31.
51. JSHCT Guideline Committee. Vaccinations. In: Guideline of the
Japan Society for Hematopoietic Cell Transplantation, 3rd edn.
Tokyo: Japan Society for Hematopoietic Cell Transplantation;
2018.
52. Kamei K, Miyairi I, Ishikura K, et al. Prospective study of live
attenuated vaccines for patients receiving immunosuppressive
agents. PLoS ONE. 2020;15: e0240217.
53. Plotkin SA. Correlates of protection induced by vaccination.
Clin Vaccine Immunol. 2010;17:1055–65.
54. McLean HQ, Fiebelkorn AP, Temte JL, et al. Prevention of
measles, rubella, congenital rubella syndrome, and mumps,
2013: summary recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR Recomm Rep.
2013;62:1–34.
55. Caldera F, Misch EA, Saha S, et al. Immunosuppression does
not affect antibody concentrations to measles, mumps, and
rubella in patients with inflammatory bowel disease. Dig Dis
Sci. 2019;64:189–95.
56. Schenk J, Abrams S, Theeten H, et al. Immunogenicity and
persistence of trivalent measles, mumps, and rubella vaccines: a
systematic review and meta-analysis. Lancet Infect Dis.
2021;21:286–95.
57. Marin M, Gu¨ris D, Chaves SS, et al. Prevention of varicella:
recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Recomm Rep. 2007;56:1–40.
58. Asada H, Nagayama K, Okazaki A, et al. An inverse correlation
of VZV skin-test reaction, but not antibody, with severity of
herpes zoster skin symptoms and zoster-associated pain. J Der-
matol Sci. 2013;69:243–9.
59. Imoto K, Okazaki A, Onishi F, et al. VZV skin-test reaction, but
not antibody, is an important predictive factor for postherpetic
neuralgia. J Dermatol Sci. 2015;79:235–40.
60. Khan N, Trivedi C, Kavani H, et al. Efficacy of live attenuated
herpes zoster vaccine in patients with inflammatory bowel dis-
eases. Clin Gastroenterol Hepatol. 2019;17:1341–7.
61. Japanese Society for Pediatric Infectious Diseases. Immuniza-
tion guideline for children post-organ transplantation and under
immunosuppressive treatment 2014. Tokyo: Kyowa kikaku;
2014.
62. Whittembury A, Ramirez G, Herna′ndez H, et al. Viscerotropic
disease following yellow fever vaccination in Peru. Vaccine.
2009;27:5974–81.
63. Cheent K, Nolan J, Shariq S, et al. Case report: fatal case of
disseminated BCG infection in an infant born to a mother taking
infliximab for Crohn’s disease. J Crohns Colitis. 2010;4:603–5.
64. Wasan SK, Zullow S, Berg A, et al. Herpes zoster vaccine
response in inflammatory bowel disease patients on low-dose
immunosuppression. Inflamm Bowel Dis. 2016;22:1391–6.
65. Wichmann A, Cleveland NK, Rubin DT. Safety and efficacy of
live measles vaccine administered to a Crohn’s disease patient
receiving vedolizumab. Am J Gastroenterol. 2016;111:577.
66. Croce E, Hatz C, Jonker EF, et al. Safety of live vaccinations on
immunosuppressive therapy in patients with immune-mediated
inflammatory diseases, solid organ transplantation or after bone-
marrow transplantation—a systematic review of randomized
trials, observational studies and case reports. Vaccine.
2017;35:1216–26.
67. Bernstein CN, Rawsthorne P, Blanchard JF. Population-based
case-control study of measles, mumps, and rubella and inflam-
matory bowel disease. Inflamm Bowel Dis. 2007;13:759–62.
68. Martinelli M, Giugliano FP, Strisciuglio C, et al. Vaccinations
and immunization status in pediatric inflammatory bowel dis-
ease: a multicenter study from the pediatric IBD Porto Group of
the ESPGHAN. Inflamm Bowel Dis. 2020;26:1407–14.
69. Veereman-Wauters G, De Ridder L, Veres G, et al. Risk of
infection and prevention in pediatric patients with IBD: ESP-
GHAN IBD Porto Group commentary. J Pediatr Gastroenterol
Nutr. 2012;54:830–7.
70. Caldera F, Ley D, Hayney MS, et al. Erratum to: Optimizing
immunization strategies in patients with IBD. Inflamm Bowel
Dis. 2021;27: e9.
71. Nguyen HT, Minar P, Jackson K, et al. Vaccinations in
immunosuppressive-dependent pediatric inflammatory bowel
disease. World J Gastroenterol. 2017;23:7644–52.
72. Cullen G, Bader C, Korzenik JR, et al. Serological response to
the 2009 H1N1 influenza vaccination in patients with inflam-
matory bowel disease. Gut. 2012;61:385–91.
73. Shirai S, Hara M, Sakata Y, et al. Immunogenicity of quadri-
valent influenza vaccine for patients with inflammatory bowel
disease undergoing immunosuppressive therapy. Inflamm Bowel
Dis. 2018;24:1082–91.
74. Gisbert JP, Villagrasa JR, Rodr?′guez-Nogueiras A, et al. Effi-
cacy of hepatitis B vaccination and revaccination and factors
impacting on response in patients with inflammatory bowel
disease. Am J Gastroenterol. 2012;107:1460–6.
75. Cossio-Gil Y, Mart?′nez-Go′mez X, Campins-Mart?′ M, et al.
Immunogenicity of hepatitis B vaccine in patients with inflam-
matory bowel disease and the benefits of revaccination. J Gas-
troenterol Hepatol. 2015;30:92–8.
76. Jacobson DL, Bousvaros A, Ashworth L, et al. Immunogenicity
and tolerability to human papillomavirus-like particle vaccine in
girls and young women with inflammatory bowel disease.
Inflamm Bowel Dis. 2013;19:1441–9.
77. Pittet LF, Verolet CM, Michetti P, et al. High immunogenicity
of the pneumococcal conjugated vaccine in immunocompro-
mised adults with inflammatory bowel disease. Am J Gas-
troenterol. 2019;114:1130–41.
78. Fiorino G, Peyrin-Biroulet L, Naccarato P, et al. Effects of
immunosuppression on immune response to pneumococcal
vaccine in inflammatory bowel disease: a prospective study.
Inflamm Bowel Dis. 2012;18:1042–7.
79. Heijstek MW, Ott de Bruin LM, Borrow R, et al. Vaccination in
paediatric patients with auto-immune rheumatic diseases: a
systemic literature review for the European League against
Rheumatism evidence-based recommendations. Autoimmun
Rev. 2011;11:112–22.
80. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG clinical
guideline: preventive care in inflammatory bowel disease. Am J
Gastroenterol. 2017;112:241–58.
81. Mamula P, Markowitz JE, Piccoli DA, et al. Immune response to
influenza vaccine in pediatric patients with inflammatory bowel
disease. Clin Gastroenterol Hepatol. 2007;5:851–6.
82. Debruyn J, Fonseca K, Ghosh S, et al. Immunogenicity of
influenza vaccine for patients with inflammatory bowel disease
on maintenance infliximab therapy: a randomized trial. Inflamm
Bowel Dis. 2016;22:638–47.
83. Lamb CA, Kennedy NA, Raine T, et al. British Society of
Gastroenterology consensus guidelines on the management of
inflammatory bowel disease in adults. Gut. 2019;68:s1-106.
84. Ferdinands JM, Gaglani M, Martin ET, et al. Waning vaccine
effectiveness against influenza-associated hospitalizations
among adults, 2015–2016 to 2018–2019, United States hospi-
talized adult influenza vaccine effectiveness network. Clin Infect
Dis. 2021;73:726–9.
85. El Omeiri N, Azziz-Baumgartner E, Thompson MG, et al.
Seasonal influenza vaccine effectiveness against laboratory-
J Gastroenterol
123
confirmed influenza hospitalizations—Latin America, 2013.
Vaccine. 2018;36:3555–66.
86. Matsumoto H, Ohfuji S, Watanabe K, et al. Booster influenza
vaccination does not improve immune response in adult
inflammatory bowel disease patients treated with immunosup-
pressives: a randomized controlled trial. J Gastroenterol.
2015;50:876–86.
87. Kimberlin DW, Whitley RJ. Varicella-zoster vaccine for the
prevention of herpes zoster. N Engl J Med. 2007;356:1338–43.
88. Dooling KL, Guo A, Patel M, et al. Recommendations of the
advisory committee on immunization practices for use of herpes
zoster vaccines. MMWR Morb Mortal Wkly Rep.
2018;67:103–8.
89. Harbecke R, Cohen JI, Oxman MN. Herpes zoster vaccines.
J Infect Dis. 2021;224:S429–42.
90. Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an
adjuvanted herpes zoster subunit vaccine in older adults. N Engl
J Med. 2015;372:2087–96.
91. Cunningham AL, Heineman TC, Lal H, et al. Immune responses
to a recombinant glycoprotein E herpes zoster vaccine in adults
aged 50 years or older. J Infect Dis. 2018;217:1750–60.
92. Kochhar GS, Desai A, Caldera FD, et al. Effectiveness of
recombinant zoster vaccine (RZV) in patients with inflammatory
bowel disease. Vaccine. 2021;39:4199–202.
93. Suzuki M, Dhoubhadel BG, Ishifuji T, et al. Serotype-specific
effectiveness of 23-valent pneumococcal polysaccharide vaccine
against pneumococcal pneumonia in adults aged 65 years or
older: a multicentre, prospective, test-negative design study.
Lancet Infect Dis. 2017;17:313–21.
94. Debruyn JCC, Hilsden R, Fonseca K, et al. Immunogenicity and
safety of influenza vaccination in children with inflammatory
bowel disease. Inflamm Bowel Dis. 2012;18:25–33.
95. Elkayam O, Bashkin A, Mandelboim M, et al. The effect of
infliximab and timing of vaccination on the humoral response to
influenza vaccination in patients with rheumatoid arthritis and
ankylosing spondylitis. Semin Arthritis Rheum. 2010;39:442–7.
96. Epidemiological information of rubella in Japan. In: National
institute of infectious diseases. https://www.niid.go.jp/niid/ja/
rubella-m-111/rubella-top/2145-rubella-related/8278-
rubella1808.html. Accessed 8 June 2022.
97. Pregnancy guidelines and recommendations by vaccine. In:
Centers for Disease Control and Prevention (CDC). https://
www.cdc.gov/vaccines/pregnancy/hcp-toolkit/guidelines.html.
Accessed 8 June 2022.
98. Mertz D, Geraci J, Winkup J, et al. Pregnancy as a risk factor for
severe outcomes from influenza virus infection: a systematic
review and meta-analysis of observational studies. Vaccine.
2017;35:521–8.
99. Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009
influenza A(H1N1) virus illness among pregnant women in the
United States. JAMA. 2010;303:1517–25.
100. Fell DB, Platt RW, Basso O, et al. The relationship between
2009 pandemic H1N1 influenza during pregnancy and preterm
birth: a population-based cohort study. Epidemiology.
2018;29:107–16.
101. Gunnes N, Gjessing HK, Bakken IJ, et al. Seasonal and pan-
demic influenza during pregnancy and risk of fetal death: a
Norwegian registry-based cohort study. Eur J Epidemiol.
2020;35:371–9.
102. Pasternak B, Svanstrom H, M?lgaard-Nielsen D, et al. Risk of
adverse fetal outcomes following administration of a pandemic
influenza A (H1N1) vaccine during pregnancy. JAMA.
2012;308:165–74.
103. Newsome K, Alverson CJ, Williams J, et al. Outcomes of infants
born to women with influenza A(H1N1)pdm09. Birth Defects
Res. 2019;111:88–95.
104. ACOG Committee Opinion No. 732: Influenza Vaccination
During Pregnancy. Obstet Gynecol. 2018; 131:e109–14.
105. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer
of anti-tumor necrosis factor agents in pregnant patients with
inflammatory bowel disease. Clin Gastroenterol Hepatol.
2013;11:286–92.
106. Julsgaard M, Kjeldsen J, Brock B, et al. Letter: vedolizumab
drug levels in cord and maternal blood in women with inflam-
matory bowel disease. Aliment Pharmacol Ther. 2018;48:386–8.
107. Rowan CR, Cullen G, Mulcahy HE, et al. Ustekinumab drug
levels in maternal and cord blood in a woman with Crohn’s
disease treated until 33 weeks of gestation. J Crohns Colitis.
2018;12:376–8.
108. Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations
of adalimumab and infliximab in mothers and newborns, and
effects on infection. Gastroenterology. 2016;151:110–9.
109. Bortlik M, Duricova D, Machkova N, et al. Impact of anti-tumor
necrosis factor alpha antibodies administered to pregnant
women with inflammatory bowel disease on long-term outcome
of exposed children. Inflamm Bowel Dis. 2014;20:495–501.
110. Duricova D, Dvorakova E, Hradsky O, et al. Safety of anti-Tnf-
alpha therapy during pregnancy on long-term outcome of
exposed children: a controlled, multicenter observation. Inflamm
Bowel Dis. 2019;25:789–96.
111. van der Woude CJ, Ardizzone S, Bengtson MB, et al. The
second European evidenced-based consensus on reproduction
and pregnancy in inflammatory bowel disease. J Crohns Colitis.
2015;9:107–24.
112. Nguyen GC, Seow CH, Maxwell C, et al. The Toronto con-
sensus statements for the management of inflammatory bowel
disease in pregnancy. Gastroenterology. 2016;150:734–57.
113. Furer V, Rondaan C, Heijstek MW, et al. 2019 update of
EULAR recommendations for vaccination in adult patients with
autoimmune inflammatory rheumatic diseases. Ann Rheum Dis.
2020;79:39–52.
114. Beaulieu DB, Ananthakrishnan AN, Martin C, et al. Use of
biologic therapy by pregnant women with inflammatory bowel
disease does not affect infant response to vaccines. Clin Gas-
troenterol Hepatol. 2018;16:99–105.
115. Moens A, van der Woude CJ, Julsgaard M, et al. Pregnancy
outcomes in inflammatory bowel disease patients treated with
vedolizumab, anti-TNF or conventional therapy: results of the
European CONCEIVE study. Aliment Pharmacol Ther.
2020;51:129–38.
116. De Lima A, Kanis SL, Escher JC, et al. Hepatitis B vaccination
effective in children exposed to anti-tumour necrosis factor
alpha in utero. J Crohns Colitis. 2018;12:948–53.
117. Beitins IZ, Bayard F, Ances IG, et al. The transplacental passage
of prednisone and prednisolone in pregnancy near term. J Pedi-
atr. 1972;81:936–45.
118. De Boer NKH, Jarbandhan SVA, De Graaf P, et al. Azathioprine
use during pregnancy: unexpected intrauterine exposure to
metabolites. Am J Gastroenterol. 2006;101:1390–2.
119. Jharap B, De Boer NKH, Stokkers P, et al. Intrauterine exposure
and pharmacology of conventional thiopurine therapy in preg-
nant patients with inflammatory bowel disease. Gut.
2014;63:451–7.
120. Zheng S, Easterling TR, Hays K, et al. Tacrolimus placental
transfer at delivery and neonatal exposure through breast milk.
Br J Clin Pharmacol. 2013;76:988–96.
121. Burrows DA, O’Neil TJ, Sorrells TL. Successful twin pregnancy
after renal transplant maintained on cyclosporine A immuno-
suppression. Obstet Gynecol. 1988;72:459–61.
122. Luu M, Benzenine E, Barkun A, et al. Safety of first year vac-
cination in children born to mothers with inflammatory bowel
disease and exposed in utero to anti-TNFa agents: a French
J Gastroenterol
123
nationwide population-based cohort. Aliment Pharmacol Ther.
2019;50:1181–8.
123. Kaneko K, Kawai T, Watanabe N, et al. Spontaneous recovery
from suppressed B cell production and proliferation caused by
intrauterine azathioprine exposure in the fetal period. Lupus.
2019;28:1027–8.
124. Cote′ CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of
prednisone and azathioprine administered to the mother during
pregnancy. J Pediatr. 1974;85:324–8.
125. Thomas C, Monteil-Ganiere C, Mirallie′ S, et al. A severe
neonatal lymphopenia associated with administration of aza-
thioprine to the mother in a context of Crohn’s disease. J Crohns
Colitis. 2018;12:258–61.
126. ACIP general best practice guidelines for immunization. In:
Centers for Disease Control and Prevention (CDC). https://
www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html.
Accessed 9 June 2022.
127. Losonsky GA, Mark Fishaut J, Strussenberg J, et al. Effect of
immunization against rubella on lactation products. II. Mater-
nal–neonatal interactions. J Infect Dis. 1982;145:661–6.
128. Krogh V, Duffy LC, Wong D, et al. Postpartum immunization
with rubella virus vaccine and antibody response in breast-
feeding infants. J Lab Clin Med. 1989;113:695–9.
129. Grillner L, Hedstro¨m CE, Bergstro¨m H, et al. Vaccination
against rubella of newly delivered women. Scand J Infect Dis.
1973;5:237–41.
130. Centers for Disease Control and Prevention (CDC). Transmis-
sion of yellow fever vaccine virus through breast-feeding—
Brazil, 2009. MMWR Morb Mortal Wkly Rep. 2010;59:130–2.
131. Traiber C, Coelho-Amaral P, Fonteles Ritter VR, et al. Infant
meningoencephalitis caused by yellow fever vaccine virus
transmitted via breastmilk. J Pediatr (Rio J). 2011;87:269–72.
132. Ben-Horin S, Yavzori M, Kopylov U, et al. Detection of
infliximab in breast milk of nursing mothers with inflammatory
bowel disease. J Crohns Colitis. 2011;5:555–8.
133. Matro R, Martin CF, Wolf D, et al. Exposure concentrations of
infants breastfed by women receiving biologic therapies for
inflammatory bowel diseases and effects of breastfeeding on
infections and development. Gastroenterology.
2018;155:696–704.
134. Fritzsche J, Pilch A, Mury D, et al. Infliximab and adalimumab
use during breastfeeding. J Clin Gastroenterol. 2012;46:718–9.
135. Drugs and Lactation Database (LactMed). In: NCBI Bookshelf.
https://www.ncbi.nlm.nih.gov/books/NBK501922/. Accessed 9
June 2022.
136. Hale TW. Hale’s medications and mothers’ milk 2021: a manual
of lactational pharmacology. 19th ed. New York: Springer
Publishing; 2021.
137. Constantinescu S, Pai A, Coscia LA, et al. Breast-feeding after
transplantation. Best Pract Res Clin Obstet Gynaecol.
2014;28:1163–73.
138. Skorpen CG, Hoeltzenbein M, Tincani A, et al. The EULAR
points to consider for use of antirheumatic drugs before preg-
nancy, and during pregnancy and lactation. Ann Rheum Dis.
2016;75:795–810.
139. Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory
bowel disease in pregnancy clinical care pathway: a report from
the American Gastroenterological Association IBD parenthood
project working group. Gastroenterology. 2019;156:1508–24.
140. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020
American College of Rheumatology guideline for the manage-
ment of reproductive health in rheumatic and musculoskeletal
diseases. Arthritis Rheumatol. 2020;72:529–56.
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