The effects of intra uterine exposure to Tumor Necrosis Factor alpha inhibitors in infants on the development of the immune system

Relapse of inflammatory bowel disease (IBD) activity during conception and
pregnancy is associated with a negative pregnancy outcome; prematurity and low
birth weight. Therefore disease remission during this period is of utmost
importance and it is advised to maintain drugs such as Anti- Tumor Necrosis
Factor alpha (anti TNFα), thiopurines and 5-aminosalicylic acid. IBD is a
disease often diagnosed in the reproductive years and most often diagnosed
before the first pregnancy. With a disease prevalence of 5-500 per 100000, this
means a considerable number of infants are born to mothers with IBD and are
possibly exposed to these drugs. Most IBD drugs are of low risk during
pregnancy, since no increase of congenital malformations has been reported so
far. However the effects on the developing immune system, after intra-uterine
exposure, remain unknown. Anti-TNF drugs are increasingly used in the treatment
of IBD. These drugs are effectively transferred through the placenta resulting
in high levels in the new-borns. Some anti-TNF drugs might even be detectable
after one year of age. It is known that live vaccines must be avoided until the
levels of anti-TNF are undetectable, as there has been one report of an infant,
who died after a BCG vaccination associated with exposure to anti TNFα in
utero. In addition, some authors have observed a higher risk of infection,
hypogammaglobulinaemia, decreased response to vaccination, neutropenia and
changes in T and B cell phenotype in a small cohort of children. In small case
series following intra uterine exposure to thiopurines and other
immunosuppressive drugs a variety of immunological chances has also been
described. Since studies are scarce and most of the data were collected
retrospectively, there is an urgent need for prospective studies focussing on
the impact of exposure to biologicals, especially anti-TNFα, in utero on the
development of the immune system and the potential risk of clinical
complications.
During the Sars-Cov2 pandemic pregnant women with severe Coronavirus disease
2019 (COVID-19) are being treated with immunomodulating drugs, like
tocilizumab. Tocilizumab, a monoclonal anti-IL6 IgG antibody is also
effectively transferred through the placenta resulting in detectable levels in
the new-borns. As is the case with anti-TNFα, the effects on the developing
immune system, after intra-uterine exposure to tocilizumab or other
immunomodulating drugs, remain unknown. But given the potential severity of
COVID-19 in pregnant women and the increasing incidence of COVID-19 in pregnant
women there is an urgent need to gain more knowledge on the effect of these
drugs on the developing immune system and the need for follow up of these
infants.

Primary Objective
In order to assess the effects of anti TNFα on the development of adaptive and
innate immunity, children exposed to anti TNFα (with or without other
immunosuppressive drugs) will be compared to children exposed to
immunosuppressive drugs (but no anti-TNFα) to evaluate for differences in
1) immunological markers in relation to anti TNFα level (immunophenotyping of T
and B cell subsets ( in particular memory B cells at 12 months), presence of
hypogammaglobulianemia at 12 months)
2) the frequency of infections

Secondary Objective(s):
1) Differences in other immunological markers (response to routine vaccinations
(Tetanus, H Influenzae type B, Pertussis, pneumococcal conjugate vaccine),
immunoglobulin levels, presence of hypogammaglobulinemia at birth, 2 and 6
months, proteomics) between children exposed to anti TNFα (with or without
other immunosuppressive drugs) and children exposed to other immunosuppressive
drugs (but no anti-TNFα)

In order to further assess the effects of anti TNFα on the development of
adaptive and innate immunity, children exposed to anti TNFα (with or without
other immunosuppressive drugs) will be compared to children exposed to
immunosuppressive drugs (but no anti-TNFα) and to healthy children for
differences in:

2) innate and adaptive immunity by measuring immunological markers in relation
to anti TNFα level (immunophenotyping of T and B cell subsets, immunoglobulin
levels, presence of hypogammaglobulinemia, response to routine vaccinations
(Tetanus, H Influenzae type B, Pertussis, pneumococcal conjugate vaccine),
proteomics)
3) the frequency of infections
4) persistent /long term effects on the immune system by detecting epigenetic
changes in mononuclear cells
5) gut microbiome

Explorative objectives
Infants with intra uterine exposure to immunomodulating drugs because of
maternal COVID-19 will be included in a separate cohort. The objectives in this
cohort will be explorative and descriptive:
1) innate and adaptive immunity: measurement of immunological markers in
relation to concentration of immunomodulating drug: immunophenotyping of T and
B cell subsets, immunoglobulin levels, response to routine vaccinations
(Tetanus, H Influenzae type B, Pertussis, (including maternal pertussis
vaccination) pneumococcal conjugate vaccine), and proteomics.
2) the frequency of infections
3) persistent /long term effects on the immune system by detecting epigenetic
changes in mononuclear cells
4) gut microbiome analysis

Prospective longitudinal observational cohort study

Given the previous observations on possible immunosuppression it seems
necessary to perform follow up on the immunological function of all children
who have been exposed to immunosuppressive drugs in utero. Currently a national
or international guideline is lacking.In the Haaglanden Medical Center (HMC)
and the Juliana Children*s hospital (JKZ) a local guideline has been used for
follow up of children who have been exposed to anti-TNFα since 2013. In the
local HMC and JKZ guideline clinical follow up and performing immunological
studies of immunoglobulin levels, flow cytometry and vaccination response are
advised. For this study 1ml extra blood will be necessary at follow up visits.
For epigenetic studies 2 ml extra blood will be drawn at the regular follow up
visit at the age of 12 months. In most other hospitals follow up of children
who have been exposed to anti-TNFα is not part of standard care. In these
hospitals follow up and blood tests will be for study purposes. In children who
have been exposed to immunosuppressive drugs other than anti-TNF α the same
follow up will be performed. Currently there is no guideline concerning follow
up of children exposed to immunosuppressive drugs other than anti-TNF α.
However, there is some evidence of an effect of these drugs on the developing
immune system, underpinning the need for a control group of these patients and
supporting the idea that some follow up might be necessary in these patients as
well. Since there is currently no guideline, blood tests in these patients are
primarily for study purposes. A biopsy of the placenta will be taken and
preserved for pharmacological studies on immunosuppressive drugs and
immunological study purpose. Mothers who breastfeed will be asked for
breastmilk samples of 10 ml shortly after birth (nutritional intake of the
neonate has to be guaranteed) and twice between 2 and 6 months after birth.
Samples will be asked to collect just before and shortly after receiving
immunosuppressive medication for future pharmacological studies on
immunosuppressive drugs and immunological study purposes. For epigenetic
studies and proteomics cord blood and blood from healthy children aged 12
months, in whom a venipuncture for other reasons (such as minor surgery) is
necessary, will be drawn after parental informed consent. Blood volume
restrictions will comply with the recommendations of the European Commission
and the World Health Organization (WHO) guidelines. Collecting faecal and
breastmilk samples are non-invasive procedures.
Results will be used to guide immunosuppressive strategies during pregnancy in
women with IBD or COVID-19. If intra uterine exposure to anti-TNFα or other
immunomodulating drugs do indeed lead to abnormalities in the development of
the immune system, immunization schedules should potentially be adapted, and
long term follow up is warranted to study the presence of potential long-term
complications such as susceptibility to infection and immune mediated disease.
Given the aim of this study investigating minors is necessary.
No serious adverse events (SAE) are expected in the study, since it is an
observational non-interventional study.