Review Article

Obstetric Medicine
2020, Vol. 13(1) 5–13
The use of biologics for autoimmune ! The Author(s) 2019
Article reuse guidelines:
rheumatic diseases in fertility sagepub.com/journals-permissions
DOI: 10.1177/1753495X19841799
and pregnancy journals.sagepub.com/home/obm

May Ching Soh1,2,3 and Marcelo Moretto4,5

Abstract
In an age where autoimmune rheumatic diseases are successfully managed with biologics, their discontinuation in pregnancy is inadvisable without
careful forethought; maternal disease activity is associated with adverse pregnancy outcomes, which has long-term implications for both mother and
offspring. We aim to provide clinicians with the necessary tools to facilitate decision-making – when a biologic should be used, when it can be
discontinued in pregnancy if appropriate. The pathophysiology of these biologic molecules and their effect on fertility, pregnancy and parturition are
discussed. A summary of the 2016 international guidelines (European League Against Rheumatism and British Society in Rheumatology) on biologics in
pregnancy has been tabulated; more recent publications are discussed in depth. Data on transplacental-transfer ratios and breastmilk excretion rates
are also included. Biologic effects on organogenesis, their implications for the exposed infant in terms of infection risks and vaccination requirements
are included, and future directions for research proposed.

Keywords
Pregnancy, fertility, biologics, infection, vaccination

Date Received: 29 August 2018; accepted: 10 March 2019

What are ‘biologics’?
Unlike chemically synthesised drugs with a known structure, biolog-
ics are complex molecules largely composed of immunoglobulin (Ig)
G with modified Fc receptors or Fab fragments that bind and neu-
tralise their target molecule. Suffixes to names of biologics convey
specific information concerning their origin and structure, e.g. ‘-mab’
indicates monoclonal antibody (mAb), while ‘-cept’ denotes fusion of
a receptor to the Fc portion of human IgG1, ‘-ximab’ chimeric mAb
and ‘-zumab’ humanised mAb1 (Table 1).
A recent survey in Europe and the USA revealed that clinicians
concerned that anti-tumour necrosis factor (TNF) causes poor preg-
nancy outcomes have discouraged women from breastfeeding while
on an anti-TNF.2 With improved disease and pregnancy outcomes
associated with ongoing biologic (especially anti-TNF) use during
pregnancy, clinicians will therefore need to address these issues
with women of childbearing potential; discontinuation of biologics
during pregnancy is not advised without due consideration of the
potential risks and benefits.3,4
Pathophysiology of cytokines in fertility,
pregnancy and delivery
In brief, pregnancy is an immune-tolerant state of the feto-maternal
relationship in which T-helper (Th) cytokines play an important role.
Normally, Th2 (humoral immunity) predominates over Th1 (cell-
mediated immunity) in early gestation. This balance will shift to a
Th1-predominant state later in pregnancy.5,6
Inflammation can shift this balance towards a Th1 dominance,
resulting in a stronger cell-mediated response and cytokine produc-
tion. The Th1-predominant environment may lead to implantation
failure during in vitro fertilisation (IVF), recurrent fetal loss and
other features of placental insufficiency such as pre-eclampsia and/
or fetal growth restriction, often cumulating in preterm deliveries.7,8
TNF is associated with ovarian follicular and embryonic devel-
opment, activation of apoptotic pathways in fetal and placental cells
and is likely to play a role in stimulation of protective mechanisms to
repair damages when structural anomalies are present or to trigger
apoptotic processes to prevent the ongoing development of embryos
with structural anomalies.9,10 A marked increase of inflammatory
cytokines occurs during infection or inflammation and together
with other chemokines may play a role in preterm delivery.11,12
Women with recurrent pregnancy loss had significantly higher
Th1/Th2 ratios of interferon-c/interleukin (IL)-4, TNF-a/IL-4 and
TNF-a/IL-10 in CD3þ/CD8 T helper cells than controls.
1
Department of Rheumatology, Tauranga Hospital, Bay of Plenty District
Health Board, Tauranga, New Zealand
2
Department of Obstetrics and Gynaecology, Elizabeth Rothwell Building,
Waikato Hospital, Waikato District Health Board, Hamilton,
New Zealand
3
Women’s Health Academic Centre, King’s College London, London, UK
4
Department of Gynaecology, Hospital S~ao Lucas da Pontifıcia
Universidade Cat olica do Rio Grande do Sul, Porto Alegre, Brazil
5
Clınica Generar-Human Reproduction, Porto Alegre, Brazil
Corresponding author:
May Ching Soh, Department of Rheumatology, Tauranga Hospital, Bay of
Plenty District Health Board, 829 Cameron Road, Tauranga 3112,
New Zealand.
Email: mayching.soh@doctors.org.uk
6 Obstetric Medicine 13(1)
Table 1. Biologic agents classified according to mode of action, used in the treatment of rheumatic diseases.
Mechanism of action Drug
TNF inhibition Infliximab
Etanercept
Adalimumab
Certolizumab
Golimumab
IL-1 inhibition Anakinra
Canakinumab
Rilonacept
IL-6 inhibition Tocilizumab
Sarilumab
IL-17 inhibition Secukinumab
Ixekizumab
IL-12/23 inhibition Ustekinumab
Co-stimulatory blockade Abatacept
B-cell depletion/inhibition Rituximab
Belimumab
CTLA: cytotoxic T-lymphocyte-associated protein; CD: complementarity-determining; IL: interleukin; mAb: monoclonal antibody; TNF: tumour necrosis factor.
Moreover, those who experienced recurrent implantation failure after
IVF had a higher proportion of TNF-a producing CD3þ/CD8 cells
and higher Th1/Th2 ratios of TNF-a/IL-4 and TNF-a/IL-10 in
CD3þ/CD8 cells when compared with controls.13 In sub-fertile
women, the preconception ratio of TNF-a: IL-10 elevation has
been associated with high oocyte die-off ratio leading to lower success
rates during IVF.14,15 Adalimumab and immunoglobulins adminis-
tration have been associated with a reduction in the oocyte die-off
ratio and a greater chance of successful IVF.14–16
Overall, these observations suggest that targeting TNF-a may be
useful in treating women with recurrent pregnancy loss, recurrent
implantation failure and early, severe pre-eclampsia due to excessive
TNF-a production.17
During delivery, IL-1, IL-6, IL-8 and TNF levels peak.
Hypothetically, preterm labour is driven by overwhelming inflamma-
tion.12 Using an experimental lipopolysaccharide-induced preterm
model, IL-6 inhibitors induced prolongation of the gestational
period in mice (without adverse effects on pups) by significantly
inhibiting IL-6-induced prostaglandin E2 production.18 Therefore, it
is possible that in the future preterm, labour might be manageable by
a combination of biologic agents that specifically targeted these path-
ways of Th1 activation.
Clinical studies in men have reassuringly demonstrated that anti-
TNF agents do not impair sperm quality, and their use has not been
associated with teratogenicity in offspring.19,20
Biologics in early pregnancy
Biologics are large molecular structures not easily transported across
the placenta, particularly during the first trimester when fetal troph-
oblasts have yet to develop Fc receptors. Prior to 14 weeks’ gestation,
these large molecules reach the fetus by passive diffusion; hence, only
limited amounts reach the fetus during the period of embryogenesis
(up to 12 weeks).21
An early and controversial study mining of the Food and Drug
Administration database attempted to link anti-TNF use with
VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-
esophageal fistula, renal anomalies, and limb abnormalities)-
association congenital abnormalities.22 Individual anomalies that
form the VACTERL are not uncommon – hence, the need for
three or more features is needed for the diagnosis. The cases reported
in the study did not necessarily adhere to these criteria for the
Structure
Chimeric mAb to TNFa
Fusion protein with a modified Fc portion that binds to TNFa
Fully human monoclonal antibody to TNFa
mAb to TNFa antibody with a pegylated Fab portion without an Fc portion
Fully human mAb to TNFa
Recombinant and modified human IL-1 receptor antagonist
Human mAb that binds specifically to IL-1ß
Fusion Fc receptor that binds IL-1ß
Humanised mAb against IL-6 receptors
Recombinant mAb to IL-6 receptors
Human mAb neutralising the effects of IL-17A
Humanised mAb against IL-17A
Fully human mAb binding specifically to IL-12/IL23 inhibiting its activity
Fusion Fc region to extra-cellular domain of CTLA-4 modifying T-cell response
Chimeric mAb with murine anti-CD variable-sequence regions
Fully humanised mAb directed against soluble B-lymphocyte stimulator
diagnosis of VACTERL-association.23 Multiple studies subsequently
failed to find any association. Therefore, many national and interna-
tional guidelines support the use of anti-TNF agents in the first
trimester.24,25
Biologics in the second and
third trimesters
From the second trimester onwards, transplacental passage of bio-
logics is facilitated by Fc receptors on the fetal trophoblasts in
tandem with increasing transplacental transfer of maternal IgG as
pregnancy advances.26,27 Fetal IgG1 levels reach 50% of maternal
levels at 28–32 weeks’ gestation and increase exponentially afterwards
with maximal transfer in the final 4 weeks prior to delivery.28 Hence,
at delivery, cord blood levels of neonates exposed to some of the
biologics in late gestation are often much higher than maternal
serum drug levels (Table 2). Cord blood levels probably depend on
several factors: (i) The gestation in which the drug was used – the
later in pregnancy, the higher the cord drug levels; (ii) structure of the
Fc receptors – biologics with modified Fc receptors (i.e. the ‘-cepts’)
or those lacking an Fc portion altogether (e.g. certolizumab) are less
efficiently transported across the placenta and can often be used
throughout pregnancy or at least until 34 weeks’ gestation (e.g. eta-
nercept); (iii) half-life of the drug – the longer its half-life, the more
likely its passage across the placenta. There are limited published
studies on maternal to neonatal cord blood drug levels, with wide
variations in the very small cohorts sampled (Supplementary Table
1). In addition to the factors just listed, drug levels are also likely
influenced by the dosing interval (i.e. proximity of cord blood collec-
tion to administration of the last dose), dosages used (e.g. infliximab
can be dosed at 3–10 mg/kg at six to eight weekly intervals) and quite
possibly a multitude of other factors which remain poorly understood
(e.g. drug antibodies). Apart from certolizumab – virtually none of
which crosses the placenta – it remains unlikely that sufficient data
will ever be available concerning the exact amount of drug trans-
ferred to the neonate in utero. Available published data on cord
blood ratios have been summarised in Table 2. Furthermore, results
from animal studies should not be extrapolated since Fc receptors
and binding to neonatal trophoblasts may differ in animals.
Additionally, doses tested in laboratory animals often exceed the
Soh and Moretto 7

Table 2. The half-life of biologics and transplacental There were no reports of serious infections or developmental
transfer ratio. delay in a median follow-up of 18 months in neonates exposed to
either canakinumab or anakinra.48 However, data on vaccinations
Transplacental transfer were lacking, especially for neonates exposed in the third trimester.49
ratio (cord blood: Canakinumab has a transplacental transfer ratio of 2.11 (Table 2)
Drug t1=2 (days) References maternal drug level)a based on a single case where the cord canakinumab level was quan-
30,31,32,33,34 tified in an infant exposed until 34 weeks’ gestation and delivered at
Infliximab 8–10 2.23
35,36 39 weeks’ gestation.42 Hitherto, despite multiple clinical cases pub-
Etanercept 4–5 0.06
37,38,33,39,34 lished in the literature, anakinra has never been quantified in cord
Adalimumab 10–20 1.11
blood, and its transplacental transfer ratio is unknown.49–52 Since
Golimumab 12–15 NA –
40,33,41 anakinra has a half-life of 4–6 h compared to 22 days in canakinu-
Certolizumab 14 0.04
42 mab, it would seem reasonable to switch to anakinra in pregnancy if
Canakinumab 22 2.11
clinically indicated. Nevertheless, this short half-life entails daily
Tocilizumab 8–14 NA –
Ustekinumab 15–32 43
1.86 administration – rather than the four- to eight-weekly dosing interval
Abatacept 8–25 NA – of canakinumab. Hence, quantification of anakinra cord, maternal
Rituximab 18–22 44,45,46
1.69 and infant serum drug levels would be very helpful in informing
Belimumab 19–20 NA clinicians and prospective mothers on the preferred IL-1 inhibitor
to use in pregnancy. Although, cord serum quantification of anakinra
Note: NA: not available in human subjects. (as a slight modification of the natural IL-1 receptor antagonist) may
a
Mean value from cumulative studies. require a special test that prevents measuring both the native-
occurring IL-1 and anakinra together.
Cases of rilonacept use during pregnancy have yet to
recommended therapeutic doses used in human subjects26,29 (full data be published.
in Supplementary Table 1).
Hence, most studies on biologics use in pregnancy have focused
on clinical outcomes in exposed offspring.
IL-6 inhibitors: Tocilizumab and sarilumab
Since EULAR and BSR guidelines, there have been four additional
publications including registry data from the Tocilizumab manufac-
Latest updates on biologic agents turer’s global safety database.53,54,55,56 There have been 358 observed
While data remain limited, there are no signals of increased rates of pregnancies; the miscarriage rate was 22.9%, though concurrent
malformations or adverse pregnancy outcomes from the various reg- methotrexate (and occasionally leflunomide) use was prevalent in
istries set up specifically to look at the use of biologics in pregnancy. these cohorts.55,56 The livebirth rate was only 60%, due to a high
This review paper will endeavour to summarise the European rate of miscarriage and elective termination of pregnancy (18.4%) in
League Against Rheumatism (EULAR) and British Society in the cohorts studied. Six malformations were noted in the literature,
but without any distinguishing pattern of malformation to suggest
Rheumatology (BSR) guidelines 2016 shown in Table 324,25,47 and
teratogenicity.55,56 Tocilizumab use (>90% in four-weekly 8mg/kg
focus on developments since publication of the guidelines.
infusions) occurred predominantly during pre-conception and the
Additional information on breastmilk excretion is available in
first trimester, the drug being discontinued upon confirmation of
Supplementary Table 1.
pregnancy for the majority of women; tocilizumab was used
beyond the first trimester in only 15 pregnancies.55,56 Of the 15 neo-
IL-1 inhibitors: Canakinumab and anakinra nates exposed to tocilizumab later in pregnancy, none had their cord
tocilizumab level quantified.
An international retrospective study of IL-1 inhibitors anakinra and
A case series of two women showed that breastmilk concentra-
canakinumab was collated by members of the International Society
tions of tocilizumab peaked at day three post-administration but
for Systemic Autoinflammatory Diseases.48 Among the eight women
remained 1/500 to 1/1000 compared to maternal serum concentra-
exposed to canakinumab during pregnancy (plus five paternal expo-
tions. Both breastfed infants remained well; they received all routine
sures in the preconception period), no congenital abnormalities were
vaccinations, including Bacillus Calmette–Guérin (BCG) and rotavi-
observed. A single early miscarriage occurred at six weeks’ gestation
rus without problems.57
in a woman with refractory Cogan’s syndrome. The seven infants Studies on sarilumab use in pregnancy have yet to be published.
exposed to canakinumab were delivered at term with normal birth The manufacturer has set up an observational study (commencing 1
weights. Maternal disease remained in remission during pregnancy, February 2018) to recruit at least 300 women (and infants) for
despite only four women continuing on canakinumab beyond the the duration of pregnancy and one year follow-up post-partum
period of organogenesis (12 weeks’ gestation); others either stopped (see: https://clinicaltrials.gov/ct2/show/NCT03378219).
treatment or switched to anakinra (n ¼ 2). Four infants were
breastfed with no adverse effects. Follow-up time of infants varied
from seven days to four years. IL-17A inhibitors: Secukinumab and ixekizumab
In the same study, 23 women (and 6 men) were exposed to ana- An abstract on secukinumab in 66 pregnancies from the manufac-
kinra. A single case of renal agenesis and ectopic neurohypophysis turer’s global safety database was recently presented.58 There were
with growth hormone deficiency was noted in an infant whose mother 8 (12.1%) miscarriages, only 15 reported livebirths (without any con-
was treated from 9 weeks’ gestation till delivery; miscarriage at genital malformation) and 11 ongoing pregnancies. Close to half
12 weeks was recorded in a woman with active Cogan’s syndrome.48 (48%) had either an elective termination of pregnancy (without any
An abstract summarising the experience of five women who received listed cause) or information on the pregnancy was missing. No infor-
anakinra 100 mg into the third trimester found no malformations or mation was provided on 18 pregnancies with paternal exposure.
neonatal problems – including the three infants breastfed while their More recently, the experience of six women with psoriatic arthritis
mothers continued treatment with anakinra.49 on secukinumab during pregnancy was published as an abstract.59
8 Obstetric Medicine 13(1)

Table 3. Summary from EULAR points to consider and BSR guidelines for use during pregnancy.
Compatible with
Compatible for use in early pregnancy What gestation to discontinue breastfeeding

Agent EULAR BSR EULAR BSR EULAR BSR

Infliximab   Up to 20 weeks a
Stop at 16 weeks  
Etanercept   Up to 32 weeksa Not compatible with  
third trimester
Adalimumab   Up to 20 weeksa Not compatible with  
third trimester
Certolizumab   Use throughout Compatible with  No data
pregnancy third trimester
Golimumab No increased  Use another agent § No data  No data
malformations §
Anakinra  ‡ Only if no other   No data No data
options
Tocilizumab § Stop three Avoid §   No data No data
months prior ‡
Ustekinumab No increased – Use another agent § –  No data –
malformations §
Abatacept §  §  No data  No data No data
Rituximab  Can be used Stop six Not specified. †   No data No data
in exceptional months prior ‡
circumstances.
Belimumab No increased ‡ §   No data No data
malformations §

Note: : yes; : avoid/not recommended; No data: no published data available; §: insufficient evidence; †: neonatal B cell depletion if used in late pregnancy; ‡: insufficient
data to recommend drug, but unintentional exposure in the first trimester is unlikely to be harmful; NA: not applicable; – not covered by publication. EULAR: European
League Against Rheumatism; BSR: British Society in Rheumatology.
a
Can be used throughout pregnancy if indicated.

Secukinumab was discontinued upon confirmation of pregnancy and
no malformation, adverse maternal or neonatal outcomes occurred.
Maternal psoriatic arthritis remained in remission throughout preg-
nancy even off secukinumab.59
Similarly, data on ixekizumab from the manufacturer’s Safety
Systems (from seven clinical trials) were limited.60 Of 18 pregnancies,
8 (44.4%) resulted in livebirths and 5 (27.8%) in miscarriages or
elective terminations. One third of cases (n ¼ 6) had no recorded out-
come; it was unclear if this represented missing information or any
other adverse pregnancy outcome (e.g. stillbirth, late pregnancy loss,
etc.). No congenital malformations were reported. Of the 34 cases
with paternal exposure to ixekizumab, the vast majority (82.4%)
resulted in livebirths, without any cases of congenital malformation.
For all studies, information on concurrent disease-modifying anti-
rheumatic drugs (DMARD) use, duration of exposure to the IL-17A
inhibitor, breastfeeding or reasons for termination of pregnancy were
not available from the abstracts.
IL-12/23 inhibitor: Ustekinumab
Only 10 published papers and abstracts exist on the use of ustekinu-
mab during pregnancy. Two of the larger studies were derived from
Phase II studies on Crohn’s and psoriasis where ustekinumab was
discontinued upon confirmation of pregnancy.61,62 To date, 63 preg-
nancies with exposure to ustekinumab and known outcomes have
been described.61–70 Ustekinumab exposure occurred within three
months pre-conceptually or in the first trimester in the majority of
cases (59/63). Three women who were prescribed ustekinumab in the
third trimester also had good neonatal outcomes.63,68,69 While the
dosage and dosing intervals for ustekinumab were different in the
two of the women in the third trimester, their exposed offspring
remained well, and one even had all his ‘routine’ vaccinations without
problems.69 Overall, the livebirth rate across all published cases was
57.1%, and miscarriage was low at 15.9%. Miscarriage occurred at
12 weeks in one mother who was a heavy smoker.64 Only one case
had concurrent DMARD documented (i.e. azathioprine 100mg
daily). Since these were largely studies for Crohn’s and psoriasis,
some women may have been co-prescribed methotrexate. No reasons
were given for elective terminations, and no congenital malforma-
tions were reported. In the three cases involving third trimester expo-
sure, neither cord drug levels nor drug excretion into breastmilk were
quantified. In one case, despite ustekinumab use until 33 weeks’ ges-
tation, the mother was advised not to breastfeed the infant once she
resumed ustekinumab post-partum.68 None of the published cases
included paternal exposure to ustekinumab.
Human data from published studies do not appear to show an
increased risk of congenital malformations or miscarriages in the
exposed group. However, ustekinumab use in later pregnancy, trans-
placental transfer ratios, neonatal infections and responses to vacci-
nations were not recorded in the reports.
B-cell inhibitors: Belimumab
Most of the data on belimumab in pregnancy come from the phar-
maceutical company’s registry (see: http://www.bprgsk.com, current-
ly collecting information till 2021).71 Data on 66 pregnancies were
presented as an abstract in EULAR in 2013 related to an open label
Phase IV (long-term extension) clinical trial and showed a lower rate
of fetal loss in women treated with belimumab compared to placebo
and a livebirth rate of only 50%. Exact information on DMARDs
was not available; there were two cases of malformations – one
Dandy–Walker syndrome, and one bilaterally enlarged kidneys.72
Soh and Moretto
Presumably belimumab was discontinued upon confirmation of preg-
nancy; a large number of women also elected to have their pregnancy
terminated.72
Two additional published case reports that described the use of
belimumab beyond the first trimester of pregnancy did not demon-
strate any adverse outcomes in either mother or neonate.73,71 There is
a single published case report of maternal use of belimumab till 26
weeks’ gestation for severe systemic lupus erythematosus (SLE). At
40 weeks, she delivered a healthy male infant who subsequently
received all routine immunisations, including the rotavirus live vac-
cine at 6 weeks, without problems. He was also noted to mount a
good response to the pneumococcal vaccine at seven months of age.74
Abatacept
To date, 162 pregnancies with abatacept exposure in early pregnancy
(152 maternal and 10 paternal) have been described.75,76 The manu-
facturer’s registry revealed 151 maternal cases resulting in 86 (59.5%)
live births, 49 miscarriages (including one late loss at 21 weeks’ ges-
tation) and 19 elective terminations.76 Methotrexate was co-
administered in 13.2%. Seven cases (8.1%) of congenital malforma-
tions were recorded, including a single case of Down’s syndrome
(terminated at 17 weeks’ gestation due to spontaneous rupture of
membranes). The cases of malformation were isolated and did not
reflect a specific pattern of abnormalities.76 In all published cases of
maternal exposure, abatacept was discontinued upon confirmation of
pregnancy in the first trimester.75,76 Paternal exposure to abatacept
was not associated with any congenital anomalies in 9/10 ongoing
pregnancies.76 Information concerning the abatacept transplacental
transfer ratio, use in late pregnancy, childhood infections and vacci-
nations has yet to be published, though follow-up in 16 of the off-
spring exposed in early pregnancy has not demonstrated any immune
deficiencies.76
Childhood infections and vaccinations
If a biologic transfers efficiently across the placenta, and maternal use
has continued beyond 28 weeks, the exposed neonate is assumed to
have cord drug levels exceeding those of maternal serum drug levels.
The drug’s effects on the neonate will resemble those in the mother,
i.e. potent immunosuppression. Hence, similar precautions are
required as those taken in the case of the mother, e.g. prompt assess-
ment and treatment of infections, avoidance of live vaccines (at least
for the first six to seven months of the neonate’s life). These early
vaccines to be avoided include rotavirus and BCG in certain coun-
tries. All other non-live vaccines are safe to be administered.
There is emerging evidence that rotavirus vaccine is safe even in
infants exposed to maternal anti-TNF use in the third trimester.77
Nevertheless, many will recall the solitary published case of the
demise of a 4.5 month infant from disseminated non-caseating gran-
ulomatous disease (likely mycobacteria, though Ziehl–Neelsen stain-
ing for acid-fast bacilli and tuberculosis polymerase chain reaction
methods were deemed equivocal) following BCG vaccination at 3
months of age; the mother had received infliximab therapy through-
out pregnancy for her underlying Crohn’s, with her last infusion just
two weeks prior to delivery.78 Since TNF is integral to formation of
the granuloma, the question then arises as to whether BCG vaccina-
tion would be safe in neonates exposed in the third trimester to other
biologics (non-TNF-inhibitors).79,80 While there has been no signifi-
cant increase in neonatal infectious complications, carers should be
advised to remain vigilant for possible infections. With dampened
cytokine release in the presence of biologics, infants may not neces-
sarily exhibit the same signs of infection that clinicians are accus-
tomed to seeing.
9
The accumulation of biologics in offspring exposed in utero can
persist for up to a year. Much depends on the timing of drug admin-
istration, the degree of transplacental transfer and the drug’s half-life.
For instance, infliximab transfers efficiently starting from the second
trimester (transplacental transfer 2.23) and remains in the infant for a
median period of 7.3 months (although persisting up until 12 months
of age), while adalimumab has a transplacental transfer of 1.11 and
remains in the infant for a median of 4 months (Table 3).34 It is
postulated that ineffective clearance by the neonate’s immature retic-
uloendothelial system could contribute to the persistence of detect-
able drug levels in the infant’s serum.33 Recent research has
demonstrated that TNF remains in complex with adalimumab even
six months after discontinuation of the drug in adults.81 Whether
persistence of the drug has any adverse effect on the neonate has
not been adequately studied.
Primate studies have shown that TNFs (particularly superfamily
members lymphotoxin (LT)a and LTb) are dispensable for the devel-
opment of the neonatal immune system.11 Golimumab in primate
studies has not demonstrated a reduction in lymphoid tissue in
macaque offspring exposed in utero.11 This laboratory observation
seems to be borne out by clinical findings – infants exposed in utero
to anti-TNF agents are not at greater risk of infections, particularly if
anti-TNF agents are used as monotherapy.34,82
Nevertheless, there have been rare reports of neonatal neutrope-
nia attributed to anti-TNF exposure in utero (women were treated
with infliximab throughout pregnancy for inflammatory bowel dis-
ease (IBD)) – a known adverse effect of the drug.83,84 However, when
combined with other immunomodulators, in particular thiopurines,
one international cohort study involving 80 women with IBD
found that infants exposed to both thiopurines and anti-TNF
agents demonstrated a three-fold increased risk of childhood infec-
tions, compared to those whose mothers were on monotherapy with
an anti-TNF agent (relative risk 2.7; 95% confidence interval 1.09–
6.78; p ¼ 0.02).34 The Groupe d’Étude Thérapeutique des Affections
du Tube Digestif cohort (n ¼ 232) found that the risk of infection and
pregnancy complications was similar in two groups of pregnant
women with IBD which, coincidentally, had similar rates of thiopur-
ine use, although one group was on anti-TNF therapy and the other
served as non-TNF control (n ¼ 99).85
Rituximab causes B-cell depletion, has a high transplacental
transfer rate of 1.7 (Table 3) and is known to cause B-cell depletion
and transient cytopenias in exposed infants.44 In the global safety
database for rituximab, 21 women receiving rituximab (for a variety
of causes, including chemotherapy) had infants (n ¼ 11) with
recorded haematologic abnormalities that included B-cell depletion,
lymphopenia, neutropenia, anaemias and thrombocytopenias.86
Most spontaneously recovered in weeks to months post-partum,
apart from one fatal case of cerebral haemorrhage in an exposed
infant born with neonatal thrombocytopenia at 39 weeks’ gestation
following the administration of rituximab to her mother at her sev-
enth month of gestation for idiopathic thrombocytopaenic purpura.
Suppressed B-cell development and depletion have not given rise to
an increase in reported infectious complications amongst the affected
neonates, and most of those studied continue to exhibit a robust
immune response to vaccinations given.44–46,86
Women on biologics planning pregnancy should be made aware
that up until the present there have been no long-term outcome stud-
ies of children following in utero exposure. A theoretical risk has
always existed of exposed offspring developing autoimmune diseases
(e.g. anti-TNF-induced lupus), or being prone to allergies, malignan-
cies, etc. However, fear of the unknown in the long term needs to be
carefully balanced against the shorter term gain of maintaining
maternal health and well-being, thereby ensuring an optimal preg-
nancy outcome. Mothers with active inflammatory/autoimmune dis-
eases are at greater risk of disease flares leading to placental
10
Table 4. Practical points for consideration when facing a woman on a new biologic contemplating pregnancy.
1. The structure of the biologic and the likelihood of its passage across the placenta
2. When (or if) the biologic should be discontinued during pregnancy
3. Clinically significant and longer term effects on the neonate exposed in utero, the risks being balanced against the immediate short-term risk of a
maternal disease flare or active disease in pregnancy resulting in an adverse outcome, preterm delivery or longer term maternal morbidity
insufficiency clinically presenting as pre-eclampsia and fetal growth
restriction – factors that in turn lead to preterm deliveries (and all the
associated morbidity accompanying a preterm growth-restricted
infant).87,88 Moreover, the mothers themselves are also at risk since
long-term population-based studies have demonstrated that women
with autoimmune diseases (in particular SLE) who have pregnancies
complicated by placental insufficiency or maternal-placental syn-
drome and preterm delivery prior to 34 weeks’ gestation are at a
two-fold increased risk of accelerated development of cardiovascular
events and premature cardiovascular death.89–91
Breastfeeding
It is unlikely that comprehensive studies will ever be carried out on all
biologics and the peak time for breastmilk excretion from time of
drug administration (Supplementary Table 1). However, basic phys-
iology indicates that breastmilk is predominantly IgA (not IgG1); the
large structure of most biologic molecules means that they are less
likely to be excreted in breastmilk. Additionally, such large protein-
aceous molecules are denatured and digested by passage through the
infant’s gastrointestinal tract and therefore do not attain significant
levels in breastfed infants,47 and hence why parenteral administration
is necessary to achieve a therapeutic response. All breastmilk studies
completed to date have borne this out by consistently showing a
steady decline in breastfed infant drug levels despite ongoing mater-
nal dosing. These data seem fairly reassuring should a woman desire
to breastfeed even while taking a biologic.
Future directions
To date, published data seem largely reassuring: rates of congenital
anomalies in offspring exposed in utero are similar to those in the
general population, and they have achieved normal milestones in the
first few years of life without an increased prevalence of allergies or
life-threatening infections.
Although data concerning many newer biologics remain limited,
the knowledge base is expanding. Pharmaceutical companies are
encouraged to include pregnant women in drug trials, and pregnancy
registries have been established for various drugs.92
It is highly desirable that pharmaceutical companies will in future
invest in developing of biologics suitable for use in pregnancy.
Perhaps biologics could be created from IgG2 molecules instead –
the latter would give rise to minimal transfer compared to other IgG
molecules. Alternatively, an expansion of the current repertoire of
larger molecule biologics (e.g. certolizumab) whose size prohibits effi-
cient transplacental transfer or modification of Fc receptors that are
not conducive to transplacental transport would also be very wel-
come.28,93 Companies could also offer complimentary maternal
drug serum testing and cord blood testing for all infants exposed
and such data should be shared in their registries and freely accessible
to all clinicians caring for (and counselling) women who are pregnant
or planning pregnancy. Additional studies looking at the combined
effects of biologic agents and other immunomodulators such ashy-
droxychloroquine or sulfasalazine on the risk of infection in neonates
are required to further delineate the contributory immunosuppressive
effects of these drugs on the risk of infection in both mother
and neonate.
Obstetric Medicine 13(1)
Biosimilars are flooding the market. Studies looking at their
effects are therefore necessary given that it remains unclear how
(dis)similar these molecular structures are and what potential
impact they might have on pregnancy.
The ongoing accumulation and sharing of information on biolog-
ic use in pregnancy are of paramount importance. It is vital to publish
case reports of early biologic use in pregnancy to facilitate informa-
tion sharing.
In addition, the reporting of pregnancy complications and their
outcomes should be standardised. Little information can be gleaned
from published statements such as ‘delivery of a normal infant at
term’. Hence, the collaborations of rheumatologists, gastroenterolo-
gists, oncologists, neurologists, obstetricians, neonatologists and pae-
diatricians are crucial for more comprehensive data collection that
would benefit multiple subspecialties. Long-term studies to determine
the safety of these drugs in exposed offspring are urgently needed.
Would better disease control in pregnancy mean better long-term
outcomes for both mother and child? Collaborative efforts and the
establishment of long-term registries for both the disease and the
drugs they are exposed to are essential for a holistic view of how
these biologics influence pregnancy and perhaps even the
next generation.
Acknowledgements
The authors thanks to Mrs. Brina Roshd who proof-read and edited
this manuscript comprehensively.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
Ethical approval
Not applicable.
Informed consent
Not applicable.
Guarantor
MCS.
Contributorship
MM contributed to the sections on reproduction and fertility; MCS is
responsible for the concept and initial drafts of the manuscript.
Both authors have contributed to the drafting and approval of
the final version of the manuscript and have agreed to be accountable
for all aspects pertaining to the accuracy and integrity of the
entire manuscript.
Soh and Moretto
ORCID iD
May Ching Soh http://orcid.org/0000-0002-7160-7550
References
1. Lamberg L. A host of novel agents for treating psoriasis, psori-
atic arthritis stir interest. JAMA 2003; 289: 2779–2783.
2. Tincani A, Taylor P, Fischer-Betz R, et al. FRI0692 Anti-TNF
treatments for women with chronic inflammatory diseases: com-
paring attitudes and perceptions of physicians in Europe and the
US. Ann Rheum Dis 2018; 77: 865–865.
3. Ursin K, Lydersen S, Skomsvoll J, et al. THU0673 disease activ-
ity during and after pregnancy in women with psoriatic arthritis.
Ann Rheum Dis 2018; 77: 530–530.
4. F€orger F, Bandoli G, Luo Y, et al. FRI0119 Effect of discontin-
uing TNF inhibitors during pregnancy on the course of rheuma-
toid arthritis and juvenile idiopathic arthritis. Ann Rheum Dis
2018; 77: 604–604.
5. Chaouat G. The Th1/Th2 paradigm: still important in pregnan-
cy? Semin Immunopathol 2007; 29: 95–113.
6. Ghaebi M, Nouri M, Ghasemzadeh A, et al. Immune regulatory
network in successful pregnancy and reproductive failures.
Biomed Pharmacother 2017; 88: 61–73.
7. Challis JR, Lockwood CJ, Myatt L, et al. Inflammation and
pregnancy. Reprod Sci 2009; 16: 206–215.
8. Kalu E, Bhaskaran S, Thum MY, et al. Serial estimation of Th1:
th2 cytokines profile in women undergoing in-vitro fertilization-
embryo transfer. Am J Reprod Immunol 2008; 59: 206–211.
9. Toder V, Fein A, Carp H, et al. TNF-alpha in pregnancy loss
and embryo maldevelopment: a mediator of detrimental stimuli
or a protector of the fetoplacental unit? J Assist Reprod Genet
2003; 20: 73–81.
10. Robertson SA, Chin P-Y, Femia JG, et al. Embryotoxic cyto-
kines – potential roles in embryo loss and fetal programming.
J Reprod Immunol 2018; 125: 80–88.
11. Arsenescu R, Arsenescu V and de Villiers WJ. TNF-alpha and
the development of the neonatal immune system: implications for
inhibitor use in pregnancy. Am J Gastroenterol 2011;
106: 559–562.
12. Di Renzo GC, Tosto V and Giardina I. The biological basis and
prevention of preterm birth. Best Pract Res Clin Obstet Gynaecol
2018; 52: 13–22.
13. Kwak-Kim J. Increased T helper 1 cytokine responses by circu-
lating T cells are present in women with recurrent pregnancy
losses and in infertile women with multiple implantation failures
after IVF. Hum Reprod 2003; 18: 767–773.
14. Winger EE, Reed JL, Ashoush S, et al. Degree of TNF-alpha/IL-
10 cytokine elevation correlates with IVF success rates in women
undergoing treatment with Adalimumab (Humira) and IVIG.
Am J Reprod Immunol 2011; 65: 610–618.
15. Winger EE, Reed JL, Ashoush S, et al. Die-off ratio correlates
with increased TNF-alpha:IL-10 ratio and decreased IVF success
rates correctable with humira. Am J Reprod Immunol 2012;
68: 428–437.
16. Winger EE, Reed JL, Ashoush S, et al. Treatment with adalimu-
mab (Humira) and intravenous immunoglobulin improves preg-
nancy rates in women undergoing IVF. Am J Reprod Immunol
2009; 61: 113–120.
17. Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R, et al.
Tumor necrosis factor-alpha and pregnancy: focus on biologics.
An updated and comprehensive review. Clinic Rev Allerg
Immunol 2017; 53: 40–53.
18. Wakabayashi A, Sawada K, Nakayama M, et al. Targeting
interleukin-6 receptor inhibits preterm delivery induced by
inflammation. Mol Hum Reprod 2013; 19: 718–726.
11
19. Micu MC, Micu R, Surd S, et al. TNF-alpha inhibitors do not
impair sperm quality in males with ankylosing spondylitis after
short-term or long-term treatment. Rheumatology (Oxford)
2014; 53: 1250–1255.
20. Larsen MD, Friedman S, Magnussen B, et al. Birth outcomes in
children fathered by men treated with anti-TNF-alpha agents
before conception. Am J Gastroenterol 2016; 111: 1608–1613.
21. Hyrich KL and Verstappen SM. Biologic therapies and pregnan-
cy: the story so far. Rheumatology (Oxford) 2014; 53: 1377–1385.
22. Carter JD, Ladhani A, Ricca LR, et al. A safety assessment of
tumor necrosis factor antagonists during pregnancy: a review of
the Food and Drug Administration database. J Rheumatol 2009;
36: 635–641.
23. Østensen M. Are TNF inhibitors safe in pregnancy? Nat Rev
Rheumatol 2009; 5: 184–185.
24. Gotestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The
EULAR points to consider for use of antirheumatic drugs
before pregnancy, and during pregnancy and lactation. Ann
Rheum Dis 2016; 75: 795–810.
25. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on
prescribing drugs in pregnancy and breastfeeding-Part I: stan-
dard and biologic disease modifying anti-rheumatic drugs and
corticosteroids. Rheumatology (Oxford) 2016; 55: 1693–1697.
26. Kuo TT, Baker K, Yoshida M, et al. Neonatal Fc receptor: from
immunity to therapeutics. J Clin Immunol 2010; 30: 777–789.
27. Fouda GG, Martinez DR, Swamy GK, et al. The impact of IgG
transplacental transfer on early life immunity. Immunohorizons
2018; 2: 14–25.
28. Saji F, Samejima Y, Kamiura S, et al. Dynamics of immunoglo-
bulins at the feto-maternal interface. Rev Reprod 1999; 4: 81–89.
29. Chambers CD, Tutuncu ZN, Johnson D, et al. Human pregnan-
cy safety for agents used to treat rheumatoid arthritis: adequacy
of available information and strategies for developing post-
marketing data. Arthritis Res Ther 2006; 8: 215.
30. Vasiliauskas EA, Church JA, Silverman N, et al. Case report:
evidence for transplacental transfer of maternally administered
infliximab to the newborn. Clin Gastroenterol Hepatol 2006;
4: 1255–1258.
31. Mahadevan U, Terdiman JP, Church J. Infliximab levels in
infants born to women with inflammatory bowel disease.
Gastroenterology 2007; 132: A144.
32. Zelinkova Z, de Haar C, de Ridder L, et al. High intra-uterine
exposure to infliximab following maternal anti-TNF treatment
during pregnancy. Aliment Pharmacol Ther 2011; 33: 1053–1058.
33. 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—292.
34. Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations
of Adalimumab and Infliximab in Mothers and Newborns, and
Effects on Infection. Gastroenterology 2016; 151: 110–119.
35. Murashima A, Watanabe N, Ozawa N, et al. Etanercept during
pregnancy and lactation in a patient with rheumatoid arthritis:
drug levels in maternal serum, cord blood, breast milk and the
infant’s serum. Ann Rheum Dis 2009; 68: 1793–1794.
36. Berthelsen BG, Fjeldsoe-Nielsen H, Nielsen CT, et al. Etanercept
concentrations in maternal serum, umbilical cord serum, breast
milk and child serum during breastfeeding. Rheumatology
(Oxford) 2010; 49: 2225–2227.
37. Mahadevan U, Miller JK, Wolf DC. Adalimumab Levels
Detected in Cord Blood and Infants Exposed in Utero.
Gastroenterology 2011; 140: S-61–S-62.
38. Julsgaard M, Brown S, Gibson P, et al. Adalimumab levels in an
infant. Journal of Crohn’s & colitis 2013; 7: 597–598.
12
39. Zelinkova Z, van der Ent C, Bruin KF, et al. Effects of discon-
tinuing anti-tumor necrosis factor therapy during pregnancy on
the course of inflammatory bowel disease and neonatal exposure.
Clin Gastroenterol Hepatol 2013; 11: 318–321.
40. Mahadevan U, Abreu MT. 960 Certolizumab Use in Pregnancy:
Low Levels Detected in Cord Blood. Gastroenterology 2009; 136:
A–146.
41. Mariette X, Forger F, Abraham B, et al. Lack of placental trans-
fer of certolizumab pegol during pregnancy: results from CRIB, a
prospective, postmarketing, pharmacokinetic study. Ann Rheum
Dis 2018; 77: 228–233.
42. Egawa M, Imai K, Mori M, et al. Placental Transfer of
Canakinumab in a Patient with Muckle-Wells Syndrome. J
Clin Immunol 2017; 37: 339—341
43. 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: 376-3-78.
44. Klink DT, van Elburg RM, Schreurs MW, et al. Rituximab
administration in third trimester of pregnancy suppresses neona-
tal B-cell development. Clin Dev Immunol 2008; 2008: 271363.
45. Decker M, Rothermundt C, Hollander G, et al. Rituximab plus
CHOP for treatment of diffuse large B-cell lymphoma during
second trimester of pregnancy. The lancet oncology 2006;
7: 693–694.
46. Friedrichs B, Tiemann M, Salwender H, et al. The effects of
rituximab treatment during pregnancy on a neonate.
Haematologica 2006; 91: 1426–1427.
47. Soh MC, MacKillop L. Biologics in pregnancy - for the obste-
trician. The Obstetrician & Gynaecologist 2016; 18: 25–32.
48. Youngstein T, Hoffmann P, Gul A, et al. International multi-
centre study of pregnancy outcomes with interleukin-1 inhibitors.
Rheumatology (Oxford) 2017; 56: 2102–2108.
49. Smith CJF, Chambers C. FRI0107 Five successful pregnancies
with antenatal anakinra exposure. Ann Rheum Dis 2018; 77: 598.
50. Berger CT, Recher M, Steiner U, et al. A patient’s wish: anakinra
in pregnancy. Ann Rheum Dis 2009; 68: 1794–1795.
51. Chang Z, Spong CY, Jesus AA, et al. Anakinra use during preg-
nancy in patients with cryopyrin-associated periodic syndromes
(CAPS). Arthritis & rheumatology (Hoboken, NJ) 2014;
66: 3227–3232.
52. Ilgen U, Kucuksahin O. Anakinra use during pregnancy: Report
of a case with Familial Mediterranean Fever and infertility. Eur J
Rheumatol 2017; 4: 66–67.
53. Kaneko K, Sugitani M, Goto M, et al. Tocilizumab and preg-
nancy: Four cases of pregnancy in young women with rheuma-
toid arthritis refractory to anti-TNF biologics with exposure to
tocilizumab. Mod Rheumatol 2016; 26: 672–675.
54. Weber-Schoendorfer C, Schaefer C. Pregnancy outcome after
tocilizumab therapy in early pregnancy-a case series from the
German Embryotox Pharmacovigilance Center. Reprod Toxicol
2016; 60: 29–32.
55. Nakajima K, Watanabe O, Mochizuki M, et al. Pregnancy out-
comes after exposure to tocilizumab: A retrospective analysis of
61 patients in Japan. Mod Rheumatol 2016; 26: 667–671.
56. Hoeltzenbein M, Beck E, Rajwanshi R, et al. Tocilizumab use in
pregnancy: Analysis of a global safety database including data
from clinical trials and post-marketing data. Semin Arthritis
Rheum 2016; 46: 238–245.
57. Saito J, Yakuwa N, Takai C, et al. Tocilizumab concentrations in
maternal serum and breast milk during breastfeeding and a safety
assessment in infants: a case study. Rheumatology (Oxford)
2018; ePub ahead of print. DOI: 10.1093/rheumatology/key091.
58. Sullivan J, Warren RB, Reich K, et al. Secukinumab in pregnan-
cy: Outcomes from the global safety database (Abstract Number:
Obstetric Medicine 13(1)
257). Australasian College of Dermatologists 2017 New South
Wales, Australia, 2017.
59. Meroni M, Generali E, Guidelli GM, et al. THU0319 Overall
safety of 7-week secukinumab exposure during pregnancy in
women with psoriatic arthritis. Ann Rheum Dis 2018;
77: 377–378.
60. Feldman S, Pangallo B, Xu W, et al. Ixekizumab and pregnancy
outcome. Journal of the American Academy of Dermatology 2017;
76: AB419.
61. Schaufelberger BW, Horn E, Cather JC, et al. Pregnancy out-
comes in women exposed to ustekinumab in the psoriasis clinical
development program. Journal of the American Academy of
Dermatology 2014; 70: AB178.
62. Scherl E, Jacobstein D, Murphy C, et al. A109 pregnancy out-
comes in women exposed to Ustekinumab in the Crohn’s disease
clinical development program. Journal of the Canadian
Association of Gastroenterology 2018; 1: 166.
63. Andrulonis R, Ferris LK. Treatment of severe psoriasis with
ustekinumab during pregnancy. Journal of drugs in dermatology:
JDD 2012; 11: 1240.
64. Fotiadou C, Lazaridou E, Sotiriou E, et al. Spontaneous abor-
tion during ustekinumab therapy. J Dermatol Case Rep 2012;
6: 105–107.
65. Sheeran C, Nicolopoulos J. Pregnancy outcomes of two patients
exposed to ustekinumab in the first trimester. Australas J
Dermatol 2014; 55: 235–236.
66. Alsenaid A, Prinz JC. Inadvertent pregnancy during ustekinu-
mab therapy in a patient with plaque psoriasis and
impetigo herpetiformis. J Eur Acad Dermatol Venereol 2016;
30: 488–490.
67. Rocha K, Piccinin MC, Kalache LF, et al. Pregnancy during
Ustekinumab Treatment for Severe Psoriasis. Dermatology
(Basel, Switzerland) 2015; 231(2): 103–104.
68. Galli-Novak E, Mook SC, Büning J, et al. Successful pregnancy
outcome under prolonged ustekinumab treatment in a patient
with Crohn’s disease and paradoxical psoriasis. Journal of the
European Academy of Dermatology and Venereology 2016; 30:
e191—e192.
69. Cortes X, Borrás-Blasco J, Antequera B, et al. Ustekinumab
therapy for Crohn’s disease during pregnancy: a case report
and review of the literature. Journal of Clinical Pharmacy and
Therapeutics 2017; 42: 234–236.
70. Lund T, Thomsen SF. Use of TNF-inhibitors and ustekinumab
for psoriasis during pregnancy: A patient series. Dermatol Ther
2017; 30. ePub ahead of print. DOI: 10.1111/dth.12454.
71. Danve A, Perry L, Deodhar A. Use of belimumab throughout
pregnancy to treat active systemic lupus erythematosus-A case
report. Semin Arthritis Rheum 2014; ePub ahead of print. DOI:
10.1016/j.semarthrit.2014.05.006.
72. Powell M, Hill D, Eudy A, et al. OP0041 Pregnancy Outcomes
for Systemic Lupus Erythematosus (SLE) Subjects with
Conception during Belimumab Intravenous (IV) and
Subcutaneous (SC) Placebo-Controlled Clinical Trials and
Long Term Extension Trials. Ann Rheum Dis 2014; 73: 75–76.
73. Emmi G, Silvestri E, Squatrito D, et al. Favorable pregnancy
outcome in a patient with systemic lupus erythematosus treated
with belimumab: A confirmation report. Semin Arthritis Rheum
2016; 45: e26—e27.
74. Bitter H, Bendvold AN, Ostensen ME. Lymphocyte changes and
vaccination response in a child exposed to belimumab during
pregnancy. Ann Rheum Dis 2018; ePub ahead of print. DOI:
10.1136/annrheumdis-2018-213004.
75. Ojeda-Uribe M, Afif N, Dahan E, et al. Exposure to abatacept or
rituximab in the first trimester of pregnancy in three women with
autoimmune diseases. Clin Rheumatol 2013; 32: 695–700.
Soh and Moretto
76. Kumar M, Ray L, Vemuri S, et al. Pregnancy outcomes follow-
ing exposure to abatacept during pregnancy. Semin Arthritis
Rheum 2015; 45: 351–356.
77. Bond SJ, Young L, Poulsen K, et al. FRI0141 Vaccination deci-
sions and incidence of neonatal infections in mothers exposed to
biologicals during pregnancy. Ann Rheum Dis 2018; 77: 614–615.
78. 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. Journal of Crohn’s & Colitis 2010;
4: 603–605.
79. Silva D, Silva MVD, Barros CCO, et al. TNF-alpha blockade
impairs in vitro tuberculous granuloma formation and down
modulate Th1, Th17 and Treg cytokines. PloS one 2018; 13:
e0194430. ePub ahead of print. DOI: 10.1371/journal.
pone.0194430.
80. Ehlers S. Tumor necrosis factor and its blockade in granuloma-
tous infections: differential modes of action of infliximab and
etanercept? Clinical infectious diseases : an official publication of
the Infectious Diseases Society of America 2005; 41 Suppl
3: S199–S203.
81. l’Ami MJ, Berkhout LC, Nurmohamed MT, et al. THU0211 Six
months after treatment discontinuation tnf is still in complex
with adalimumab. Ann Rheum Dis 2018; 77: 325.
82. Mahadevan U, Martin CF, Sandler RS, et al. 865 PIANO: A
1000 Patient Prospective Registry of Pregnancy Outcomes in
Women With IBD Exposed to Immunomodulators and
Biologic Therapy. Gastroenterology 2012; 142(5): S–149.
83. Sebastian S, Ashton K, Houston Y, et al. Anti-TNF therapy
induced immune neutropenia in Crohn’s disease- report of 2
cases and review of literature. J Crohns Colitis 2012; 6: 713–716.
84. Guiddir T, Fremond ML, Triki TB, et al. Anti-TNF-alpha ther-
apy may cause neonatal neutropenia. Pediatrics 2014; 134:
e1189—e1193.
85. Seirafi M, de Vroey B, Amiot A, et al. Factors associated with
pregnancy outcome in anti-TNF treated women with
13
inflammatory bowel disease. Aliment Pharmacol Ther 2014;
40(4): 363–373.
86. Chakravarty EF, Murray ER, Kelman A, et al. Pregnancy out-
comes after maternal exposure to rituximab. Blood 2011;
117: 1499–1506.
87. Skorpen CG, Lydersen S, Gilboe I-M, et al. Influence of disease
activity and medications on offspring birth weight, pre-eclampsia
and preterm birth in systemic lupus erythematosus: a population-
based study. Ann Rheum Dis 2018; 77: 264–269.
88. Soh MC, Nelson-Piercy C. High-risk pregnancy and the rheuma-
tologist. Rheumatology 2015; 54: 572–587.
89. Soh MC, Nelson-Piercy C, Dib F, et al. Association between
pregnancy outcomes and cardiovascular deaths in women with
systemic lupus erythematousus utilising Swedish population reg-
istries. Arthritis & rheumatology (Hoboken, NJ) 2015;
67: 2376–2382.
90. Soh MC, Dib F, Nelson-Piercy C, et al. Maternal-placental syn-
drome and future risk of accelerated cardiovascular events in
Parous Swedish women with systemic lupus erythematosus - a
population-based retrospective cohort study with time-to-event
analysis. Rheumatology (Oxford) 2016; Jul 55: 1235–1242.
91. Soh MC, Nelson-Piercy C, Westgren M, et al. Do adverse preg-
nancy outcomes contribute to accelerated cardiovascular events
seen in young women with systemic lupus erythematosus? Lupus
2017; 26: 1351–1367.
92. Kavanaugh A, Cush JJ, Ahmed MS, et al. Proceedings from the
American College of Rheumatology Reproductive Health
Summit: the management of fertility, pregnancy, and lactation
in women with autoimmune and systemic inflammatory diseases.
Arthritis Care Res (Hoboken) 2015; 67: 313–325.
93. Malek A. Role of IgG antibodies in association with placental
function and immunologic diseases in human pregnancy. Expert
Review of Clinical Immunology 2013; 9: 235–249.