Safety of New Biologics (Vedolizumab and Ustekinumab) and Small Molecules (Tofacitinib) During Pregnancy: A Review
Javier P. Gisbert1 · María Chaparro1

© Springer Nature Switzerland AG 2020

Abstract
Two new biological drugs (vedolizumab and ustekinumab) and one small molecule (tofacitinib) have been recently approved for the treatment of inflammatory bowel disease. Therefore, we must be familiar with the safety of these “new” drugs dur- ing pregnancy and breastfeeding. In the present article, we critically review available data on the safety of new biologics (vedolizumab and ustekinumab) and small molecules (tofacitinib) during pregnancy and breastfeeding, with special focus on women with inflammatory bowel disease. Bibliographical searches (MEDLINE) up to April 2020 were performed. The timing and mechanisms of placental transfer of vedolizumab and ustekinumab are expected to be similar to anti-TNF agents. Animal studies show no evidence of adverse effects on pre- or post-natal development after administration of vedolizumab and ustekinumab. Just a few studies including patients treated with vedolizumab or ustekinumab during pregnancy have been published, reporting uneventful pregnancies in most cases. The clinical programme of both drugs and post-marketing stud- ies showed no new safety concerns. Due to the expected safety of vedolizumab and ustekinumab during pregnancy, it may be recommended to plan the final pregnancy dose approximately 8 or 12 weeks, respectively, before the estimated date of delivery. Live vaccines should be avoided for up to a year in children exposed in utero to vedolizumab or ustekinumab unless drug elimination has been documented. Miniscule amounts of vedolizumab and ustekinumab are transferred to breast milk, so breastfeeding is probably safe. There is no evidence of adverse effect of vedolizumab or ustekinumab paternal exposure. Regarding tofacitinib, it is reasonable to assume that this molecule crosses the placenta from the beginning of pregnancy. In animal studies, tofacitinib was feticidal and teratogenic in rats and rabbits, although at exposures many times greater than the standard human dose. Reported outcomes of pregnancy cases identified from tofacitinib randomised controlled trials, post-approval and non-interventional studies, and spontaneous adverse-event reporting appear similar to those observed in the general population. Nevertheless, at present, the use of tofacitinib during pregnancy should be avoided. Although no human studies have reported outcomes of breastfeeding with small molecules such as tofacitinib, this drug is present in lactating rat milk so, at present, breastfeeding should be avoided. Pregnancy among patients with paternal exposure to tofacitinib appears to be safe. In summary, we can conclude that new biologic agents (vedolizumab and ustekinumab) and small molecules (tofacitinib) should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother and unborn child.

*
[email protected]
1 Gastroenterology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Diego de León, 62, 28006 Madrid, Spain

Key Points

Vedolizumab and ustekinumab are probably safe during pregnancy, although the experience is quite limited and therefore more studies are needed to confirm it
Breastfeeding is probably safe in mothers under vedoli- zumab or ustekinumab treatment
The use of tofacitinib during pregnancy is contraindi- cated

1Introduction

Most women with inflammatory bowel disease (IBD)— Crohn’s disease and ulcerative colitis—or other inflamma- tory/immune-mediated diseases are affected during their peak reproductive years. The issues of greatest concern during consultation with women affected by IBD are the effects of the disease on the foetus and how treatment will affect conception, pregnancy and breastfeeding. Therefore, providing appropriate information about conception and pregnancy is an essential component of the management of women with IBD [1–3].
Although a diagnosis of IBD per se does not pose a risk for pregnant women, having active disease is associated with poor obstetric outcomes, such as preterm delivery and low birth weight. As a result, effective control of disease activ- ity is vitally important during pregnancy [2]. In fact, it has been shown that the most important factor in the success of a pregnancy in patients with IBD is the state of disease activity [3]. A flare-up of disease during pregnancy may be more deleterious to neonatal outcome than any potential risk from the medication. Therefore, disease control should be optimised through medical therapy both before and during pregnancy.
The use of medication at conception and during preg- nancy is a cause of great concern for patients and the phy- sicians caring for them. Most women do not contemplate taking any sort of medication when trying to become preg- nant. Therefore, discussing options with the patient (and her partner if appropriate) before conception facilitates the formulation of a management plan [2].
Most of the medications prescribed for the treatment of IBD do not have significant adverse effects [4–6]. In par- ticular, most evidence for the use of biologics in pregnancy exists for anti-tumour necrosis factor (anti-TNF) antibodies, and the use of these agents has been demonstrated to be safe for the mother and the baby [2, 4–7].

However, two new biological drugs that target different inflammatory pathways have been approved for IBD in the last years: vedolizumab and ustekinumab [8]. Vedolizumab acts by blocking the interaction between an integrin present on the surface of gut-specific lymphocytes and a receptor on the vascular endothelium of the intestinal tract (α4β7 and MAdCAM-1, respectively) [9], and ustekinumab is directed against the common p40 subunit of interleukin (IL)-12 and IL-23 [10]. More recently, small molecules that act on sig- nal transduction within cells or modulate immune cell traf- fic, have become available; n particular, tofacitinib, a Janus kinase (JAK) inhibitor, has been recently approved for the treatment of ulcerative colitis [11]. Not surprisingly, due to the still limited experience with these drugs in IBD, their safety data, in particular in pregnancy, are very scarce. In fact, because of the unknown risks of vedolizumab/usteki- numab/tofacitinib to mother and child, randomised con- trolled trial protocols obviously exclude pregnant patients and require the use of highly effective contraception by women with child-bearing potential.
Fortunately, ongoing registries will hopefully provide, in the near future, further insight into the benefit-risk profile of new biologics and tofacitinib during pregnancy. These include, among others, the PIANO registry (NCT00904878, a multicentre US registry of pregnancy in IBD), the Organi- zation of Teratology Information Services (OTIS) registry (NCT02678052, enrolling pregnant patients with IBD), a prospective ustekinumab exposure registry (NCT02103361, comprised of Crohn’s disease, psoriasis, and psoriatic arthri- tis patients), and the DUMBO Registry (NCT03894228, enrolling pregnant patients from 70 Spanish centres with IBD on any treatment, including vedolizumab, ustekinumab and tofacitinib, and following children for 4 years).
The aim of the present article is to critically review avail- able data on the safety of new biologics (vedolizumab and ustekinumab) and small molecules (tofacitinib) during preg- nancy and breastfeeding, with special focus on women with IBD.

2Search Strategy

Bibliographical searches were performed in the MEDLINE electronic database up to April 2020 based on the following words (all fields): (“pregnancy” OR “pregnant” OR “breast- feeding” OR “breast-feeding” OR “congenital abnormality” OR “congenital anomaly” OR “birth defect”) AND (vedoli- zumab OR ustekinumab OR tofacitinib). Articles published in any language were included. Reference lists from the arti- cles selected by electronic searching were examined in detail to further identify relevant studies. Abstracts of the articles selected in each of these multiple searches were reviewed, and those meeting the inclusion criteria (i.e., providing data

regarding the safety of the aforementioned drugs during pregnancy, especially in women with IBD) were recorded.

3Vedolizumab

Vedolizumab is a humanised immunoglobulin G1 (IgG1) monoclonal antibody directed against the gut-homing integ- rin, α4β7. α4β7 integrin is expressed on T cells, B cells, and NK cells as well as subsets of innate immune cells. It binds to mucosal addressin cell adhesion molecule (MAdCAM-1) expressed on the endothelium of the gastrointestinal tract and gut-associated lymphoid tissue [9].

3.1Role of MAdCAM‑1 During Pregnancy

Murine experiments have shown that MAdCAM-1 is expressed by maternal vessels during placental development and recruits α4β7-expressing cells of the macrophage/mono- cyte lineage, which are assumed to play a role in maternal/
foetal tolerance [12]. In humans, placental expression of MAdCAM-1 was confirmed, although it seems to be only expressed during the first trimester of pregnancy and is absent from the placenta at birth [13]. Therefore, blocking this α4β7 integrin–MAdCAM-1 interaction by vedolizumab might potentially affect pregnancy and lead to maternal and/
or foetal complications. Animal models have shown the importance of integrins during the formation of the placenta and embryogenesis [14]. In mice, null mutations in the α4 subunit gene cause dysfunctional formation of the placenta and consequently embryo death [15].

3.2Placental Transport of Vedolizumab

The timing and mechanisms of placental transfer of ved- olizumab are expected to be similar to that of other IgG1 antibodies. IgG antibodies are the only class of antibod- ies that significantly cross the human placenta and provide short-term passive immunity to the newborn. IgG antibod- ies are actively transported via Fc receptors on the syncy- tiotrophoblast and cannot cross the placenta by simple dif- fusion, because of their size (> 100 kDa). The absence of Fc-receptors in the first trimester implies that the foetus in this period is not exposed to IgG class monoclonal antibod- ies. Active transfer of IgG antibodies from mother to foetus begins in the second trimester and the rate increases as preg- nancy progresses, with the majority of transfer occurring during the third trimester [16, 17].
Several studies have demonstrated the placental transfer of anti-TNF biological agents in IBD [18, 19]. It is reason- able to assume that the transplacental passage of all the compounds containing the Fc fragment of IgG, including vedolizumab, is similar to that of anti-TNF and that the

concentrations of these drugs in the foetal circulation is min- imal at the beginning of pregnancy, during the organogenesis stage. Actually, the low rate of malformations reported after unintended exposure of the foetus to all biological agents, as will be reviewed in detailed below, supports this hypothesis.

3.3Safety During Pregnancy: Animal Studies with Vedolizumab

Although the role of α4β7 signalling in embryonic and infant development is unclear, animal studies using supra- therapeutic doses of vedolizumab showed no signs of tera- togenicity, stillbirth, impaired intrauterine growth, or altered post-natal physical development up to 6 months of age [20]. The potential effects of vedolizumab on development were assessed by standard preclinical toxicity studies in rabbits and cynomolgus monkeys [21, 22]. In rabbits, vedolizumab did not affect maternal net body weight or net gains, gravid uterine weights, or mean maternal food consumption, nor did it affect intrauterine growth or foetal survival. There were also no vedolizumab effects on embryo-foetal develop- ment compared to controls. Finally, a reproductive study of vedolizumab in pregnant primates has shown no evidence of any adverse effects on pre- or post-natal development after intravenous administration of vedolizumab at dose levels 20 times the equivalent of those recommended for humans [23].

3.4Experience in Inflammatory Bowel Disease Patients Treated with Vedolizumab

The characteristics of patients treated with vedolizumab dur- ing pregnancy, including both the pregnancy and the infant complications, in studies published in the literature, are sum- marised in Table 1. The experience includes 7 studies and 131 patients (with 141 pregnancies). Most of the studies were retrospective and without an appropriate control group and all of the patients were diagnosed with either Crohn’s disease or ulcerative colitis. As can be seen in Table 1, stud- ies reported uneventful pregnancies in most cases.
The Belgian study carried out by Moens et al. in 2019 stand among the included studies [24]. This was the first multicentre cohort study reporting on pregnancy outcomes in female patients treated with vedolizumab in clinical practice. Although this retrospective study did not include a control group, the authors observed complications with fre- quencies in the same range as those reported in previous his- torical case series with other biological agents [2]. Most of these complications, such as preterm delivery, small for ges- tational age, miscarriage and stillbirth, could be explained by underlying active IBD disease. In this relatively small cohort, the major confounding factor for poor pregnancy outcome was the presence of active disease at conception and during pregnancy. Regarding the congenital anomalies

described in this study (hip dysplasia, congenital pulmonary valve stenosis and Hirschsprung’s disease), no association was found between the mechanism of action of vedolizumab and the underlying molecular pathways of these malforma- tions. However, based on this study a possible causal rela- tionship between vedolizumab and the mentioned complica- tions cannot be excluded or confirmed.
More recently, and since the previously mentioned Bel- gian study was too small to draw firm conclusions and underlying active disease was a major confounding factor, a pan-European study was performed to increase the number of vedolizumab-exposed pregnancies and thus the statistical power [25]. The CONCEIVE study aimed to assess preg- nancy and child outcomes of vedolizumab-exposed pregnan- cies and to compare these results to pregnancies exposed to anti-TNF or unexposed to both immunomodulatory and biologics (controls). Seventy-nine pregnancies in 73 IBD women were included in this study, which is the largest study to date to report on pregnancy outcomes in IBD patients treated with vedolizumab. No significant difference in mis- carriage rates were found between groups (vedolizumab- exposed, anti-TNF exposed, and controls without biological or immunosuppressive treatment: 16% vs. 13% vs. 10%), even after excluding patients with reported active disease at any time point in pregnancy. The frequency of congenital anomalies was also comparable between groups. Finally, infants’ infection risk did not significantly differ between treatment groups. Although this study was controlled, it should be noted that the two control groups (anti-TNF exposed and not exposed to any treatment) were collected in two independent centres with a specialised IBD preg- nancy clinic that included standardised preconception con- sultation and pregnancy monitoring, whereas the follow-up of vedolizumab-exposed pregnancies varied according to standard clinical practice at each participating centre, ques- tioning whether the clinical care was different between the groups [26].
Another study including a control group was performed by Bar-Gil Shitrit et al. [27]. This prospective study included IBD women treated with vedolizumab (n = 21, 24 preg- nancies), anti-TNF agents or conventional therapy. All patients except for one were exposed to vedolizumab for at least 3 months before conception, and continued treatment throughout the third trimester, except for one who decided to stop treatment on week 14 without consultation. Gravid- ity, parity and infant outcome were similar between the 3 groups: vedolizumab, anti-TNF and conventional therapy.
In addition to published cases in the literature (summa- rised in Table 1), [73]aimed to assess pregnancy outcomes in females who received vedolizumab, analysing all preg- nancy data collected during the clinical programme (from May 2007 to June 2013) and in the post-marketing setting (up to November 2015) [23]. Across six studies, there were

27 pregnancies in female participants. Among 24 vedoli- zumab treated females (23 with Crohn’s disease or ulcerative colitis, and one healthy volunteer), there were 11 live births, five elective terminations, four spontaneous abortions and four undocumented outcomes. A congenital corpus callo- sum agenesis anomaly was reported in one live birth from a healthy volunteer with extensive obstetric history exposed to single-dose vedolizumab 79 days before the estimated con- ception (given the virtual elimination of vedolizumab at the estimated time of the corpus callosum organogenesis, mater- nal factors other than vedolizumab exposure may potentially provide an explanation for this congenital anomaly). Post- marketing reports recorded 81 pregnancies, resulting in four live births, 11 spontaneous abortions and 66 pregnancies that were ongoing or reported undocumented outcomes. Based on these results, the authors concluded that initial analysis, limited by sample size and follow-up, identified no new safety concerns for pregnancy outcomes in females exposed to vedolizumab.

3.5Serum Levels of Vedolizumab in the Newborn

Vedolizumab has a longer half-life than adalimumab or infliximab (25.5 days as compared to 7.7–9.5 days and 10–20 days, respectively) and would theoretically result in significant concentrations in the neonate, even if it is discon- tinued in the third trimester [28]. However, unlike the IgG1 anti-TNFs, for which cord and infant levels exceed those of the mother [18, 29], vedolizumab levels in the newborn have been demonstrated to be only half the maternal levels at time of delivery [30], as has been shown in the PIANO registry [31], where the median infant:maternal vedolizumab ratio among four mother–child pairs was 0.5 (range 0.4–0.8); furthermore, a low detectable vedolizumab concentration was found at the age of six months in one infant. Likewise, more recently, Julsgaard et al. found lower vedolizumab cord blood levels than maternal levels in two mother–child pairs [32].
Flanagan et al. presented a case series of five patients with IBD who were treated with vedolizumab during preg- nancy, confirming that neonatal levels of vedolizumab are lower than maternal levels at delivery [33]. This study was the first report of time to clearance in infants following intrauterine exposure. The vedolizumab levels were unde- tectable at 6–8 weeks in two infants, and at 15 weeks in one baby. These results indicate that both placental transfer of vedolizumab and infant time to clearance, respectively, may be potentially lower than those documented for anti-TNF monoclonal antibodies.
Previous studies in adult healthy volunteers have dem- onstrated that low serum concentrations of vedolizumab (< 10 µg/mL) are cleared at a much faster rate than the 25.5- day half-life of concentrations > 10 µg/mL [28]. Therefore,

following birth, with observed vedolizumab concentrations
< 10 µg/mL, the serum concentration of vedolizumab in infants is expected to be cleared before 25 days. This analy- sis is reassuring and encouraging to physicians and patients who continue vedolizumab treatment throughout preg- nancy. However, circulating serum levels of vedolizumab do not accurately reflect the degree of α4β7 saturation [8]. Therefore, the role of integrins in foetal development and its potential impact on altering gut lymphocyte trafficking in infants remains unknown.

3.6Should (and If So, When) Vedolizumab be Stopped During Pregnancy?

The general strategy for patients on anti-TNF therapy has been classically to withdraw treatment during the third trimester if disease control allows it, minimising neonatal drug levels. Initially, it was generally recommended even to stop anti-TNF agents during the second trimester (around week 20–22)—if the mother was in remission—in order to avoid intra-uterine exposure. More recently, however, with increasing post-marketing experience of the use of anti-TNF during pregnancy, most recent recommendations advise con- tinuing anti-TNF throughout pregnancy [6, 34].
As previously mentioned, the half-lives of infliximab and adalimumab at gestational weeks 24–26 are 7.7–9.5 and 10–20 days, respectively [23], whereas the half-life of ved- olizumab in non-pregnant individuals is longer, 25.5 days [35]. Consequently, assuming dosing according to the label, withholding vedolizumab administration during the third tri- mester would still result in substantial concentrations being present in the mother’s system as the third trimester begins, and would theoretically result in substantial concentrations in the foetus prior to delivery [31]. Thus, it is possible that drug clearance may take 6–12 months in the babies of moth- ers who stopped vedolizumab in the third trimester [36]. However, as has also been previously noted, vedolizumab levels in the newborn have been shown to be only half the maternal level at the time of delivery [30–33].
In summary, due to the expected safety of vedolizumab during pregnancy [37], it may be recommended to plan final pregnancy vedolizumab dose 6–10 weeks (i.e. approxi- mately 8 weeks) before the estimated date of delivery [34]. Undoubtedly, more experience is needed to confirm the safety of vedolizumab in IBD patients during pregnancy.

3.7Efficacy and Safety of Vaccination in Infants Exposed to Vedolizumab

Neonatal vaccinations are essential to prevent a number of serious and potentially deadly infections. The high rate of placental transfer in the third trimester means that the bio- logical agent can be present in the infant for several months

after birth. This raises concerns about immune system development, risk of infection and response to live vaccines. There have been case reports of adverse outcomes to live immunisations including a fatal case of disseminated Bacil- lus Calmette-Guerin (BCG) infection following vaccination in an infant with in utero exposure to infliximab [38]. Cur- rent guidelines recommend avoiding any live vaccinations (BCG, rotavirus, oral polio) for at least 6–12 months (the orally administered rotavirus vaccine is the only live vaccine that is administered before 6 months) unless anti-TNF serum levels in the infant are undetectable [39]. On the other hand, non-live vaccinations should be administered according to local immunisation schedules. Additionally, in utero expo- sure to anti-TNF drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children [40].
When feasible and as is customary in Europe, vedoli- zumab therapy was stopped during the second trimester of pregnancy. However, it has been suggested that applying identical rules to vedolizumab and anti-TNF therapy in preg- nancy may not be appropriate because vedolizumab has a longer half-life than anti-TNF agents. Therefore, discontinu- ation of vedolizumab in the second trimester may lead to significantly higher serum levels in the infant compared to infliximab, which theoretically may have implications for the administration of live-attenuated vaccines as well as the newborn’s risk of infections [23].
However, the response to hepatitis B vaccination was similar in 54 adults treated with vedolizumab as compared to placebo [41]. The response to oral cholera vaccination however was reduced, probably reflecting the gut selective mechanism of action of vedolizumab [41]. Finally, in utero exposure to a biological therapy (including anti-TNFs and also one vedolizumab treated patient) was not found to affect antibody titter concentrations against common vaccinations (Haemophilus influenzae B and tetanus toxin) [42].
In summary, in line with the recommendations regarding intrauterine exposure to anti-TNF treatment [43], it may be suggested that live vaccines should be avoided for up to a year in children exposed in utero to vedolizumab unless drug elimination has been documented.

3.8Safety of Vedolizumab During Breastfeeding

Regarding anti-TNFs, there is limited available data about breast milk levels, and although it has been reported that it is found in the mother’s breast milk at miniscule amounts, the concentration is considered too low to result in systemic immunosuppression of the child [44].
Low levels (< 300 μg/L) of vedolizumab were detected on day 28 post-partum in the milk of three of 11 cynomolgus monkeys that were treated with 100 mg/kg of vedolizumab, dosed every 2 weeks. In contrast, no drug was detected in

breast milk samples from any of the primates treated with 10 mg/kg vedolizumab [22, 45].
The first study to report that vedolizumab, similarly to infliximab and adalimumab, is excreted into women’s breast milk at low concentrations was performed by Julsgaard et al. in 2018 [46]. This study of five IBD patients demon- strated vedolizumab detectable at various concentrations in samples collected between 30 min and 14 days after ved- olizumab administration [46]. The peak concentration was only 0.318 μg/mL, equivalent to less than 1% of the corre- sponding serum concentration [46]. This is well under the recommended arbitrary cut-off value of 10% for excretion of drugs into breast milk. If the highest vedolizumab milk con- centration measured in any of the samples (0.318 mg/mL) is multiplied by the amount of milk ingested by the infant, approximately 150 mL per kilogram of bodyweight per day, the infant is estimated to receive only 0.048 mg vedolizumab per kilogram bodyweight per day. As expected, normal developmental milestones were recorded in all infants at the age of 3.5 to 10.0 months [46].
More recently, Lahat et al. measured vedolizumab in five lactating women who received vedolizumab [47]. Daily sequential vedolizumab measurement in breast milk follow- ing drug infusion allowed for a broader understanding of vedolizumab breast milk levels. It suggests that levels peak at 3–4 days following infusion to maximal levels of 480 ng/
ml, and then slowly subside. Notably, milk drug levels were minute and more than two orders less than its level in serum [47]. Intriguingly, although it was found that breast milk vedolizumab levels were much lower than serum levels, in some cases they were more than triple the previously pub- lished levels of infliximab in milk. This may be related to the fact that overall vedolizumab levels in serum are nearly ten times higher than those of infliximab [48].
Furthermore, the minute quantity of vedolizumab in breast milk is anticipated to undergo proteolysis in the stom- ach, and it may undergo degradation and finally excretion through the IgG Fc binding protein in the gastrointestinal tract, thereby having a negligible impact on the infant’s immune system [46, 47]. However, this assertion was not assessed herein directly, so further studies are warranted to address systemic effects, if any, of oral vedolizumab expo- sure on the suckling infant.
In summary, based on few small studies, the concen- trations of vedolizumab in breast milk are minute and are therefore unlikely to result in systemic or gastro-intestinal immune-suppression of the infant. Consequently, breast- feeding may be considered safe in mothers on vedolizumab therapy; however, it is evident that larger studies looking at the infant’s immune system and ability to cope with infec- tions are warranted [39].

3.9Safety in Pregnancy When the Father is Exposed to Vedolizumab

As previously mentioned, Mahadevan et al. [73] aimed to assess pregnancy outcomes in females who received vedoli- zumab, as well as in females whose partners received this drug, analysing all pregnancy data collected during the clini- cal programme of vedolizumab and in the post-marketing setting [23].
Of 19 pregnancies in partners of male recipients of ved- olizumab, there were 11 live births, two spontaneous abor- tions, three elective terminations and three undocumented outcomes [23]. There was no evidence of adverse effects of vedolizumab exposure on pregnancy outcome [23].

4Ustekinumab

The monoclonal antibody ustekinumab, which inhibits the p40 subunit of IL-12 and IL-23, has recently been intro- duced as an effective therapeutic option for the treatment of Crohn’s disease [49] and ulcerative colitis [50].

4.1Role of IL‑12 and IL‑23 During Pregnancy

Both IL-12 and IL-23, which are specifically blocked by ustekinumab, are implicated in the pathophysiology of IBD but also have been involved in uterine physiology since they have been related to impaired embryo implantation and sub- sequent development of the trophoblast [51]. IL-12 is an important cytokine in uterine angiogenesis and the vascular remodelling process. In pregnancy, both high and low con- centrations of IL-12 appear to be associated with early spon- taneous abortions [51, 52]. IL-12 is involved in regulation of trophoblast invasion and acts as an anti-invasive factor [53]. On the other hand, IL-12 at lower dose is required for local vascular remodelling during implantation [51]. Accord- ingly, elevated and possibly absent levels of IL-12 have been linked to impaired embryo implantation due to the effects of this cytokine on uterine physiology [51]. Additionally, in prematurely born infants, higher concentrations of IL-12 are associated with lower rates of foetuses that are small for ges- tational age [54]. Finally, in a study on cytokine profiles of trophoblast-antigen stimulated maternal lymphocytes in 36 women with a pregnancy complicated by intrauterine growth retardation, high levels of IL-12 and, interestingly, low levels of IL-23 compared to 22 women without intrauterine growth retardation were observed [55]. In this regard, a study in human decidual samples showed that IL-23 regulates the function of human decidual immune cells [56]. Moreover, expression of IL-23 was increased in deciduae and periph- eral blood in women with recurrent spontaneous abortion compared to controls [57].

4.2Placental Transport of Ustekinumab

As previously mentioned, it is reasonable to assume that the transplacental passage of all the compounds contain- ing the Fc fragment of IgG (including vedolizumab and ustekinumab) is similar to that of anti-TNFs and that the concentrations of all these biologics in the foetal circulation is minimal at the beginning of pregnancy, during the organo- genesis stage. Accordingly, the transplacental transport of ustekinumab is minor until the end of the second quarter of pregnancy due to the characteristic large size of IgG [58]. As previously noted, IgG is actively transported from mother to foetus across the placenta by the neonatal Fc receptor FcRn; this process begins at week 16 of gestation, but the majority of IgG is acquired by the foetus during the last 4 weeks of pregnancy [16].

4.3Safety During Pregnancy: Animal Studies with Ustekinumab

An initial report on an IL 12/23 inhibitor similar to usteki- numab described masculinisation effects on female monkeys whose mothers were treated with this medication [59]. On the other hand, a study of ustekinumab treatment during pregnancy and nursing in macaques showed the medica- tion to be safe for foetuses and neonates regarding mortal- ity, growth, sexual and morphological development, and immunological development [58]. In conclusion, this lim- ited experience suggests that administration of high doses of ustekinumab during pregnancy in the cynomolgus macaque produce no adverse effects on the pregnant females or their infants.

4.4Experience in Non‑inflammatory Bowel Disease Patients Treated with Ustekinumab

Most safety data with ustekinumab come from women using this drug to treat psoriasis. The characteristics of psoriasis patients treated with ustekinumab during pregnancy, includ- ing both the pregnancy and the infant complications, in stud- ies published in the literature, are summarised in Table 2. The experience includes 11 studies and 21 patients (with 27 pregnancies). All of the studies were retrospective and without an appropriate control group. Studies reported une- ventful pregnancies in most cases. Accordingly, at present, most dermatologists tend to consider ustekinumab as a safe drug during pregnancy [60]. Similarly, the European League Against Rheumatism (EULAR) suggests that the use of ustekinumab during pregnancy, based on current evidence, does not indicate an increased rate of congenital malforma- tions [61].

4.5Experience in Inflammatory Bowel Disease Patients Treated with Ustekinumab

In IBD, higher ustekinumab doses are generally prescribed compared with the dermatological and rheumatological indi- cations. Thus, the safety results observed in psoriasis or pso- riatic arthritis patients may not be necessarily extrapolated to those with IBD. The characteristics of IBD patients treated with ustekinumab during pregnancy in studies published in the literature are summarised in Table 2. The experience includes four studies and four patients (one in each study). All of the studies were retrospective and without an appro- priate control group. Studies reported uneventful pregnan- cies in three cases, and one miscarriage (at 8 weeks of ges- tation); in one case no infant complications were reported.

4.6Serum Levels of Ustekinumab in the Newborn

In humans, ustekinumab concentrations in cord blood were higher than maternal serum levels, similar to the experi- ence with anti-TNF agents [62]. In a woman with Crohn’s disease, who was treated with ustekinumab until week 30 of pregnancy, the cord blood ustekinumab level was markedly higher than the measured maternal serum drug level [63].

4.7Should (and If So, When) Ustekinumab be Stopped During Pregnancy?

As it was the case with vedolizumab, due to the expected safety of ustekinumab during pregnancy [37], it may be sug- gested to plan final pregnancy ustekinumab dose approxi- mately 8–12 weeks before the estimated date of delivery (depending on the ustekinumab time schedule that is being administered to the patient). However, it is clear that addi- tional studies are needed to confirm the safety of usteki- numab during pregnancy.

4.8Efficacy and Safety of Vaccination in Infants Exposed to Ustekinumab

In utero exposure to a biological therapy (including anti- TNFs, vedolizumab or ustekinumab) was not found to affect antibody titter concentrations against common vaccinations (Haemophilus influenzae type B and tetanus toxin) in a study of 153 women exposed to biologics, although this study only included two patients treated with ustekinumab [42]. Current guidelines recommend avoiding any live vaccination for at least 6–12 months unless anti-TNF serum levels in the infant are undetectable [39]. In line with the recommendations regarding intrauterine exposure to anti-TNF treatment [43], it may be suggested that live vaccines should be avoided for up to a year in children exposed in utero to ustekinumab unless drug elimination has been documented.

4.9Safety of Ustekinumab During Breastfeeding

Previous studies on macaques have shown that there is a very small amount of ~ 1/1000th of the serum blood concentra- tion of ustekinumab in breast milk [58]. More recently, a study conducted in humans detected low ustekinumab levels in the breast milk of four of six women treated with this drug for IBD (maximum 1.57 μg/mL) [64]. Finally, in a woman with Crohn’s disease who was treated with ustekinumab until week 30 of pregnancy, the trough level in the breast milk after re-initiating post-partum ustekinumab therapy was ini- tially in the same range as the corresponding serum trough level, and then decreased during maintenance therapy [63].
As it was stated for vedolizumab, the minute quantity of ustekinumab in breast milk is assumed to undergo proteoly- sis in the stomach, and it may undergo degradation and finally excretion in the gastrointestinal tract through the IgG Fc bind- ing protein, thereby having a negligible impact on the infant’s immune system. However, this conclusion has not been directly demonstrated, so further studies are needed to confirm the aforementioned safety of ustekinumab during breastfeeding.
In summary, based on very limited experience, the con- centrations of ustekinumab in breast milk seem to be minute and are therefore unlikely to result in immune-suppression of the infant. Thus, although breastfeeding is probably safe in mothers on ustekinumab therapy, more studies evaluating the infant’s immune system and its ability to deal with infections are needed before any solid recommendation can be given.

5Tofacitinib

Tofacitinib is a Janus kinase (JAK) inhibitor that has been approved for the treatment of rheumatoid arthritis, psoriatic arthritis and, more recently, ulcerative colitis [11, 65]. The present article will deal with tofacitinib, which is a non- selective JAK inhibitor; in the future, more selective agents will be approved and their safety profile during pregnancy will need to be properly evaluated.

5.1Placental Transport of Tofacitinib

Although there are no data on placental transfer of tofaci- tinib, it is reasonable to assume that this drug, a small-sized molecule, crosses the placenta from the beginning of preg- nancy [66, 67].

5.2Safety During Pregnancy: Animal Studies with Tofacitinib

In preclinical animal studies, tofacitinib was feticidal and teratogenic in rats and rabbits at exposures 146 times and 13 times greater, respectively, than the human dose of 5 mg

twice daily that has been approved for maintenance in rheu- matoid arthritis and Crohn’s disease, and at exposures 73 times and 6.3 times greater, respectively, than the human dose of 10 mg twice daily [68, 69]. Teratogenic effects included external and soft tissue malformations such as ana- sarca and membranous ventricular septal defects, respec- tively, and skeletal malformations or variations. There was an observed increase in post-implantation loss and a decrease in the number of viable foetuses and mean foetal body weight [68, 69]. The link between animal studies and human risk, however, is variable, and it is challenging to pre- dict the impact of tofacitinib on human pregnancy or fertility based on these data [66].

5.3Experience in Non‑inflammatory Bowel Disease Patients Treated with Tofacitinib

Clowse et al. reported outcomes of pregnancy cases iden- tified through April 2014 from tofacitinib rheumatoid arthritis/psoriasis randomised controlled trials, rheumatoid arthritis post-approval non-interventional studies, and spon- taneous adverse-event reporting [70]. This study reported pregnancies from a large database of patients in the tofaci- tinib clinical development programme (n = 9815). Thirty- three women receiving tofacitinib became pregnant. No foe- tal deaths were reported. One congenital pulmonary valve stenosis, seven spontaneous abortions, and eight medical ter- minations were identified. Remaining cases reported healthy newborns (n = 25) or were pending/lost to follow-up (n = 6). Thus, the pregnancy outcomes reported in this small number of rheumatoid arthritis/psoriasis patients treated with tofaci- tinib appear to be similar to those observed in the general population and in patients treated with biological therapies for inflammatory diseases [70].
More recently, Mahadevan et al. [73] identified a total of 158 pregnancies with maternal (n = 74) or paternal (n = 84) exposure to tofacitinib identified in the rheumatoid arthritis, psoriasis and psoriatic arthritis, intervention studies. There were no reports of foetal demise. One case of congenital malformation (pulmonary valve stenosis) and 19 spon- taneous abortions were reported. The remaining known outcomes were healthy newborns (n = 93) or medical ter- minations (n = 13), and 32 cases were pending or lost to follow-up. In addition to the pregnancy cases reported in the tofacitinib programme, 45 pregnancies (including 42 cases of maternal exposure) were identified in non-interventional safety studies and spontaneous adverse event reporting (up to March 7, 2017). Outcomes included 7 healthy newborns, a ventricular septal defect congenital malformation, 3 spon- taneous abortions, 1 medical termination, and 33 pending or lost to follow-up cases. In summary, the observed frequen- cies of congenital malformations and spontaneous abortions (1.0% and 10.8%, respectively) reported in the tofacitinib

clinical development programme studies, non-interventional safety studies, and spontaneous adverse event reporting appeared to be consistent with the background risks in the general population [66, 71].

5.4Experience in Inflammatory Bowel Disease Patients Treated with Tofacitinib

Mahadevan et al. reported pregnancy and newborn outcomes among patients in ulcerative colitis clinical studies with pre- natal exposure to tofacitinib [66]. Thus, outcomes reported in five tofacitinib ulcerative colitis interventional studies (up to March 2017) were collected. Outcomes from tofaci- tinib rheumatoid arthritis, psoriasis, and psoriatic arthritis interventional studies, and rheumatoid arthritis non-inter- ventional post-approval safety studies, spontaneous adverse event reporting, and registry data are also reported. In par- ticular, 11 cases of maternal exposure to tofacitinib (doses of 5 mg or 10 mg twice daily) before/at the time of conception or during pregnancy were identified among ulcerative colitis patients. Outcomes included 15 healthy newborns, no foetal deaths, no neonatal deaths, no congenital malformations, two spontaneous abortions, and two medical terminations. Outcomes across other tofacitinib studies and post-market- ing cases were consistent, with a healthy newborn being the most common outcome and no foetal deaths. Therefore, based on the limited data available, pregnancy and newborn outcomes among patients with maternal exposure to tofaci- tinib in ulcerative colitis studies appear to be similar to those reported for the general population [66, 71].

5.5Should (and If So, When) Tofacitinib be Stopped During Pregnancy?

Even if very preliminary reports have described a low rate of foetal abnormalities, at present the use of small mole- cules such as tofacitinib during conception and pregnancy should be avoided. The half-life of tofacitinib is 3.2 h [72], therefore, a washout period of at least one week should be adequate before attempting conception [73]. In fact, the cur- rent manufacturer recommendations are to use effective con- traception during treatment and for 4–6 weeks after the last dose of tofacitinib [74]. In the patient with limited treatment options who desires pregnancy, the medication informa- tion should be reviewed with all stakeholders—patient and provider(s)—and a consensus should be reached regarding continuation of the drug [34].

5.6Efficacy and Safety of Vaccination in Infants Exposed to Tofacitinib

It remains unknown whether a mother who is taking tofaci- tinib and breastfeeding at the time the varicella and measles,

mumps, rubella vaccines are due should hold the medication for a short period of time to minimise any immunosuppres- sant effect on the child who is receiving the vaccine. More data are needed before any recommendation can be made with regard to tofacitinib interaction with live vaccines.

5.7Safety of Tofacitinib During Breastfeeding

Tofacitinib is present in rat milk at twice the concentration of that in the serum of lactating rats, which is in accord- ance with the drug being a small molecule [68]. No human studies have reported outcomes of breastfeeding with small molecules such as tofacitinib. However, the presence of drug in animal milk makes it likely that it would be present in human milk as well [67]. Thus breastfeeding should be avoided [34]. Until more data become available, the recom- mendation is to avoid breastfeeding for at least 18 h after taking tofacitinib [67, 69].

5.8Safety in Pregnancy When the Father is Exposed to Tofacitinib

Tofacitinib had no effects on male fertility, sperm quality, sperm motility, or sperm concentration in male rats at expo- sures 133 times and 67 times greater, respectively, than the human doses of 5 mg twice daily and 10 mg twice daily [68, 69].
In the aforementioned study by Clowse et al., reporting outcomes of pregnancy cases identified from tofacitinib ran- domised controlled trials, post-approval non-interventional studies, and spontaneous adverse-event reporting, 44 cases of paternal exposure to tofacitinib were reported, including five spontaneous abortions, 23 healthy newborns, and 16 pending/lost to follow-up [70].
Finally, in the study by Mahadevan et al. previously men- tioned, reporting pregnancy and newborn outcomes among 84 cases with paternal exposure to tofacitinib (including all clinical indications), there were no reports of foetal deaths or congenital malformation [66]. The negative outcomes included seven spontaneous abortions and one neonatal death, while most of the outcomes included healthy new- borns. In particular, among ulcerative colitis patients, 14 cases of paternal exposure to tofacitinib (doses of 5 mg or 10 mg twice daily) before/at the time of conception or during pregnancy were identified, healthy newborn being the most common outcome with no foetal deaths [66].
In summary, based on the limited data available, preg- nancy and newborn outcomes among patients with paternal exposure to tofacitinib appear to be similar to those reported for the general population [66, 71].

6Limitations of Studies Evaluating Safety of Drugs During Pregnancy

The studies carried out so far evaluating the safety of new biologics (vedolizumab/ustekinumab) or tofacitinib dur- ing pregnancy and breastfeeding have relevant limitations, which are summarised as follows.

1.Small number of studies and small number of patients (pregnancies) included in each study. As summarised in Table 1, where patients treated with vedolizumab during pregnancy in studies published in the literature were included, the experience includes only 7 studies and 131 patients (with 141 pregnancies). In addition, as presented in Table 2, only 15 studies (with 25 patients and 31 pregnancies) have been published evaluating the safety of ustekinumab during pregnancy. The informa- tion regarding safety of tofacitinib during pregnancy is even more limited.
2.Limited time of exposure to the drug during pregnancy. In many cases, women were required to discontinue ved- olizumab/ustekinumab/tofacitinib if they became preg- nant and therefore the patients were frequently exposed only during the first trimester, when it is known that maternal-foetal IgG transport is poor. Consequently, data are frequently lacking on the intentional and con- tinued use of the drug throughout the pregnancy.
3.Short period of follow-up. Although some pregnancy outcomes or congenital malformations may need just a few hours or days to be confirmed, other potential com- plications—including effects on the immune system such as infections in the offspring or the interference with vaccines—may need longer follow-up.
4.Retrospective study design, with the consequent meth- odological limitations. Most of the studies including patients treated with vedolizumab during pregnancy that have been published in the literature are retrospective, and this is the case of all studies evaluating ustekinumab in pregnant women.
5.Lack of control group. The studies evaluating safety of drugs during pregnancy only exceptionally included a control group [25, 27], that is, a group suffering the same underlying disease as the cases (such as IBD) but not receiving vedolizumab/ustekinumab/tofacitinib (in addition to a group from the general population, which is always desirable). This is key, as patients with dis- eases such as rheumatoid arthritis, psoriasis or IBD (mainly those with active disease) may have, per se, an increased rate of pregnancy complications [2, 75, 76]. In the exceptional cases where a control group was included, cases and controls were not entirely compara- ble, as the cases (treated with vedolizumab, ustekinumab

of tofacitinib) were more refractory than those treated with anti-TNF or with non-biological drugs. Typically, most of the vedolizumab/ustekinumab/tofacitinib treated patients had previously been treated with, at least, two other biologics. Furthermore, although the frequencies of negative outcomes of pregnancies in the general pop- ulation have been widely described, they do not always coincide in all populations, ranging from 10 to 25% for spontaneous abortions, and from 2 to 3% for congenital malformations [70, 71, 77].
6.Limited information about the drug dose. For example, for the dermatological and rheumatological indications, higher ustekinumab doses are applied, and therefore the safety results observed, for example in psoriasis, may not be necessarily extrapolated to those with IBD. In addi- tion, the experience with different tofacitinib doses is also very limited: only one patient receiving 5 mg twice daily at the time of conception was available (among the 11 ulcerative colitis maternal cases), so meaning- ful comparisons of outcomes between the 5 and 10 mg doses cannot be made.
7.Selection bias. The well-recognised reporting bias of post-marketing data, where adverse events are more likely to be reported than favourable outcomes, should be taken into account [78]. Therefore, given the incom- plete information reported and the known tendency of reporting negative outcomes, meaningful interpretation is constrained as pregnancies with positive outcomes are likely to have been under-reported [23].
8.Lack of consideration of potential confounders. The major confounding factor for poor pregnancy outcome seems to be the presence of active disease at conception and during pregnancy. Furthermore, when assessed, IBD disease activity is generally evaluated through clinical indexes, which are known to correlate poorly with— true—endoscopic disease activity. Other potential con- founders include smoking status, alcohol intake and use of concomitant medications.

7Conclusions

At present, the safety of anti-TNF agents during pregnancy and breastfeeding is confirmed. However, two new biologi- cal drugs (vedolizumab and ustekinumab) and one small molecule (tofacitinib) that target different inflammatory pathways have been approved for the treatment of IBD in the last years. Therefore, we must know and be familiar with the safety of these “new” drugs during pregnancy and breastfeeding.
The timing and mechanisms of placental transfer of ved- olizumab are expected to be similar to that of other IgG1 antibodies, such as anti-TNF agents. Animal studies show

no evidence of adverse effects on pre- or post-natal develop- ment after administration of vedolizumab. Just a few stud- ies including IBD patients treated with vedolizumab during pregnancy have been published, reporting uneventful preg- nancies in most cases. The clinical programme of vedoli- zumab and post-marketing studies showed no new safety concerns. Unlike anti-TNFs, for which cord and infant drug levels exceed those of the mother, vedolizumab levels in the newborn are only half the maternal levels at time of delivery. Due to the expected safety of vedolizumab during pregnancy, it may be recommended to plan final pregnancy vedolizumab dose approximately 8 weeks before the esti- mated date of delivery. Vaccination of infants exposed to vedolizumab therapy in utero should be given according to standard vaccine schedules, with the exception of live-virus vaccines, which should be provided at 6–12 months post- partum or when there is no detectable biological drug in the blood. Miniscule amounts of vedolizumab are transferred to breast milk, so breastfeeding is probably safe in mothers on vedolizumab therapy. There is no evidence of adverse effect of vedolizumab paternal exposure on pregnancy outcome.
As previously mentioned with vedolizumab, it is reasona- ble to assume that the transplacental passage of ustekinumab is similar to that of anti-TNFs. Ustekinumab treatment dur- ing pregnancy in macaques has been safe for foetuses and neonates. Most safety data with ustekinumab come from women with psoriasis, reporting uneventful pregnancies in most cases. Regarding IBD, only four studies (including only 4 patients) have evaluated the safety of ustekinumab during pregnancy specifically in IBD patients, and have reported uneventful pregnancies in 3/4 cases. In humans, usteki- numab concentrations in cord blood were higher than mater- nal serum levels, similar to the experience with anti-TNF agents. Due to the expected safety of ustekinumab during pregnancy, it may be recommended to plan final pregnancy dose of ustekinumab approximately 8–12 weeks before the estimated date of delivery. In line with the recommenda- tions regarding intrauterine exposure to anti-TNF treatment, it may be suggested that live vaccines should be avoided for up to a year in children exposed in utero to ustekinumab unless drug elimination has been documented. The concen- trations of ustekinumab in breast milk seem to be minute and are therefore unlikely to result in immune-suppression of the infant, thus breastfeeding is probably safe, but more studies are necessary.
Although there are no data on placental transfer of tofacitinib, it is reasonable to assume that this drug, a small-sized molecule, crosses the placenta from the begin- ning of pregnancy. In preclinical animal studies, tofacitinib was feticidal and teratogenic in rats and rabbits, although at exposures many times greater than the standard human dose. Reported outcomes of pregnancy cases identified from tofacitinib randomised controlled trials, post-approval and

non-interventional studies, and spontaneous adverse-event reporting appear to be similar to those observed in the gen- eral population. In particular, pregnancy and newborn out- comes among patients with maternal exposure to tofacitinib in ulcerative colitis studies appear to be also similar to those reported for the general population. Nevertheless, at present, the use of small molecules such as tofacitinib during concep- tion and pregnancy should be avoided. The current manu- facturer recommendations are to use effective contraception during treatment and for 4–6 weeks after the last dose of tofacitinib. Tofacitinib should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Although no human studies have reported outcomes of breastfeeding with small molecules such as tofacitinib, this drug is present in lactating rat milk so, at present, breast- feeding should be avoided. Based on the limited data avail- able, pregnancy and newborn outcomes among patients with paternal exposure to tofacitinib appear to be safe.
Finally, it should be emphasised that most of the studies evaluating the safety of drugs during pregnancy and breast- feeding suffer from relevant methodological limitations, and that it is evident that large prospective studies are needed. In the future, results from ongoing registries will hopefully shed more light on the safety of new drugs in pregnancy and breastfeeding. Meanwhile, new biological agents (vedoli- zumab and ustekinumab) and small molecules (tofacitinib) should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother and unborn child.

Author Contributions JPG wrote the first draft of the manuscript and critically reviewed the final version. MC complemented draft sections and critically reviewed the final version.

Compliance with ethical standard

Funding None.

Conflict of interest Dr. Gisbert has served as a speaker, a consultant and advisory member for or has received research funding from MSD, Abbvie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Sandoz, Celgene, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, Vifor Pharma. Dr. Chaparro has served as a speaker, or has received research or education funding from MSD, Ab- bvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma.

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