Fetal immunity is achieved through the passive and active transfer of IgG from the maternal circulation to the fetal circulation [16]. Active transfer occurs at the surface of the syncytiotrophoblast placental layer through the selective binding of the Fc gamma portion of the maternal IgG antibody to the Fc receptor neonatal molecule which then transports the IgG antibody to the fetal circulation [17]. There is a continuous, linear increase in the active transport of IgG starting at approximately 13 weeks of gestation and continually progressing until delivery [18–20]. There is a preferential transport of IgG1 followed by IgG4, IgG3, and then IgG2, which is important as many of the new medications used to treat inflammatory bowel disease are IgG antibodies [21] (Table 6.2).

Anti-TNF agents with complete antibodies, including infliximab (IFX), adalimumab (ADA), and golimumab (GOL), are actively transported to the fetal circulation through the mechanism described above. As certolizumab pegol (CZP) is a fragmented Fc portion, it is only passively transferred from the maternal to fetal circulation.

Several studies have confirmed the placental transfer of IFX and ADA as evidenced by detectable drug levels in cord blood [22–28]. In a prospective study looking specifically at placental transfer of anti-TNF medications, Mahadevan et al. included 31 pregnant women with IBD (11 IFX, 10 ADA, and 10 CZP) and measured drug concentrations in the maternal serum, infant serum, and cord blood at the time of birth then monthly in the infant serum until the drug concentrations were no longer detectable [23]. At the time of birth, the median ratio of cord blood to maternal drug concentration for IFX was 160% (range 87–400%); for ADA, it was 179% (range 98–293%); and for CZP, it was 3.9% (range 1.5–24%). In this study, the ADA levels remained detectable in the infant serum for up to 11 weeks from birth, while the IFX was detectable for up to 7 months. More recently, a prospective multicenter study of 80 pregnant women with IBD exposed to anti-TNF medications, including 44 on IFX and 36 on ADA with 39 on concomitant thiopurines, measured maternal blood and cord blood drug levels at the time of birth as well as infant blood levels every 3 months until the drug concentrations were no longer detectable [26]. Similar to previous studies, the median cord blood drug concentration was more than the median maternal drug concentration at the time of birth for both medications (for IFX: 5.9 μg/mL (range 0.12–28.7) vs. 2.0 μg/mL (range 0–22.2); for ADA: 2.0 μg/mL (range 0–12.1) vs. 1.5 μg/mL (range 0–10.0)). At birth, the mean ratio of infant to mother drug concentration was 1.97 for IFX (95% CI 1.50–2.43) and 1.21 for ADA (95% CI 0.94–1.49). Notably, this study found a much longer time for drug clearance in the infants with the mean time for drug clearance of ADA of 4 months (95% CI 2.9–5.0) and 7.3 months for IFX (95% CI 6.2–8.3; P < 0.0001); however, the drugs remained detectable in some infants until 12 months of age. In all of the studies, the presence of detectable anti-TNF drug concentrations did not result in an increase in adverse pregnancy or fetal outcomes. However, while these drug concentrations are detectable, the infants are essentially immunosuppressed and should not be administered live vaccines until serum concentrations are no longer detectable. The previous recommendation was to avoid the rotavirus, oral polio virus, and bacille Calmette-Guerin (BCG) vaccines for the first 6 months [29, 30]; however, this time frame may need to be extended to the first 12 months of life, or the use of anti-TNF drug concentration testing may need to be implemented prior to administration of a live vaccine to an infant with intrauterine anti-TNF exposure.

Few studies looking at pregnancy outcomes in women with IBD have limited their study cohorts to those only exposed to IFX. A study using data from an infliximab safety database included 96 pregnant women with autoimmune diseases (82 Crohn’s disease, 1 UC, 8 rheumatoid arthritis (RA), 2 juvenile rheumatoid arthritis, 3 unknown) who were exposed to IFX (ranging from within 3 months prior to conception to exposure during the first trimester) [31]. The 96 pregnancies resulted in 64 (67%) live births, 14 (15%) SAs, and 18 (19%) elective abortions, which were reported to be similar to the expected rates for the general US population. Review of the FDA-mandated infliximab safety registry (TREAT) revealed 142 pregnancies in women exposed to IFX with 83.1% (118/142) live births, 92.4% (109/118) of which were healthy without any congenital defects or adverse events compared to 90.7% (68/75) live births and 85.3% (58/68) of which were healthy with no congenital defects or adverse events in the IBD patients on other therapies [32]. An early retrospective chart review including ten women exposed to IFX during pregnancy reported live births of normal infants in all cases, three were born premature (<37 weeks gestation) and one had a low birth weight (<2500 g) [33]. In another case series of four women who continued IFX treatment during pregnancy, all delivered full-term, healthy infants, with detectable cord blood drug levels in 75% (3/4) and undetectable drug levels in one infant with the longest duration between last infusion, at gestational week (GW) 21, and delivery [28]. None of the children were noted to have an increased rate of infections, and all developed protective antibody levels at 6 months of age to the Haemophilus influenzae type B and pneumococcal vaccines.

With respect to studies tha t only included ADA, there are several case reports of ADA use during preconception, and into the first trimester [34], several reports of ADA continued throughout pregnancy due to ongoing active IBD [35, 36] and a report of the use of ADA during pregnancy for worsening, steroid-refractory disease [37]. In each of these case reports, regardless of when treatment with ADA was initiated or how long into the pregnancy it was continued, all pregnancies resulted in the birth of a healthy infant without any developmental abnormalities at 6 months [35, 36], at 1 year [37], and at up to 2 years of observation [34]. In a prospective cohort study by the Organization of Teratology Information Specialists (OTIS), data presented in abstract form showed no increase in adverse fetal outcomes among women with RA treated with ADA compared to a cohort of women with RA not treated with ADA and compared to a cohort of healthy controls [38]. A recent analysis of adverse events data from the Adalimumab Pregnancy Exposure Registry (APER), which is a prospective observational cohort study conducted by OTIS, includes 15,132 patients with RA exposed to ADA and found no increase in the risk of SA or major birth defects in the ADA-exposed RA cohort compared to the unexposed RA cohort and the heal thy controls [39].

An initial case report of the use of CZP during pregnancy included a 22-year-old woman who received 11 injections preconception, 1 injection during the first trimester, and 1 injection in the third trimester due to active Crohn’s disease [40]. The patient delivered a normal healthy infant with normal development as of 1 month of age. More recently, outcomes from 339 pregnancies (192 in women with Crohn’s disease, 118 in women with rheumatic disease) exposed to CZP were obtained through review of a large pharmaceutical safety database [41]. Of the 339 pregnancies (113 reported retrospectively and 226 reported prospectively), 254 (74.9%) resulted in live births, 52 (15.3%) miscarriages, 32 (9.4%) induced abortions, and 1 stillbirth. Of the 226 prospectively reported pregnancies, there were 182 (80.5%) live births, 21 (9.3%) miscarriages, 22 (9.7%) induced abortions, and 1 stillbirth. Overall, the authors found that there were some differences in outcomes by report source (i.e., prospective vs. retrospective reporting) with improved outcomes in the prospectively reported cohort, but overall there was no increase in the risk of adverse pregnancy or fetal outcomes with the use of CZP in pregnancy.

Using individual patient cases reported to the manufacturer, one study presented in abstract form has looked at the outcomes of 47 pregnancies among women with autoimmune diseases (30 RA, 1 psoriatic arthritis [PsA], 5 ankylosing spondylitis, 11 UC) treated with golimumab [42]. There were 26 (55.3%) live births, 13 (27.7%) SAs, 7 (14.9%) induced abortions, and 1 (2.1%) ectopic pregnancy. Methotrexate was taken concurrently in 12 pregnancies and was used in 4 of the 13 (30.8%) of the reported SAs and in the 1 case of reported congenital anomaly. Overall, however, the rate of SA was noted to be similar to the back ground rate.

Most studies looking at pregnancy and neonatal outcomes follo wing exposure to anti-TNF agents during pregnancy have not found any difference in the rates of adverse outcomes between those exposed to these medications compared to the women who are treated with alternative therapies [43–46]. In fact, one study reported improved pregnancy and neonatal outcomes with anti-TNF monotherapy (OR 0.57, 95% CI 0.41–0.79) and particularly with CZP use (OR 0.12, 95% CI 0.07–0.20, P < 0.001) [47]. To address the specific questions raised about the risks of adverse pregnancy and fetal outcomes with intrauterine anti-TNF exposure, the Multicenter National Prospective Study of Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry was created [48]. The study cohorts are divided into groups based on drug exposures and, at the time of initial data presentation, included 1052 women (337 unexposed; 265 in AZA/6MP; 102 in IFX, ADA, or CZP; 59 on combination) and found no increased risk for adverse pregnancy or fetal outcomes associated with use of thiopurines or anti-TNF agents; however, there was an increased rate of infections noted at 12 months in the infants who had been exposed to combination therapy in utero.

Several studies have found an increased r isk for SA following anti-TNF exposure during pregnancy. Using the British Society for Rheumatology Biologics Register (BSRBR) to determine outcomes of 130 pregnancies in RA patients exposed to anti-TNF medications (including exposure to IFX, ADA, and etanercept) prior to or during pregnancy, the authors found a slightly, but not significantly, increased rate of SA in those exposed to anti-TNF medications at the time of conception; however, this rate was most pronounced in the cohort on concomitant methotrexate (MTX) or leflunomide (LEF) (33%) compared to the group exposed to anti-TNF without MTX or LEF (24%), to those exposed to anti-TNF medications prior to conception (17%), and to those in the TNF-naïve group (1 0%) [49]. Another retrospective database study including 86 pregnancies in women with autoimmune diseases who were counseled by the Israeli Teratology Information Service regarding exposure to anti-TNF medications (35 IFX, 25 etanercept, 23 ADA), 97.6% exposed only in the first trimester, found an increased rate of SA in the TNF-exposed group (10.8%) compared to the rate in a group of women who were not exposed to potentially teratogenic agents (2.9%), but not significantly increased compared to pregnancies in a disease-matched cohort (5.8%) [50]. Similarly, a recent study of pregnancy outcomes of women with IBD in Japan included 24 pregnancies with exposure to anti-TNF agents (23 IFX, 1 ADA), 7 pregnancies in women with thiopurine monotherapy, 10 pregnancies in women treated with combined IFX and thiopurines, and 31 pregnancies in nonexposed women and also found an increased rate of SA in the TNF-exposed groups (monotherapy and combination therapy groups) compared to the other non-TNF-exposed groups (17.7% vs. 0%, P = 0.009) [51]. In all three of these studies, there were no differences between the groups in fetal outcomes.

A prospective observational cohort study comparing adverse events reported to the European Network of Teratology Information Services (ENTIS) in 495 pregnancies in women with autoimmune diseases exposed to anti-TNF medications (including IFX, ADA, CZP, GOL, and ETA) in the first trimester to outcomes of 1532 pregnancies in women not exposed to anti-TNF agents but who had contacted ENTIS for other non-medication-related concerns found no increased risk of SA or stillbirth with TNF exposure but, however, did find a higher incidence of preterm birth (ORadj 1.69, 95% CI 1.1–2.5) [52]. In addition, the study found an increased risk of major birth defects in the TNF-exposed cohort compared to the nonexposed cohort (5.0 % vs. 1.5%, adjusted odds ratio [ORadj] 2.20, 95% CI 1.01–4.8); however, there was no distinct pattern of birth defects to suggest a drug-related effect.

With respect to risk factors associated with adverse pregnancy and neonatal outcomes, a retrospective study including 124 IBD pa tients with 133 pregnancies followed in Groupe d’Etude Thérapeutique des Affections due Tube Digestif (GETAID) centers with exposure to anti-TNF medications during pregnancy or less than 3 months prior to pregnancy showed no difference in the pregnancy or neonatal outcomes compared to a control group [46]. However, on multivariate analysis, the risk factors associated with adverse pregnancy outcomes included current smoking (P = 0.004), occurrence of a flare during pregnancy (P = 0.006), a stenotic Crohn’s phenotype (P = 0.004), and prior pregnancy complications (P = 0.007), while the only risk factor associated with newborn complications was having a disease duration of >10 years (P = 0.007). Prior exposure to anti-TNF therapy during pregnancy was not found to be a risk factor. Because of the lack of consistent evidence showing a risk for adverse pregnancy or neonatal outcomes, the use of anti-TNF medications during pregnancy has been deemed to be low risk in rheumatologic and gastroenterological expert recommendations [29, 30, 53, 54].

Following the Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) trial , which showed improved remission rates with combination anti-TNF and thiopurine medications compared to treatment with either agent alone [55], as well as the recommendations for treating to target therapeutic endpoints in IBD, including treating with immunosuppressive therapy for patients with characteristics of more aggressive disease [15], more IBD patients are frequently on combination therapy. Several studies have included a cohort of women receiving anti-TNF medications in combination with thiopurines to compare the pregnancy and fetal outcomes with women on other treatment regimens. A sub-analysis of a retrospective, multicenter trial found improved outcomes with combination therapy as evidence by a higher rate of adverse pregnancy and fetal outcomes, due to a higher rate of preterm delivery, in the anti-TNF monotherapy cohort compared to the combined anti-TNF and thiopurine cohort (60.9% vs. 39.1%, P = 0.04 and 16% vs. 0%, P = 0.02) [45]. In the previously mentioned PIANO registry, data from 2012 presented in abstract form included 1052 women enrolled with 337 unexposed, 265 on thiopurine monotherapy, 102 on anti-TNF therapy, and 59 on combination therapy and reported no increase in any complication associated with the use of anti-TNF medications; however, there was a significant increase in fetal infections at 12 months of age in the infants exposed to combination therapy compared to the infants in the unexposed group (RR 1.50, 1.08–2.09) [48]. Similarly, a recent prospective study including 80 pregnancies in women with IBD including 39 women on combination therapy found a greater than twofold increased risk for any infection in the first year of life for the infants with in utero exposure to combination therapy compared to those exposed to anti-TNF monotherapy (RR 2.7, 95% CI 1.09–6.78, P = 0.02) [26]. All of the noted infections had a benign course without adverse sequelae.

This possible increased risk of infection in the newborn needs to be weighed carefully against the need to continue combination therapy in the mother in order to maintain disease remission. As such, two studies have shown no increase in short-term relapse rates after transitioning from combination therapy to anti-TNF monotherapy [56, 57]; however, this needs to be completed early in the preconception stage in order to ensure continued disease remission at the time of conception [30].

Intrauterine anti-TNF exposure, particularly later in pregnancy, has raised concerns about an increased risk for infections in the infant as well as concerns about altering neonatal immune development. One case series of four newborns with intrauterine exposure to IFX, including in the third trimester (T3), reported severe neutropenia at birth in all of the infants, which returned to normal by 14 weeks of age [58]. This finding has not been replicated in other studies. Using the PIANO registry, Mahadevan et al. assessed outcomes related to anti-TNF exposure during T3, including 422 pregnant women exposed to biologics in the third trimester of pregnancy compared with 597 pregnant women unexposed to biologics in the third trimester (70 with exposure to an anti-TNF in the first and/or second trimester but discontinued prior to T3), and found no difference in the risk of preterm birth, risk of worsening disease activity in T3 or in the first 4 months postpartum, or an increased risk of infant infections in up to 12 months of follow-up [59]. Specifically looking at immune response following vaccination in infants with gestational exposure to anti-TNF agents, a recent prospective study of a subset of subjects from the PIANO registry, including ten infants exposed to IFX and two exposed to ADA, measured immunoglobulin levels and antibodies to tetanus and Haemophilus influenzae after vaccination and found five infants with low IgM levels, with unclear clinical significance, but an adequate vaccine response in 92% of the infants [60]. Other similar studies have confirmed an adequate immune response to vaccinations in infants with intrauterine anti-TNF exposure [22, 28].

Following a case report [61] and systematic review [62] that suggested intrauterine anti-TNF exposure leads to a VACTERL (includes vertebral defects, anal atresia or imperforate anus, cardiac abnormalities, tracheoesophageal fistula or tracheal atresia/stenosis, esophageal atresia, renal and/or radial abnormalities, preaxial limb abnormalities) congenital anomaly, a subsequent population database study evaluated this association and could not confirm an increased risk for congenital anomalies within the VACTERL spectrum [63]. Despite these few studies and the previously mentioned studies which found an increased risk of infection within the first year of life following intrauterine exposure to combined anti-TNF and immunomodulatory medications [26, 48], most studies of neonatal outcomes in pregnancy following intrauterine anti-TNF medication exposure have not found an increased risk of adverse fetal outcomes, particularly congenital malformations, compared to disease-matched cohorts or cohorts on immunomodulators [43–47, 50, 51, 64].

Several studies have investigated long-term outcomes following intrauterine anti-TNF exposure. A study of 25 children ages ≥12 months who were exposed to anti-TNF agents during gestation were all found to have normal growth and development except 1 child (a dizygotic twin, diagnosed with a mild delay at 6 months of age) [65]. Twenty (80%) of the children had at least one infection with 60% receiving antibiotics. Vaccinations were given according to the recommended protocol, including BCG within 1 week of birth in 15 of the children with intrauterine exposure to IFX, which resulted in large skin reactions in three of the children, but no other complications. Cellular immunity was noted to be normal in all infants, and response to vaccination, which was evaluated in 15 of the children, was adequate. One of the most recent updates from the PIANO registry includes an assess ment of developmental milestones using the Denver Developmental Score completed by the mother at 4, 9, and 12 months as well as by using the Ages and Stages Questionnaire at 1, 2, 3, and 4 years of age which showed that, in all areas of development, the infants exposed to thiopurines, anti-TNF agents, or combination therapy had similar or better achievement of milestones compared to the unexposed infants [66].

Disease remission in the pregnant IBD patient is the driving factor regarding when to discontinue anti-TNF therapy during pregnancy. The current recommendations are to give the last IFX infusion at around 20 weeks of gestation or the last ADA injection around 24 weeks of gestation in those in disease remission; CZP may be safely continued throughout pregnancy [30]. The purpose of tailoring the dosing schedule is to maintain remission in the mother while minimizing exposure to the fetus. In one case-control study, 51 women in remission discontinued anti-TNF therapy before GW 25 which did not result in an increased rate of disease flare (5/51, 9.8%) compared to the rate of flare in the cohort who continued anti-TNF therapy beyond week 30 (5/32, 15.6%; P = 0.14) [25]. In another study of 31 pregnancies in 28 women, all with quiescent disease, 12/18 (71%) discontinued IFX before GW 30, and all women remained in remission, while all of the women on ADA discontinued treatment before GW 30 which resulted in a disease flare in 2/13 (15.3%) [24]. Both of these studies concluded that anti-TNF medications can be safely discontinued in the second trimester in women with quiescent disease.

The goal of discontinuing anti-TNF the rapy in the second trimester is to limit drug exposure during the time of highest transmission of immunoglobulins from the mother to the fetus. Several studies have shown that timing of the last anti-TNF administration correlates with maternal serum and cord blood levels, however, not in a linear fashion. In a study looking at cord blood levels of IFX, ADA, and CZP, Mahadevan et al. noted that a longer duration of time from the last dose to delivery did not always correlate with lower cord blood drug concentrations [23]. For example, there were two infants with intrauterine ADA exposure, one last exposed 7 days prior to birth and the other 56 days prior to birth, yet they had similar cord blood drug concentrations at birth (6.17 and 6.01 μg/mL). Similarly, in two infants with intrauterine IFX exposure, cord blood drug levels at birth were 23.6 and 28.2 μg/mL despite the last dose in the first at 14 days prior to delivery and at 55 days prior to birth in the second. This variability is likely due to differences in maternal dose and interval, individual pharmacokinetics, as well as immaturity of the newborn reticuloendothelial systems. A similar variability in cord blood drug concentrations was also noted by Julsgaard et al. to which they concluded that it is “not possible to identify a gestational week to stop maternal anti-TNF treatment that would reliably predict undetectable drug concentrations at birth.” [26] However, despite the variability in cord blood drug concentrations, no studies have shown an increase in adverse neonatal outcomes that correlate with infant drug levels. Because of the persistence of these drug levels, it is imperative that all live vaccines be held for at least 6 months and possibly up to 1 year, in infants with a history of intrauterine anti-TNF exposure.

Studies of supratherapeutic doses of natalizumab (NAT) in animals have shown mixed outcomes, including no fetotoxic or teratogenic effects [67] to increased spontaneous abortion rate and hematologic effects including mild anemia and thrombocytopenia [68]. The current recommendations are for anyone considering conception to discontinue NAT 3 months prior to conception due to the role α4-integrins and their ligands play in mammalian development and due to the absence of data on pregnancy and fetal outcomes following intrauterine exposure to NAT. Several case reports of NAT exposure during pregnancy, including three women with MS, have all resulted in healthy, full-term infants, one of which was small for gestational age [69–71]. Several prospective studies of NAT exposure during pregnancy in 137 women with MS have not showed an increase in adverse pregnancy or fetal outcomes that could be attributed to NAT exposure [72, 73]. A study from the Tysabri (natalizumab) Pregnancy Exposure Registry (TPER), presented in abstract form, included 375 women with autoimmune diseases (368 with MS, 7 with Crohn’s disease) who were exposed to NAT within 90 days of conception [74]. Of these pregnancies, there were 314 live births, 13 elective abortions, 34 spontaneous abortions, 1 stillbirth, and 11 ongoing pregnancies, and 10 women were lost to follow-up. The authors reported that in 28 pregnancies in 26 women, major and/or minor defects were observed, but no further details are provided. Overall, however, the study did not show any effect of NAT exposure on pregnancy outcomes.