Inflammatory bowel disease (IBD) is increasing worldwide and is associated with significant healthcare utilization and suboptimal quality of life (1). The incidence of IBD is highest among women of reproductive age, with 25% of women becoming pregnant after diagnosis (2). Among women with IBD, active disease is associated with an increased risk of pregnancy complications and adverse outcomes (3). Although many studies have investigated the frequency of adverse pregnancy outcomes attributable to a variety of IBD therapies, the magnitude of these effects as they relate to infantile infections subsequent to exposed pregnancies remains a topic of debate (4).
Immunosuppressive medications are a mainstay of treatment for IBD, and biologic therapies such as monoclonal antibodies that abrogate tumor necrosis factor (TNF) activity increasingly form the backbone of management (5). The introduction of a variety of novel biologic therapies such as those targeting the integrin α4β7 (vedolizumab) (6) and p40 subunit of IL-12/IL-23 (ustekinumab) (7) have expanded the armamentarium of IBD therapies and led to a dramatic increase in the proportion of patients with controlled disease (8). Although biologics are effective treatments for IBD, their immunosuppressive effects increase the risk of infection (9–11).The risk of infection in infants exposed to biologics during pregnancy is of particular concern for patients and clinicians.
A broad array of biologics used to treat IBD have been detected in infants, with some persisting for up to 1 year through transplacental transfer in utero (12). Data regarding the risk of infantile infections after in utero exposure to biologic therapy are conflicting. A widely cited case report (13) demonstrated a fatal case of disseminated mycobacterial infection after BCG vaccination in an infant born to a mother with Crohn's disease treated with infliximab. Another study (12) showed that infants born to mothers treated with concomitant TNF inhibitor and thiopurine therapy during pregnancy had a 3-fold increased risk of infantile infection compared with anti-TNF monotherapy. By contrast, a large cohort study of patients with IBD (14) found that biologics during pregnancy were associated with an increased risk of maternal, but not infantile, infections. In light of these conflicting data, some clinicians turned to certolizumab, a monovalent Fab' fragment incapable of crossing the placental barrier (15). Although certolizumab may be a more appealing therapy during pregnancy in IBD, a previous network meta-analysis showed that infliximab and adalimumab are more effective than certolizumab in induction and maintenance therapy in IBD (16). To address these conflicts and to better guide clinicians and patients, we performed a systematic review and meta-analysis to quantify the subsequent risk of infantile infections after fetal exposure to biologics.
Our systematic review and meta‐analysis was conducted according to the MOOSE (17) guidelines (see Supplementary Table 2, Supplementary Digital Content 2, http://links.lww.com/AJG/B753, MOOSE checklist), reported according to the PRISMA guideline (18), and was preregistered at the PROSPERO Database (http://www.crd.york.ac.uk/PROSPERO) Reg. No. CRD42019135721. We performed a search of major electronic databases from inception to June 2020 including (i) MEDLINE (PubMed), (ii) EMBASE, (iii) Scopus, (iv) Web of Science, and (v) CENTRAL (Cochrane Central Register of Controlled Trials). The following research strategy was performed in MEDLINE and adapted to the other databases: (“Inflammatory Bowel Diseases” [MeSH] OR Inflammatory Bowel Disease*[TIAB] OR Crohn*[TIAB] OR Ulcerative Colitis*[TIAB] OR IBD[TIAB] OR Proctocolitis*[TIAB] OR Proctosigmoiditis*[TIAB] OR Rectocolitis*[TIAB] OR Rectosigmoiditis*[TIAB] OR Proctitis*[TIAB]) OR “Pregnancy”[MeSH] OR Pregnanc*[TIAB] OR new-born*[TIAB] OR Lactation*[TIAB] OR “Infant”[MeSH] OR Infant*[TIAB]) AND (“Biological Products”[MeSH] OR Biological Products*[TIAB] OR biologics*[TIAB] OR infliximab*[TIAB] OR adalimumab*[TIAB] OR golimumab*[TIAB] OR certolizumab*[TIAB] OR vedolizumab*[TIAB] OR natalizumab*[TIAB] OR ustekinumab*[TIAB]).
Definitions of clinical outcomes
Biologic exposure: any use of biologic therapy (infliximab, adalimumab, golimumab, certolizumab, natalizumab, vedolizumab, and ustekinumab) from the time of conception to the end of pregnancy. Patients with IBD who stopped using biologics during the third trimester of pregnancy were included. Primary outcome: infantile infections defined as any infection occurring within the first year of life. Secondary outcomes: (i) infantile antibiotic use and (ii) infection-related hospitalizations.
Inclusion and exclusion criteria
Two authors (J.G. and O.H.N.) independently reviewed the abstracts and manuscripts for eligibility. Conflicts were resolved with consultation of another author (C.B.J.). Our inclusion criteria included (i) interventional or observational studies, (ii) pregnant women with IBD with or without biologic exposure, and (iii) reported infantile infections. Our exclusion criteria were (i) case reports, (ii) studies only including patients without exposure to biologic therapy, (iii) no data on infantile infections, and (iv) no control group (pregnancy not exposed to biologics).
The following data were extracted: (i) author names, publication year, and country (or countries) of patient population; (ii) study design; (iii) type of biologic exposures and proportion of mothers with IBD continuing biologics during the third trimester of pregnancy; (iv) maternal IBD type and proportion of patients with active (moderate or severe) disease (defined by individual studies) during pregnancy; (v) proportion of mothers with IBD on steroids during pregnancy; (vi) cohort mean maternal age at the time of pregnancy; (vii) the total number of live births/infants; (viii) the total number of infantile infections; (ix) infections requiring antibiotic use; (x) infection-related hospitalizations; and (xi) the number of acute otitis media (AOM), upper respiratory infection (URI), urinary tract infection (UTI), and gastrointestinal (GI) infection cases.
Assessment of study bias
Two authors (J.G. and O.H.N.) independently assessed the risk of bias in included studies using a modified Newcastle‐Ottawa scale for case‐control studies or cohort studies (19). Significant conflicts between Newcastle‐Ottawa scores were resolved with the consultation of another author (C.B.J.). The following criteria were evaluated: selection, representativeness of cases, definition of controls, comparability (of cases and controls), ascertainment of exposure, and assessment of outcomes. Each domain of the Newcastle‐Ottawa scale was judged for the risk of bias as low, uncertain, or high.
Outcomes were extracted from individual manuscripts or calculated using raw data and pooled using a random effects model. Review Manager v5.3 was used to calculate the pooled odds (and 95% confidence interval [CI] and P values) of our clinical outcomes. Heterogeneity was assessed using I2 statistics defined by the Cochrane Handbook for Systematic Reviews (20). We performed a subgroup analysis for the type of infantile infections (AOM, URI, UTI, and GI). Because certolizumab does not cross the placenta and should not affect the risk of infections, we performed a sensitivity analysis comparing the risk of infantile infections in studies including certolizumab vs studies not including this drug. Additional sensitivity analyses included restricting the meta-analysis to studies with only anti-TNF agents, performing the meta-analysis according to the study design (retrospective vs prospective) and risk of bias (low vs high/uncertain). We also performed meta-regression analyses (metareg function, Stata/IC 15.1 for Windows; StataCorp, College Station, TX) to determine whether the proportion of mothers with IBD continuing biologics during the third trimester, on steroids, or with active disease during pregnancy associated with the effect size (Log odds ratio [OR]) of our clinical outcomes. A funnel plot and Egger test were used to assess for publication bias.
Our systematic review PRISMA flowchart is summarized in Figure 1. After removing duplicates, our search strategy yielded 1,262 citations. A total of 903 studies involving IBD and pregnancy but not biologic therapy were excluded by title and abstract. A total of 359 studies with IBD, pregnancy, and biologic therapy underwent full-text assessment for eligibility. Of these, 350 studies were excluded because they did not report infantile infections, were case reports, or lacked a control group. A total of 9 studies were included for qualitative assessment and meta-analysis.
Characteristics of included studies
The baseline characteristics of included studies are summarized in Table 1. The 9 included studies (14,21–28) comprised 8,013 women with IBD (5,212 Crohn's disease, 2,801 ulcerative colitis) who gave birth to 8,490 infants. The mean maternal age at the time pregnancy of was 31 years. 1,965 pregnancies were exposed to biologics, whereas 6,525 pregnancies were not exposed. All included studies were observational. All studies reported infantile infection outcomes with anti-TNF exposure except for 1 study (22), which also reported exposure to vedolizumab and another study which included patients with a mix of biologics including anti-TNF agents and ustekinumab (28). The risk of bias of included studies is summarized in Supplementary Table 1 (see Supplementary Digital Content 2, http://links.lww.com/AJG/B753): 6 studies had low risk of bias (14,21,23–25,27), 1 study was deemed to have uncertain risk of bias (22), and 2 studies had high risk of bias (26,27).
Risk of all infantile infections
Of the 1,965 pregnancies exposed to biologics, the incidence of all infections was 0.27 cases per infant-year, whereas of the 6,525 pregnancies not exposed to biologics, the incidence was 0.40 cases per infant-year. There were no reported infection-related deaths. We were unable to assess for age of infants at the time of infection because of limited data. Use of biologics in women with IBD during pregnancy was not associated with increased risk of all infantile infections (OR 0.91, 95% CI 0.73–1.14, I2 = 30%) as summarized in Figure 2.
Subgroup analysis: risk of specific types of major infantile infections
Table 2 summarizes the major types of infantile infections (AOM, URI, UTI, and GI) documented in the included studies. Table 3 summarizes the incidence of major infections from our study compared with meta-analyses of infants in the general population (29–32). In infants exposed to biologics during pregnancy, the pooled incidence (cases per infant-year) of AOM, URI, UTI, and GI were 0.04, 0.02, 0.01, and 0.01, respectively, which were not higher than that of the general population (0.05, 0.18, 0.07, and 0.01, respectively). In infants not exposed to biologics during pregnancy, the pooled incidence (cases per infant-year) of AOM, URI, UTI, and GI were 0.02, 0.01, 0.01, and 0.01, respectively, which were not higher than that of the general population (0.05, 0.18, 0.07, and 0.01, respectively). In a subgroup analysis, biologic use during pregnancy was associated with an increased risk of URIs (OR 1.57, 95% CI 1.02–2.40, I2 = 4%), but not AOM (OR 0.97, 95% CI 0.42–2.23, I2 = 67%), UTIs (OR 1.50, 95% CI 0.82–2.75, I2 = 0%), or GI infections (OR 1.33, 95% CI 0.78–2.27, I2 = 0%) as summarized in Figure 3.
Risk of antibiotic use and infection-related hospitalizations
Eight studies (14,21–25,27,28) reported the rates of infantile antibiotic use, whereas all 9 studies (14,21–28) reported the rates of infection-related hospitalizations. In infants exposed to biologics during pregnancy, the incidence (cases per infant-year) of infections requiring antibiotics and infection-related hospitalizations were 0.13 and 0.13, respectively. In infants not exposed to biologics during pregnancy, the incidence (cases per infant-year) of infections requiring antibiotics and infection-related hospitalizations were 0.15 and 0.15, respectively. Biologic use in pregnant women with IBD was not associated with increased risk of infantile antibiotic use (OR 0.91, 95% CI 0.73–1.14, I2 = 30%) or increased risk of infection-related hospitalizations (OR 1.33, 95% CI 0.95–1.86, I2 = 26%) as summarized in Figure 4.
Publication bias and sensitivity analyses
A funnel plot (see Supplementary Figure 1, Supplementary Digital Content 1, http://links.lww.com/AJG/B752) of included studies showed no evidence of publication bias. An Egger test did not suggest publication bias (P = 0.57). In a sensitivity analysis restricted to only anti-TNF studies (see Supplementary Figure 2, Supplementary Digital Content 1, http://links.lww.com/AJG/B752), biologics during pregnancy in women with IBD was not associated with the risk of infantile infections (OR 1.00, 95% CI 0.77–1.29, I2 = 25%). There was no association between biologics in pregnancy and infantile infections in meta-analyses (see Supplementary Figure 3, Supplementary Digital Content 1, http://links.lww.com/AJG/B752) including studies without certolizumab (OR 1.12, 95% CI 0.52–2.39, I2 = 59%) or with certolizumab (OR 0.91, 95% CI 0.80–1.04, I2 = 0%). The meta-analysis (see Supplementary Figure 4, Supplementary Digital Content 1, http://links.lww.com/AJG/B752) stratified by study design (retrospective vs prospective) revealed significant differences (P = 0.04) in the risk of infantile infections. In prospective studies (2 studies), biologic exposure during pregnancy in women with IBD was associated with the decreased risk of infantile infections (OR 0.69, 95% CI 0.51–0.93, I2 = 0%). By contrast, in retrospective studies (7 studies), there was no association (OR 1.04, 95% CI 0.80–1.35, I2 = 19%) between biologic exposure and infantile infections. The meta-analysis stratified by the risk of bias (low vs uncertain/high bias) (see Supplementary Figure 5, Supplementary Digital Content 1, http://links.lww.com/AJG/B752) revealed no significant differences in the risk of infantile infections. Meta-regression analyses revealed that the proportion of mothers with IBD continuing biologics during the third trimester (Figure 5) on steroids during pregnancy (see Supplementary Figure 6, Supplementary Digital Content 1, http://links.lww.com/AJG/B752) or with active disease during pregnancy (see Supplementary Figure 7, Supplementary Digital Content 1, http://links.lww.com/AJG/B752) were not associated with the risk of all infantile infections, 4 major infantile infections (AOM, URI, UTI, and GI), antibiotic use, or infected-related hospitalizations.
To our knowledge, this is the first meta-analysis quantifying the risk of infantile infections after in utero biologic exposure as part of IBD therapy in pregnancy. In this systematic review and meta-analysis comprising over 8,000 infants, we demonstrate that biologic use is not associated with an increased risk of all infantile infections. Although we observed an increased risk of URIs in the subgroup analysis, biologic use during pregnancy was not associated with an increased risk of serious infections requiring antibiotics or hospitalizations. There was no reported infection-related infant mortality. We also show that the risk of infantile infection is comparable between certolizumab vs other TNF inhibitors and that continuing biologics during the third trimester does not seem to confer an increased infection risk.
The incidence of major infections in infants born to mothers with IBD with or without biologic exposure in our meta-analysis did not seem to be increased compared with infants in the general population. In a meta-analysis of 114 studies (29), the pooled global incidence of AOM was 0.05 cases per infant-year, which was comparable with our results. In another meta-analysis (30), the global incidence of viral respiratory infections was 0.18, which was much higher than our incidence of URIs in infants with or without biologic exposure during pregnancy. The incidence of UTI and GI infections in infants in our study were not higher than that reported in previous meta-analyses (31,32) of infants in the general population.
Our finding that the use of biologics during pregnancy in women with IBD is not associated with an increased risk of infantile infections could have several explanations. First, although biologics undergo transplacental transfer and persist at detectable drug concentrations in infantile circulation, it is possible that any immunocompromising effects are transient and changes in immune function normalize once the drug is cleared. Indeed, this is supported by a previous prospective study (33) which showed that infants exposed to TNF inhibitors in utero had detectable concentrations of anti-TNF at birth and a more immature B and helper-T phenotype and decreased regulatory T cell frequency. These immune changes normalized after anti-TNF levels became undetectable at 6 months of age. None of the infants experienced any infections. This idea is further supported by recent data demonstrating that biologic use by pregnant women with IBD does not affect infant response to routine (nonlive) vaccines at 2–6 months of age, which are routinely given in the first year of life (34). Second, it is possible that biologic exposure does cause some immunocompromise in the infant but that passive immunity from maternal transfer of cytokines and protective antibodies through the placenta and breastmilk (35–37) abrogates this effect. Transfer of biologics through breast milk have been reported to be very low (28). Third, an alternative explanation is that blockade of pathways by biologics may not be critical for common infections in infants or infections that are affected by biologic blockade (e.g., tuberculosis) were not endemic in the included patient populations and not captured by our analysis.
We observed that biologic therapy during pregnancy was associated with an increased risk of infantile URIs. The only other study adequately powered to detect this subtle risk did not quantify URIs in infants born to mothers treated with biologics (29). We hypothesize that this association may have been missed by other studies because the effect is subtle, and all of the infections were self-limited and not associated with an increased risk of hospitalization. The self-limited alterations in the immune cell repertoire of infants exposed in utero to biologics (33) may cause a mildly immunocompromised state reflected in an increase in URI frequency, without compromising vaccine efficacy or predisposing to serious infections requiring hospitalization.
Our study has several strengths. First, we conducted a meta-analysis of multiple large populations, increasing the statistical power to detect a subtle association between biologic use during pregnancy and infantile infections and to resolve conflicting data and uncertainty from previous studies. Second, we included diverse cohorts of pregnant women with IBD from different countries to overcome geographic and institutional bias broadening the generalizability of our findings. Third, the clinical outcomes we examined were comprehensive including the risk of all infantile infections and more clinically meaningful end points such as infantile antibiotic use and infection-related hospitalizations while being granular enough to detect subtle immune derangements that may result from biologic exposure. Fourth, heterogeneity and risk of bias of included studies was mostly low. Finally, we performed sensitivity analyses including meta-regression analyses to assess potential confounders for the association between biologics and infantile infection, such as maternal use of biologics during the third trimester, steroid use, and disease activity with our results remaining robustly consistent with our central conclusion. Our study has, however, some limitations. First, we performed meta-analyses of observational studies and thus cannot establish causality. Nevertheless, some factors in our study may support causality such as temporality (biologic exposure in pregnancy preceding outcome of infantile infection) and biologic plausibility (we provided possible mechanisms to explain why biologic therapy during pregnancy may not affect the risk of infection). Performing interventional studies to assess the impact of biologic therapy during pregnancy on the risk of infantile infections poses serious ethical dilemmas. Second, some of our pooled ORs were unadjusted, thus we were unable to adjust for unmeasured confounders such as maternal comorbidities, infant age, and concurrent thiopurine use. Third, our results predominantly reflect the impact of TNF inhibitors because our meta-analyses included only 1 study with vedolizumab and 1 mixed study with ustekinumab.
In conclusion, we provide reassuring evidence that biologic therapy in pregnant women with IBD is not associated with increased risk of infantile infections or serious infections requiring antibiotics or hospitalizations, although biologics may be associated with a subtle URI risk. We show that the risk of infantile infections in certolizumab is comparable with other anti-TNF agents, suggesting that avoiding more efficacious anti-TNF therapy in pregnant women with IBD may not be warranted. Finally, we demonstrate that continuing biologics during the third trimester does not confer additional infection risk. Our study addresses critical questions raised by patients and clinicians and reinforces that the benefits of continuing biologic therapy throughout pregnancy to maintain disease remission outweighs the risks of infantile infections.
CONFLICTS OF INTEREST
Guarantor of the article: John Gubatan, MD.
Specific author contributions: J.G. and O.H.N. planned and designed the study and analyzed the data. J.G. and O.H.N. performed the systematic review and extracted the data from manuscripts. J.G. and O.H.N. performed the quality assessment of studies. J.G. performed the statistical analyses in collaboration with C.B.J. S.L. assisted with background literature review and manuscript drafting and provided clinical insight regarding pediatric infections. O.H.N., C.M., S.E.S., C.B.J., and A.H. provided critical review of the manuscript. J.G. drafted the manuscript. All authors interpreted the results and contributed to the critical review of the manuscript. J.G. had full access to the study data and takes responsibility for the integrity of the data and accuracy of the analysis.
Financial support: J.G. is in part supported by a Chan Zuckerberg Biohub Physician Scientist Scholar Award and an NIH NIDDK LRP Award.
Potential competing interests: None to report.
WHAT IS KNOWN
- ✓ Biologic use in patients with inflammatory bowel disease is associated with an increased risk of infections.
- ✓ Biologics can cross the placenta during pregnancy and persist at detectable concentrations in infants.
- ✓ Maternal transfer of biologics during pregnancy may affect infant immune development.
- ✓ The risk of infections in infants exposed to biologics in utero is controversial.
WHAT IS NEW HERE
- ✓ Biologics during pregnancy is not associated with an increased risk of all infantile infections.
- ✓ The risk of upper respiratory infections may be higher in infants exposed to biologics during pregnancy.
- ✓ Biologics during pregnancy is not associated with the risk of infantile antibiotic use or infection-related hospitalizations.
- ✓ Therisk of infantile infections was not different between exposure to certolizumab vs other antitumor necrosis factor agents.
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