Anti-TNF Levels in Cord Blood at Birth are Associated with Anti-TNF Type

Anti-TNF Levels in Cord Blood at Birth are Associated with Anti-TNF Type Abstract Background and aims Pregnancy guidelines for women with inflammatory bowel disease [IBD] provide recommendations regarding anti-TNF cessation during pregnancy, in order to limit foetal exposure. Although infliximab [IFX] leads to higher anti-TNF concentrations in cord blood than adalimumab [ADA], the recommendations are similar. We aimed to demonstrate the effect of anti-TNF cessation during pregnancy on foetal exposure, for IFX and ADA separately. Methods We conducted a prospective single-center cohort study. Women with IBD, using IFX or ADA, were followed-up during pregnancy. In case of sustained disease remission, anti-TNF was stopped in the third trimester. At the birth, the anti-TNF concentration was measured in the cord blood. A linear regression model was developed to demonstrate anti-TNF concentration in cord blood at birth. In addition, outcomes such as disease activity, pregnancy outcomes and 1-year health outcomes of infants were collected. Results We included 131 pregnancies that resulted in a live birth [73 IFX, 58 ADA]. At birth, 94 cord blood samples were obtained [52 IFX, 42 ADA], showing significantly higher levels of IFX than ADA [p < 0.0001]. Anti-TNF type and stop week were used in the linear regression model. During the third trimester, IFX transportation over the placenta increased exponentially; however, ADA transportation was limited and increased in a linear fashion. Overall, health outcomes were comparable. Conclusions Our linear regression model shows that ADA may be continued longer during pregnancy, because transportation over the placenta is lower than for IFX. This may reduce relapse risk of the mother, without increasing foetal anti-TNF exposure. Infliximab, adalimumab, pregnancy 1. Introduction Active inflammatory bowel disease [IBD] during conception and pregnancy has been associated with adverse pregnancy outcomes such as spontaneous abortion, intrauterine growth restriction, preterm birth and low birth weight.1–4 Current pregnancy guidelines therefore advise conception during a time of disease remission.5,6 In order to maintain disease remission, anti-TNF IgG1 monoclonal antibodies such as infliximab [IFX] and adalimumab [ADA] are increasingly being used. These drugs, however, are actively transported over the placenta to the foetus.7,8 The transportation of IgG1 antibodies over the placenta increases exponentially during the third trimester, resulting in higher foetal levels than maternal levels at term.9–11 Previous studies among women suffering from IBD have suggested that the use of IFX and ADA during pregnancy is not related to adverse pregnancy outcomes, nor to adverse health outcomes of children until 1 year of age.12–17 However, a case series reported severe neutropenia at birth in four IFX-exposed children18; also, a case of a fatal disseminated Bacille Calmette-Guerin [BCG] infection of an IFX-exposed child has been reported.19 In addition, an increased infection risk has been seen in children exposed in utero to a combination of an immunomodulator and either IFX or ADA,20,21 and it should be noted that long-term health outcomes of anti-TNF–exposed infants have scarcely been studied. In view of this data, the safety of in utero exposure to high levels of anti-TNF is difficult to take for granted and should preferably be avoided. Current pregnancy guidelines provide recommendations on how to balance the limiting of drug exposure in utero to avoid health risks for the foetus with maintaining maternal disease remission. If women are not in sustained disease remission, it is advised to continue anti-TNF treatment throughout the entire pregnancy, because active IBD increases the risk of adverse pregnancy outcomes. However, in the case of women in sustained disease remission, anti-TNF treatment cessation may be considered in the third trimester to minimize foetal drug exposure. Anti-TNF cessation in the third trimester seems feasible in this latter group because it does not lead to an increased relapse risk.17 These current pregnancy guidelines, however, do not differentiate between IFX and ADA, although different pharmacokinetics are expected. A recent study, comparing anti-TNF levels in cord blood and the time of infant drug clearance between IFX-exposed infants and ADA-exposed infants, found significantly higher anti-TNF levels in cord blood and a longer time to anti-TNF clearance in IFX-exposed infants than in ADA-exposed infants.20 This suggests that it may be possible to extend ADA treatment longer during the third trimester of pregnancy than IFX treatment, without increasing anti-TNF levels in the newborn. The primary aim of our study was to illustrate the effect of gestational anti-TNF cessation on foetal drug exposure in a linear regression model for IFX and ADA separately. The secondary aims were to assess disease course during pregnancy, birth outcomes, adverse events after anti-TNF re-initiation, and infants’ health outcomes at 1 year for IFX and ADA separately. 2. Material and Methods 2.1. Study design All IBD women treated with either IFX or ADA who visited the preconception outpatient clinic at the Erasmus University Medical Center Rotterdam, a tertiary health centre, from December 2008 through June 2016 were prospectively enrolled. If patients did not attend follow-up visits at our clinic and/or if the pregnancy outcomes could not be retraced, they were excluded from analyses. This cohort consisted partly of women from a previously published cohort17 and partly of additional follow-up information. During visits at our IBD outpatient clinic, patients were counselled before pregnancy and seen bi-monthly during pregnancy by an experienced IBD physician. In case of disease activity, women were seen every second week at the outpatient clinic. Patients were counselled on medication use, folic acid intake, life style habits [e.g. smoking, alcohol use] and the importance of achieving and maintaining disease remission before conception and during pregnancy. Data regarding disease activity, medication adherence, smoking, alcohol use, folic acid intake and obstetric complications were collected during each visit. Disease activity was assessed based on clinical symptoms. (Harvey Bradshaw Index [HBI] or Simplified Clinical Colitis Activity Index [SCCAI], blood analysis, fecal calprotectin [FCP] measurement and an endoscopy was performed when necessary.) In case of disease relapse at any time from 6 months before conception until Gestational Week 20, anti-TNF treatment would be continued during the entire pregnancy. In case of sustained disease remission from 6 months before conception until Gestational Week 20, the option of discontinuing anti-TNF treatment in the third trimester was discussed in a multidisciplinary team, including the gynaecologist and the patient. All patients were additionally informed by an experienced IBD nurse regarding anti-TNF measurements in cord blood and peripheral maternal blood at birth. During this consult, patients received written instructions on how to obtain the blood samples at birth, which they handed over to their gynaecologist. During delivery, blood samples were collected by the gynaecologist and sent directly to the Laboratory of Gastroenterology at the Erasmus University Medical Center. Birth outcomes such as gestational age at birth, birth weight, and the presence of congenital abnormalities were noted during the first visit after delivery. After 1 year, health outcomes from infants were obtained through telephonic questionnaire with mothers and/or by obtaining medical information from the general practitioner after the consent of both parents. The 1-year outcomes included growth, infections for which systemic antibiotic treatment were needed, hospitalization for an infection, allergies, chronic diseases, adverse reactions to vaccinations, and the presence of eczema. 2.2. Outcome measurements Anti-TNF serum level measurements were performed since 2010 at our clinic. These measurements were done by ELISA from peripheral blood, as described in previous papers.9,22 2.3. Definitions Abnormal growth is defined as a growth or height for age and gender deviating >2 standard deviations [SD] from the mean Dutch growth chart. Preterm birth is defined as a delivery before 37 weeks of gestation. Small for gestational age [SGA] is a weight below the 2 SD for gestational age according to the Dutch reference curve.23 The presence of disease activity was assessed by the treating physician and based on the combination of clinical symptoms [HBI > 5 or SCCAI > 2], C-reactive protein [CRP] > 9.0 mgL, FCP measurement > 200 µg/g and when strongly indicated, an endoscopy was performed. The standard dose of anti-TNF treatment is 5 mg/kg intravenously every 8 weeks for IFX and 40 mg subcutaneously every 2 weeks for ADA. 2.4. Study size The primary aim was to assess the difference in anti-TNF cord blood concentrations between IFX and ADA and subsequently use the anti-TNF cord blood concentrations as a dependent variable in a linear regression model. The null hypothesis assumed no difference in anti-TNF cord blood concentration between IFX users and ADA users. We used the median anti-TNF level in cord blood and the range from a previous study20 and estimated the mean and SD according to the method devised by Hozo et al.24 We expected the mean anti-TNF concentration of ADA users to be lower than the mean anti-TNF concentration of IFX users; therefore, a one-sided test with alpha of 2.5% was used. To detect a lower mean anti-TNF concentration in cord blood of 3.5 µg/mL in ADA users, with a power of 90%, the estimated sample size was 31 per arm. 2.5. Statistical considerations All analyses were performed using IBM SPSS statistics [version 21.0 Chicago III, USA]. Descriptive statistics of continuous data are displayed as median with interquartile ranges [IQRs] or means with SDs, and compared using Students t-tests or Mann–Whitney U tests. Categorical data are shown as absolute numbers with percentages, and compared using Fisher’s exact tests. The tests were performed two-tailed, unless stated differently, and tested at a significance level of 0.05. Univariate and multivariate analysis are shown with a 95% confidence interval [CI]. Anti-TNF cord blood data was normalized by log transformation. Simple linear regression analyses were performed to determine the association between variables and anti-TNF concentration in cord blood at birth. All possible predictors [i.e. maternal age, diagnosis, pre-pregnancy body mass index [BMI], pre-pregnancy weight, anti-TNF stop week, smoking, type of anti-TNF, thiopurine use, steroid use, gestational age at birth, birth weight, bowel resection prior to pregnancy, anti-TNF dose, and disease relapse during pregnancy] were considered. Subsequently, only variables with a p-value < 0.20 in the univariate analysis and variables based on clinician’s rationale [i.e. disease activity during pregnancy, anti-TNF dose, and concomitant thiopurine use] were considered for the multiple linear regression model. These variables were carefully weighted to create the most favorable model. In the final multivariate model, interactions were tested between the independent variables and were included when significant [p < 0.01]. 2.6. Ethical statement This study was approved by the local ethics committee of the Erasmus University Medical Center [Rotterdam, The Netherlands]. Legal guardians of the children signed informed consent before data was collected from the general practitioner. 3. Results A total of 416 pregnancies were recorded at our outpatient clinic; during 170 [41%] pregnancies, mothers were treated with anti-TNF. Of these pregnancies, 136 [80%] resulted in a live birth, 28 [16%] resulted in spontaneous abortion, 5 [3%] were pregnant at the time of analyses, and 1 [1%] pregnancy was terminated by an elective abortion. 3.1. Live births We included 136 live births from 102 mothers (82 [80%] with Crohn’s disease [CD], 19 [19%] with ulcerative colitis [UC] and 1 [1%] with IBD unclassified). During conception and/or pregnancy, 76 [56%] infants were exposed to IFX and 60 [44%] were exposed to ADA in utero. There were 5 women who stopped anti-TNF treatment before the second trimester [3 IFX, 2 ADA], which was advised by a physician other than a gastroenterologist. These women were excluded from further analyses. Baseline characteristics per pregnancy are shown in Table 1. In our cohort, women with CD more often used ADA, and women with UC more often used IFX. In addition, IFX was more often prescribed in the case of extensive CD and in combination with a thiopurine. There were no other differences in the baseline characteristics between IFX users and ADA users. Table 1 Baseline characteristics per pregnancy [n = 131]. IFX [n = 73] ADA [n = 58] p value Median maternal age during conception [IQR] 30 [27–33] 30 [28–33] 0.59 Education level [%] High 27 [43] 18 [35] 0.44 Middle 34 [55] 33 [65] 0.34 Low 1 [2] 0 [0] 1.00 Diagnosis [%] Crohn’s disease 54 [74] 51 [88] 0.05 Ulcerative colitis 18 [25] 6 [10] 0.04 IBD unclassified 1 [1] 1 [2] 1.00 Disease location CD [Montreal] [%]  L1 Ileal 10 [19] 15 [30] 0.25  L2 Colonic 8 [15] 15 [30] 0.10  L3 Ileocolonic 35 [66] 20 [40] 0.01 Disease behaviour CD [Montreal] [%]  B1 Non-stricturing non-penetrating 44 [61] 28 [51] 0.28  B2 Stricturing 2 [3] 4 [7] 0.40  B3 Penetrating 14 [19] 14 [26] 0.52  B2 + B3 Stricturing and penetrating 12 [17] 9 [16] 1.00 P Perianal fistulizing disease [%] 20 [28] 19 [33] 0.57 Disease extent UC/IBDU [Montreal] [%]  E1 Proctitis 0 [0] 0 [0] 1.00  E2 Left-sided colitis 4 [21] 4 [57] 0.15  E3 Pancolitis 15 [79] 3 [43] 0.15 Disease duration in years [IQR] 7 [3–11] 7 [5–11] 0.58 Duration of anti-TNF treatment in months [IQR] 24 [8–40] 23 [8–38] 0.74 Anti-TNF dose [%]  Standard dose 50 [69] 47 [81] 0.11  Increased dose 3 [4] 0 [0] 0.13  Increased frequency 19 [26] 11 [19] 0.30  Increased dose and frequency 1 [1] 0 [0] 1.00 Co-medication  Mesalazine 5 [7] 5 [9] 0.75  Steroids [systemic] 9 [12] 10 [17] 0.46  Thiopurine 29 [40] 5 [9] 0.0001 IBD surgery [%]  Abdominal surgery 14 [19] 14 [25] 0.52  Perianal surgery 13 [19] 12 [22] 0.82 EIM prior to pregnancy [%] 15 [22] 14 [26] 0.68 Parity [%]  Nulliparous 47 [65] 30 [54] 0.21  Multiparous 24 [34] 26 [46] 0.20 Median pre-pregnancy BMI [IQR] 25 [22–27] 23 [21–27] 0.25 Disease relapse in the preceding year [%] 20 [29] 22 [47] 0.08 Folic acid intake [%] 55 [83] 45 [83] 1.00 Smoking [%] 5 [7] 6 [11] 0.53 Fertility treatment [%] 3 [4] 5 [9] 0.47 IFX [n = 73] ADA [n = 58] p value Median maternal age during conception [IQR] 30 [27–33] 30 [28–33] 0.59 Education level [%] High 27 [43] 18 [35] 0.44 Middle 34 [55] 33 [65] 0.34 Low 1 [2] 0 [0] 1.00 Diagnosis [%] Crohn’s disease 54 [74] 51 [88] 0.05 Ulcerative colitis 18 [25] 6 [10] 0.04 IBD unclassified 1 [1] 1 [2] 1.00 Disease location CD [Montreal] [%]  L1 Ileal 10 [19] 15 [30] 0.25  L2 Colonic 8 [15] 15 [30] 0.10  L3 Ileocolonic 35 [66] 20 [40] 0.01 Disease behaviour CD [Montreal] [%]  B1 Non-stricturing non-penetrating 44 [61] 28 [51] 0.28  B2 Stricturing 2 [3] 4 [7] 0.40  B3 Penetrating 14 [19] 14 [26] 0.52  B2 + B3 Stricturing and penetrating 12 [17] 9 [16] 1.00 P Perianal fistulizing disease [%] 20 [28] 19 [33] 0.57 Disease extent UC/IBDU [Montreal] [%]  E1 Proctitis 0 [0] 0 [0] 1.00  E2 Left-sided colitis 4 [21] 4 [57] 0.15  E3 Pancolitis 15 [79] 3 [43] 0.15 Disease duration in years [IQR] 7 [3–11] 7 [5–11] 0.58 Duration of anti-TNF treatment in months [IQR] 24 [8–40] 23 [8–38] 0.74 Anti-TNF dose [%]  Standard dose 50 [69] 47 [81] 0.11  Increased dose 3 [4] 0 [0] 0.13  Increased frequency 19 [26] 11 [19] 0.30  Increased dose and frequency 1 [1] 0 [0] 1.00 Co-medication  Mesalazine 5 [7] 5 [9] 0.75  Steroids [systemic] 9 [12] 10 [17] 0.46  Thiopurine 29 [40] 5 [9] 0.0001 IBD surgery [%]  Abdominal surgery 14 [19] 14 [25] 0.52  Perianal surgery 13 [19] 12 [22] 0.82 EIM prior to pregnancy [%] 15 [22] 14 [26] 0.68 Parity [%]  Nulliparous 47 [65] 30 [54] 0.21  Multiparous 24 [34] 26 [46] 0.20 Median pre-pregnancy BMI [IQR] 25 [22–27] 23 [21–27] 0.25 Disease relapse in the preceding year [%] 20 [29] 22 [47] 0.08 Folic acid intake [%] 55 [83] 45 [83] 1.00 Smoking [%] 5 [7] 6 [11] 0.53 Fertility treatment [%] 3 [4] 5 [9] 0.47 IBD, inflammatory bowel disease; IQR, interquartile range; IFX, infliximab; ADA, adalimumab; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, IBD unclassified; EMI, extra-intestinal manifestation; BMI, body mass index. View Large Table 1 Baseline characteristics per pregnancy [n = 131]. IFX [n = 73] ADA [n = 58] p value Median maternal age during conception [IQR] 30 [27–33] 30 [28–33] 0.59 Education level [%] High 27 [43] 18 [35] 0.44 Middle 34 [55] 33 [65] 0.34 Low 1 [2] 0 [0] 1.00 Diagnosis [%] Crohn’s disease 54 [74] 51 [88] 0.05 Ulcerative colitis 18 [25] 6 [10] 0.04 IBD unclassified 1 [1] 1 [2] 1.00 Disease location CD [Montreal] [%]  L1 Ileal 10 [19] 15 [30] 0.25  L2 Colonic 8 [15] 15 [30] 0.10  L3 Ileocolonic 35 [66] 20 [40] 0.01 Disease behaviour CD [Montreal] [%]  B1 Non-stricturing non-penetrating 44 [61] 28 [51] 0.28  B2 Stricturing 2 [3] 4 [7] 0.40  B3 Penetrating 14 [19] 14 [26] 0.52  B2 + B3 Stricturing and penetrating 12 [17] 9 [16] 1.00 P Perianal fistulizing disease [%] 20 [28] 19 [33] 0.57 Disease extent UC/IBDU [Montreal] [%]  E1 Proctitis 0 [0] 0 [0] 1.00  E2 Left-sided colitis 4 [21] 4 [57] 0.15  E3 Pancolitis 15 [79] 3 [43] 0.15 Disease duration in years [IQR] 7 [3–11] 7 [5–11] 0.58 Duration of anti-TNF treatment in months [IQR] 24 [8–40] 23 [8–38] 0.74 Anti-TNF dose [%]  Standard dose 50 [69] 47 [81] 0.11  Increased dose 3 [4] 0 [0] 0.13  Increased frequency 19 [26] 11 [19] 0.30  Increased dose and frequency 1 [1] 0 [0] 1.00 Co-medication  Mesalazine 5 [7] 5 [9] 0.75  Steroids [systemic] 9 [12] 10 [17] 0.46  Thiopurine 29 [40] 5 [9] 0.0001 IBD surgery [%]  Abdominal surgery 14 [19] 14 [25] 0.52  Perianal surgery 13 [19] 12 [22] 0.82 EIM prior to pregnancy [%] 15 [22] 14 [26] 0.68 Parity [%]  Nulliparous 47 [65] 30 [54] 0.21  Multiparous 24 [34] 26 [46] 0.20 Median pre-pregnancy BMI [IQR] 25 [22–27] 23 [21–27] 0.25 Disease relapse in the preceding year [%] 20 [29] 22 [47] 0.08 Folic acid intake [%] 55 [83] 45 [83] 1.00 Smoking [%] 5 [7] 6 [11] 0.53 Fertility treatment [%] 3 [4] 5 [9] 0.47 IFX [n = 73] ADA [n = 58] p value Median maternal age during conception [IQR] 30 [27–33] 30 [28–33] 0.59 Education level [%] High 27 [43] 18 [35] 0.44 Middle 34 [55] 33 [65] 0.34 Low 1 [2] 0 [0] 1.00 Diagnosis [%] Crohn’s disease 54 [74] 51 [88] 0.05 Ulcerative colitis 18 [25] 6 [10] 0.04 IBD unclassified 1 [1] 1 [2] 1.00 Disease location CD [Montreal] [%]  L1 Ileal 10 [19] 15 [30] 0.25  L2 Colonic 8 [15] 15 [30] 0.10  L3 Ileocolonic 35 [66] 20 [40] 0.01 Disease behaviour CD [Montreal] [%]  B1 Non-stricturing non-penetrating 44 [61] 28 [51] 0.28  B2 Stricturing 2 [3] 4 [7] 0.40  B3 Penetrating 14 [19] 14 [26] 0.52  B2 + B3 Stricturing and penetrating 12 [17] 9 [16] 1.00 P Perianal fistulizing disease [%] 20 [28] 19 [33] 0.57 Disease extent UC/IBDU [Montreal] [%]  E1 Proctitis 0 [0] 0 [0] 1.00  E2 Left-sided colitis 4 [21] 4 [57] 0.15  E3 Pancolitis 15 [79] 3 [43] 0.15 Disease duration in years [IQR] 7 [3–11] 7 [5–11] 0.58 Duration of anti-TNF treatment in months [IQR] 24 [8–40] 23 [8–38] 0.74 Anti-TNF dose [%]  Standard dose 50 [69] 47 [81] 0.11  Increased dose 3 [4] 0 [0] 0.13  Increased frequency 19 [26] 11 [19] 0.30  Increased dose and frequency 1 [1] 0 [0] 1.00 Co-medication  Mesalazine 5 [7] 5 [9] 0.75  Steroids [systemic] 9 [12] 10 [17] 0.46  Thiopurine 29 [40] 5 [9] 0.0001 IBD surgery [%]  Abdominal surgery 14 [19] 14 [25] 0.52  Perianal surgery 13 [19] 12 [22] 0.82 EIM prior to pregnancy [%] 15 [22] 14 [26] 0.68 Parity [%]  Nulliparous 47 [65] 30 [54] 0.21  Multiparous 24 [34] 26 [46] 0.20 Median pre-pregnancy BMI [IQR] 25 [22–27] 23 [21–27] 0.25 Disease relapse in the preceding year [%] 20 [29] 22 [47] 0.08 Folic acid intake [%] 55 [83] 45 [83] 1.00 Smoking [%] 5 [7] 6 [11] 0.53 Fertility treatment [%] 3 [4] 5 [9] 0.47 IBD, inflammatory bowel disease; IQR, interquartile range; IFX, infliximab; ADA, adalimumab; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, IBD unclassified; EMI, extra-intestinal manifestation; BMI, body mass index. View Large 3.2. Maternal outcomes Maternal outcomes are displayed in Table 2. There were no differences regarding weight gain during pregnancy, anti-TNF stop week, disease relapse during pregnancy, or successful treatment of the relapse between IFX users and ADA users. In addition, we observed no differences in adverse events after restarting anti-TNF post-partum, such as allergic reactions, loss of response, or disease relapse within 3 months post-partum between these groups. Table 2 Maternal and pregnancy outcomes [n = 131]. IFX [n = 73] ADA [n = 58] p value Median weight gain in kilograms during pregnancy [IQR] 12 [10–18] 12 [10–15] 0.90 Anti-TNF stopped during pregnancy <Week 25 [%] 37 [52] 33 [57] 0.60 Median anti-TNF stop week during pregnancy [IQR] 23 [21–32] 23 [22–37] 0.19 Total disease activity during pregnancy [%] 19 [26] 19 [35] 0.33 Activity ongoing from conception [%] 7 [10] 8 [15] 0.42 New relapse during pregnancy [%] 12 [16] 11 [20] 0.65 Successful relapse treatment before delivery [%] 14 [78] 11 [58] 0.30 Median anti-TNF restart week postpartum [IQR] 3 [1–4] 2 [0–3.5] 0.20 Allergic reaction at restart anti-TNF [%] 2 [3]a 1 [2]b 1.00 Loss of response after restart anti-TNF [%] 1 [1]c 1 [2]d 1.00 Disease relapse within 3 months postpartum [%] 7 [12] 8 [19] 0.40 Median birthweight in kilograms [IQR] 3.3 [3.0–3.7] 3.4 [3.1–3.6] 0.50 Low birth weight [%] 6 [9] 4 [7] 1.00 Median gestational age [IQR] 39 [38–40] 39 [38–40] 0.75 Preterm birth [%] 7 [10] 2 [3] 0.18 Small for gestational age [SGA] [%] 3 [4] 1 [2] 0.63 Major congenital abnormalities [%] 3 [4.7]e 0 [0] 0.25 Breastfeeding >2 weeks [%] 18 [30] 16 [33] 0.68 Mode of delivery [%] Vaginal delivery 32 [48] 34 [61] 0.21 Caesarean section 35 [52] 22 [39] 0.21 IFX [n = 73] ADA [n = 58] p value Median weight gain in kilograms during pregnancy [IQR] 12 [10–18] 12 [10–15] 0.90 Anti-TNF stopped during pregnancy <Week 25 [%] 37 [52] 33 [57] 0.60 Median anti-TNF stop week during pregnancy [IQR] 23 [21–32] 23 [22–37] 0.19 Total disease activity during pregnancy [%] 19 [26] 19 [35] 0.33 Activity ongoing from conception [%] 7 [10] 8 [15] 0.42 New relapse during pregnancy [%] 12 [16] 11 [20] 0.65 Successful relapse treatment before delivery [%] 14 [78] 11 [58] 0.30 Median anti-TNF restart week postpartum [IQR] 3 [1–4] 2 [0–3.5] 0.20 Allergic reaction at restart anti-TNF [%] 2 [3]a 1 [2]b 1.00 Loss of response after restart anti-TNF [%] 1 [1]c 1 [2]d 1.00 Disease relapse within 3 months postpartum [%] 7 [12] 8 [19] 0.40 Median birthweight in kilograms [IQR] 3.3 [3.0–3.7] 3.4 [3.1–3.6] 0.50 Low birth weight [%] 6 [9] 4 [7] 1.00 Median gestational age [IQR] 39 [38–40] 39 [38–40] 0.75 Preterm birth [%] 7 [10] 2 [3] 0.18 Small for gestational age [SGA] [%] 3 [4] 1 [2] 0.63 Major congenital abnormalities [%] 3 [4.7]e 0 [0] 0.25 Breastfeeding >2 weeks [%] 18 [30] 16 [33] 0.68 Mode of delivery [%] Vaginal delivery 32 [48] 34 [61] 0.21 Caesarean section 35 [52] 22 [39] 0.21 aInfusion reaction, both treated with hydrocortisone and clemastine; bItch after ADA administration, treated with antihistamine; cDecreased effect of IFX after restart, switched to ADA after 5 months; dDecreased effect of ADA, switched to vedolizumab after 5 months; eVSD [n = 1], cleft palate [n = 1] and polydactyly [n = 1]. IQR, interquartile range. View Large Table 2 Maternal and pregnancy outcomes [n = 131]. IFX [n = 73] ADA [n = 58] p value Median weight gain in kilograms during pregnancy [IQR] 12 [10–18] 12 [10–15] 0.90 Anti-TNF stopped during pregnancy <Week 25 [%] 37 [52] 33 [57] 0.60 Median anti-TNF stop week during pregnancy [IQR] 23 [21–32] 23 [22–37] 0.19 Total disease activity during pregnancy [%] 19 [26] 19 [35] 0.33 Activity ongoing from conception [%] 7 [10] 8 [15] 0.42 New relapse during pregnancy [%] 12 [16] 11 [20] 0.65 Successful relapse treatment before delivery [%] 14 [78] 11 [58] 0.30 Median anti-TNF restart week postpartum [IQR] 3 [1–4] 2 [0–3.5] 0.20 Allergic reaction at restart anti-TNF [%] 2 [3]a 1 [2]b 1.00 Loss of response after restart anti-TNF [%] 1 [1]c 1 [2]d 1.00 Disease relapse within 3 months postpartum [%] 7 [12] 8 [19] 0.40 Median birthweight in kilograms [IQR] 3.3 [3.0–3.7] 3.4 [3.1–3.6] 0.50 Low birth weight [%] 6 [9] 4 [7] 1.00 Median gestational age [IQR] 39 [38–40] 39 [38–40] 0.75 Preterm birth [%] 7 [10] 2 [3] 0.18 Small for gestational age [SGA] [%] 3 [4] 1 [2] 0.63 Major congenital abnormalities [%] 3 [4.7]e 0 [0] 0.25 Breastfeeding >2 weeks [%] 18 [30] 16 [33] 0.68 Mode of delivery [%] Vaginal delivery 32 [48] 34 [61] 0.21 Caesarean section 35 [52] 22 [39] 0.21 IFX [n = 73] ADA [n = 58] p value Median weight gain in kilograms during pregnancy [IQR] 12 [10–18] 12 [10–15] 0.90 Anti-TNF stopped during pregnancy <Week 25 [%] 37 [52] 33 [57] 0.60 Median anti-TNF stop week during pregnancy [IQR] 23 [21–32] 23 [22–37] 0.19 Total disease activity during pregnancy [%] 19 [26] 19 [35] 0.33 Activity ongoing from conception [%] 7 [10] 8 [15] 0.42 New relapse during pregnancy [%] 12 [16] 11 [20] 0.65 Successful relapse treatment before delivery [%] 14 [78] 11 [58] 0.30 Median anti-TNF restart week postpartum [IQR] 3 [1–4] 2 [0–3.5] 0.20 Allergic reaction at restart anti-TNF [%] 2 [3]a 1 [2]b 1.00 Loss of response after restart anti-TNF [%] 1 [1]c 1 [2]d 1.00 Disease relapse within 3 months postpartum [%] 7 [12] 8 [19] 0.40 Median birthweight in kilograms [IQR] 3.3 [3.0–3.7] 3.4 [3.1–3.6] 0.50 Low birth weight [%] 6 [9] 4 [7] 1.00 Median gestational age [IQR] 39 [38–40] 39 [38–40] 0.75 Preterm birth [%] 7 [10] 2 [3] 0.18 Small for gestational age [SGA] [%] 3 [4] 1 [2] 0.63 Major congenital abnormalities [%] 3 [4.7]e 0 [0] 0.25 Breastfeeding >2 weeks [%] 18 [30] 16 [33] 0.68 Mode of delivery [%] Vaginal delivery 32 [48] 34 [61] 0.21 Caesarean section 35 [52] 22 [39] 0.21 aInfusion reaction, both treated with hydrocortisone and clemastine; bItch after ADA administration, treated with antihistamine; cDecreased effect of IFX after restart, switched to ADA after 5 months; dDecreased effect of ADA, switched to vedolizumab after 5 months; eVSD [n = 1], cleft palate [n = 1] and polydactyly [n = 1]. IQR, interquartile range. View Large 3.3. Disease relapse Overall, 42 [32%] women had a disease relapse in the year before conception, and 38 [30%] women experienced disease activity during pregnancy, of which, 15 [40%] were ongoing from conception and 23 [60%] were new relapses. The types of disease activity were as follows: 33 [87%] women had luminal disease activity, 4 [10%] women had an active perianal fistula, and 1 [3%] woman had an active extra-intestinal manifestation [EIM]. Active perianal fistula and EIM were diagnosed during clinical physical examination. Luminal disease activity was diagnosed by endoscopy [n = 12, 37%], abdominal ultrasound [n = 1, 3%], or based on clinical symptoms and laboratory work-up [CRP and/or FCP measurement] [n = 20, 60%]. Disease activity was treated as follows: in 6 cases anti-TNF was restarted or never discontinued because of disease activity, 11 women were treated with corticosteroids, 2 women were treated with antibiotics, and 1 woman was treated by means of nasogastric feeding. In other cases, the delivery was advanced or activity was not treated, as requested bythe patient. Treatment was successful in 25 [68%] cases before delivery. As advised by current pregnancy guidelines, women discontinued anti-TNF treatment before the third trimester in the case of sustained disease remission. Overall, there were 37 [52%] women using IFX and 33 [57%] women using ADA who discontinued treatment between Gestational Weeks 12 and 25 [p = 0.60]. In those cases in which women stopped treatment between Gestational Weeks 12 and 25, the rate of new relapses during pregnancy was 4 [11%] for women using IFX and 3 [10%] for women using ADA; this difference was not statistically significant [p = 1.00]. In those cases in which women continued anti-TNF after Gestational Week 25, the rate of new relapses during pregnancy was 8 [24%] for women using IFX and 8 [33%] for women using ADA; however, this difference was also not statistically significant [p = 0.55]. 3.4. Pregnancy outcomes No differences were observed in terms of birth weight, gestational age at birth, the presence of congenital abnormalities, or mode of delivery between IFX-exposed infants and ADA-exposed infants [Table 2]. Three children were born with a congenital abnormality. Two of the 3 mothers did not use folic acid at the time of conception. In addition, the mother of the child born with a polydactyly used methotrexate at the time of conception. She stopped the methotrexate and started folic acid after she discovered her pregnancy. The other mothers did not use teratogenic medication. 3.5. Drug concentration in cord blood and maternal blood At birth, cord blood samples in which anti-TNF concentration was measured were obtained from 94 mothers; 52 used IFX and 42 used ADA during pregnancy. The results are shown in Table 3. Anti-TNF levels in cord blood, and the ratio of cord blood level / maternal level were both higher in IFX users than in ADA users. In addition, anti-TNF levels in maternal blood were higher in IFX users than in ADA users [p = 0.05]. There were no other differences between women using IFX and women using ADA regarding anti-TNF stop week during pregnancy, duration of anti-TNF treatment before conception, relapse rate, or number of women using the standard dose. Table 3 Outcomes for mother–newborn pairs with anti-TNF measurement in cord blood [n = 94]. IFX [n = 52] ADA [n = 42] p value Median anti-TNF concentration in cord blood [µg/mL] [IQR] 4.9 [1.9–14.7] 1.1 [0.4–37.0] 0.0001 Median anti-TNF level in maternal blood at birth [µg/mL] [IQR] 1.7 [0.4–6.9] 0.6 [0.3–3.6] 0.05 Median ratio of cord blood level / maternal level [IQR] 2.63 [1.67–4.03] 1.36 [1.00–2.08] 0.0001 Median anti-TNF stop week [IQR] 25 [21–32] 23 [22–37] 0.56 Anti-TNF stopped during pregnancy before gestational Week 25 [%] 26 [50] 26 [62] 0.30 Disease relapse during pregnancy [%] 15 [29] 14 [36] 0.50 Median duration of anti-TNF treatment in months before pregnancy [IQR] 24 [8–40] 22 [8–38] 0.73 Standard dose anti-TNF [%] 35 [67] 33 [79] 0.25 IFX [n = 52] ADA [n = 42] p value Median anti-TNF concentration in cord blood [µg/mL] [IQR] 4.9 [1.9–14.7] 1.1 [0.4–37.0] 0.0001 Median anti-TNF level in maternal blood at birth [µg/mL] [IQR] 1.7 [0.4–6.9] 0.6 [0.3–3.6] 0.05 Median ratio of cord blood level / maternal level [IQR] 2.63 [1.67–4.03] 1.36 [1.00–2.08] 0.0001 Median anti-TNF stop week [IQR] 25 [21–32] 23 [22–37] 0.56 Anti-TNF stopped during pregnancy before gestational Week 25 [%] 26 [50] 26 [62] 0.30 Disease relapse during pregnancy [%] 15 [29] 14 [36] 0.50 Median duration of anti-TNF treatment in months before pregnancy [IQR] 24 [8–40] 22 [8–38] 0.73 Standard dose anti-TNF [%] 35 [67] 33 [79] 0.25 Italic values signifies that all test were performed two-tailed unless stated differently and tested at a significant level of 0.05 as stated in the statistical considerations. IQR, interquartile range; IFX, infliximab; ADA, adalimumab. View Large Table 3 Outcomes for mother–newborn pairs with anti-TNF measurement in cord blood [n = 94]. IFX [n = 52] ADA [n = 42] p value Median anti-TNF concentration in cord blood [µg/mL] [IQR] 4.9 [1.9–14.7] 1.1 [0.4–37.0] 0.0001 Median anti-TNF level in maternal blood at birth [µg/mL] [IQR] 1.7 [0.4–6.9] 0.6 [0.3–3.6] 0.05 Median ratio of cord blood level / maternal level [IQR] 2.63 [1.67–4.03] 1.36 [1.00–2.08] 0.0001 Median anti-TNF stop week [IQR] 25 [21–32] 23 [22–37] 0.56 Anti-TNF stopped during pregnancy before gestational Week 25 [%] 26 [50] 26 [62] 0.30 Disease relapse during pregnancy [%] 15 [29] 14 [36] 0.50 Median duration of anti-TNF treatment in months before pregnancy [IQR] 24 [8–40] 22 [8–38] 0.73 Standard dose anti-TNF [%] 35 [67] 33 [79] 0.25 IFX [n = 52] ADA [n = 42] p value Median anti-TNF concentration in cord blood [µg/mL] [IQR] 4.9 [1.9–14.7] 1.1 [0.4–37.0] 0.0001 Median anti-TNF level in maternal blood at birth [µg/mL] [IQR] 1.7 [0.4–6.9] 0.6 [0.3–3.6] 0.05 Median ratio of cord blood level / maternal level [IQR] 2.63 [1.67–4.03] 1.36 [1.00–2.08] 0.0001 Median anti-TNF stop week [IQR] 25 [21–32] 23 [22–37] 0.56 Anti-TNF stopped during pregnancy before gestational Week 25 [%] 26 [50] 26 [62] 0.30 Disease relapse during pregnancy [%] 15 [29] 14 [36] 0.50 Median duration of anti-TNF treatment in months before pregnancy [IQR] 24 [8–40] 22 [8–38] 0.73 Standard dose anti-TNF [%] 35 [67] 33 [79] 0.25 Italic values signifies that all test were performed two-tailed unless stated differently and tested at a significant level of 0.05 as stated in the statistical considerations. IQR, interquartile range; IFX, infliximab; ADA, adalimumab. View Large 3.6. Linear regression model The simple linear regression analyses, assessing the association between variables and anti-TNF concentration in cord blood at birth, are shown in Table 4. Only the variables anti-TNF stop week and type of anti-TNF were strongly associated with anti-TNF concentration in cord blood. There was no significant correlation between these two variables. No other variables improved the model. Therefore, in the final multiple linear regression model, anti-TNF stop week and type of anti-TNF were used as independent variables, and anti-TNF cord blood concentration at birth as a dependent variable [Figure 1]. This model shows that IFX transportation over the placenta increases exponentially during the third trimester of pregnancy. However, ADA transportation over the placenta is significantly lower than IFX and increases in a linear fashion. Table 4 Simple linear regression analyses: assessing association between variables and anti-TNF cord blood concentration. Independent variables Standardized β coefficients p value Maternal age 0.031 0.71 Diagnosis –0.078 0.41 Pre-pregnancy BMI –0.174 0.35 Pre-pregnancy weight –0.004 0.98 Anti-TNF stop week 0.738 0.0001 Smoking –0.071 0.39 Type anti-TNF –0.510 0.0001 Thiopurine –0.020 0.81 Steroids 0.027 0.77 Gestational age –0.113 0.27 Birth weight 0.053 0.56 Prior bowel resection 0.012 0.89 Standard anti-TNF dose 0.003 0.97 Relapse during pregnancy –0.118 0.24 Mode of delivery 0.05 0.58 Independent variables Standardized β coefficients p value Maternal age 0.031 0.71 Diagnosis –0.078 0.41 Pre-pregnancy BMI –0.174 0.35 Pre-pregnancy weight –0.004 0.98 Anti-TNF stop week 0.738 0.0001 Smoking –0.071 0.39 Type anti-TNF –0.510 0.0001 Thiopurine –0.020 0.81 Steroids 0.027 0.77 Gestational age –0.113 0.27 Birth weight 0.053 0.56 Prior bowel resection 0.012 0.89 Standard anti-TNF dose 0.003 0.97 Relapse during pregnancy –0.118 0.24 Mode of delivery 0.05 0.58 Italic values signifies that all test were performed two-tailed unless stated differently and tested at a significant level of 0.05 as stated in the statistical considerations. BMI, body mass index. View Large Table 4 Simple linear regression analyses: assessing association between variables and anti-TNF cord blood concentration. Independent variables Standardized β coefficients p value Maternal age 0.031 0.71 Diagnosis –0.078 0.41 Pre-pregnancy BMI –0.174 0.35 Pre-pregnancy weight –0.004 0.98 Anti-TNF stop week 0.738 0.0001 Smoking –0.071 0.39 Type anti-TNF –0.510 0.0001 Thiopurine –0.020 0.81 Steroids 0.027 0.77 Gestational age –0.113 0.27 Birth weight 0.053 0.56 Prior bowel resection 0.012 0.89 Standard anti-TNF dose 0.003 0.97 Relapse during pregnancy –0.118 0.24 Mode of delivery 0.05 0.58 Independent variables Standardized β coefficients p value Maternal age 0.031 0.71 Diagnosis –0.078 0.41 Pre-pregnancy BMI –0.174 0.35 Pre-pregnancy weight –0.004 0.98 Anti-TNF stop week 0.738 0.0001 Smoking –0.071 0.39 Type anti-TNF –0.510 0.0001 Thiopurine –0.020 0.81 Steroids 0.027 0.77 Gestational age –0.113 0.27 Birth weight 0.053 0.56 Prior bowel resection 0.012 0.89 Standard anti-TNF dose 0.003 0.97 Relapse during pregnancy –0.118 0.24 Mode of delivery 0.05 0.58 Italic values signifies that all test were performed two-tailed unless stated differently and tested at a significant level of 0.05 as stated in the statistical considerations. BMI, body mass index. View Large Figure 1 View largeDownload slide Multiple linear regression model predicting IFX and ADA cord blood concentration at birth, based on gestational stop week. The means are represented by the continuous lines, and the 95% confidence intervals are represented by the dotted lines. Figure 1 View largeDownload slide Multiple linear regression model predicting IFX and ADA cord blood concentration at birth, based on gestational stop week. The means are represented by the continuous lines, and the 95% confidence intervals are represented by the dotted lines. 3.7. One-year health outcomes of infants exposed to anti-TNF in utero Out of all live births, health outcomes until 1 year of age were obtained from 93 infants [71%]. These results are shown separately [Table 5]. Information was not obtained if infants did not yet reach the age of 1, or if we were unable to contact the mother for a telephonic questionnaire. There were no differences regarding growth, infection rate, hospitalization because of an infection, allergies, chronic diseases, adverse reactions to vaccinations, or the presence of eczema between IFX-exposed infants and ADA-exposed infants. Table 5 Health outcomes of infants at 1 year [n = 93]. IFX [n = 50] ADA [n = 43] p value Growth [%]  Normal 49 [98] 42 [98] 1.00  Abnormal 1 [2]a 1 [2]b 1.00 Number of infections treated with antibiotics [%]  0 35 [76] 31 [71] 0.82  1–2 10 [22] 10 [23] 0.48  3 1 [2] 3 [7] 0.35 Hospitalization because of infection [%] 5 [10] 3 [7] 0.72 Allergies [%] 3 [7] 5 [11] 0.48 Chronic diseases [%] 0 [0] 1 [2]c 1.00 Adverse reaction to vaccination [%] 0 [0] 0 [0] 1.00 Eczema [%] 12 [26] 6 [14] 0.20 IFX [n = 50] ADA [n = 43] p value Growth [%]  Normal 49 [98] 42 [98] 1.00  Abnormal 1 [2]a 1 [2]b 1.00 Number of infections treated with antibiotics [%]  0 35 [76] 31 [71] 0.82  1–2 10 [22] 10 [23] 0.48  3 1 [2] 3 [7] 0.35 Hospitalization because of infection [%] 5 [10] 3 [7] 0.72 Allergies [%] 3 [7] 5 [11] 0.48 Chronic diseases [%] 0 [0] 1 [2]c 1.00 Adverse reaction to vaccination [%] 0 [0] 0 [0] 1.00 Eczema [%] 12 [26] 6 [14] 0.20 aSecondary growth failure; bprimary growth failure; ccystic fibrosis. View Large Table 5 Health outcomes of infants at 1 year [n = 93]. IFX [n = 50] ADA [n = 43] p value Growth [%]  Normal 49 [98] 42 [98] 1.00  Abnormal 1 [2]a 1 [2]b 1.00 Number of infections treated with antibiotics [%]  0 35 [76] 31 [71] 0.82  1–2 10 [22] 10 [23] 0.48  3 1 [2] 3 [7] 0.35 Hospitalization because of infection [%] 5 [10] 3 [7] 0.72 Allergies [%] 3 [7] 5 [11] 0.48 Chronic diseases [%] 0 [0] 1 [2]c 1.00 Adverse reaction to vaccination [%] 0 [0] 0 [0] 1.00 Eczema [%] 12 [26] 6 [14] 0.20 IFX [n = 50] ADA [n = 43] p value Growth [%]  Normal 49 [98] 42 [98] 1.00  Abnormal 1 [2]a 1 [2]b 1.00 Number of infections treated with antibiotics [%]  0 35 [76] 31 [71] 0.82  1–2 10 [22] 10 [23] 0.48  3 1 [2] 3 [7] 0.35 Hospitalization because of infection [%] 5 [10] 3 [7] 0.72 Allergies [%] 3 [7] 5 [11] 0.48 Chronic diseases [%] 0 [0] 1 [2]c 1.00 Adverse reaction to vaccination [%] 0 [0] 0 [0] 1.00 Eczema [%] 12 [26] 6 [14] 0.20 aSecondary growth failure; bprimary growth failure; ccystic fibrosis. View Large 3.8. Growth There were 2 infants [2%] with an abnormal growth [1 IFX, 1 ADA]. One infant, diagnosed with cystic fibrosis [CF], had a primary growth failure. The second infant had a secondary growth failure; however, the cause was still unknown at the time of analyses. 3.9. Infections In total, 25 infants [27%] received one or more antibiotic treatments in the first year of life, of whom 12 [48%] were exposed to IFX. None of the infants received more than three antibiotic treatments. Anti-TNF type was not associated with the number of antibiotic-treated infections. A total of 33 oral antibiotic treatments were prescribed for the following types of infections: acute otitis media [n = 16], upper respiratory infections [n = 11], urinary tract infection [n = 2], infected toe [n = 1], paronychia [n = 1], impetigo [n = 1], and furuncles [n = 1]. Information regarding anti-TNF cord blood level and infection rate was collected from 55 mother–child pairs. The correlation between cord blood level at birth and infection rate is demonstrated in Figure 2. The median cord blood level of children who did not receive antibiotics for an infection [n = 38] was 2.0 µg/mL [IQR 1.0–7.8], of children who had one antibiotic-treated infection [n = 13] was 3.1 µg/mL [IQR 0.4–10.6], and of children who received two or more antibiotic treatments for an infection [n = 4] was 3.9 µg/mL [IQR 0.1–18.7]. There was no statistically significant difference regarding anti-TNF cord blood level between children without antibiotic-treated infections, children with one antibiotic-treated infection, and children with two or more antibiotic-treated infections. Figure 2 View largeDownload slide Anti-TNF cord blood levels compared with infection rates. Boxplot showing the association between anti-TNF cord blood level and infections rate within 1 year. One extreme outlier in the 1 infection group is not shown. One child–mother couple had an anti-TNF cord blood level of 56.0. The mother used 10 mg/kg IFX every 7 weeks. This pregnancy was complicated by preeclampsia with preterm birth after 35.5 gestational weeks. The last infusion was given 36 days before delivery. Figure 2 View largeDownload slide Anti-TNF cord blood levels compared with infection rates. Boxplot showing the association between anti-TNF cord blood level and infections rate within 1 year. One extreme outlier in the 1 infection group is not shown. One child–mother couple had an anti-TNF cord blood level of 56.0. The mother used 10 mg/kg IFX every 7 weeks. This pregnancy was complicated by preeclampsia with preterm birth after 35.5 gestational weeks. The last infusion was given 36 days before delivery. The rate of children who received at least one antibiotic treatment was similar for infants who were exposed to combination treatment of anti-TNF and an immunomodulator [n = 6, 26%] and infants exposed to anti-TNF monotherapy [n = 17, 30%] [p = 1.00]. There were eight infants [9%] admitted to hospital because of a severe infection. The indications for hospital admission were as follows: respiratory infections [n = 4], respiratory syncytial virus [RS-virus] [n = 2], furuncles [n = 1], and staphylococcal infection of the skin [n = 1]. There were four children exposed to IFX [50%]. The median cord blood level at birth of children admitted to hospital was 3.5 µg/mL [IQR 0.3–8.9], and the median cord blood level at birth of children not admitted to hospital was 2.0 µg/mL [IQR 0.9–7.8]. There was no statistically significant difference regarding anti-TNF cord blood level between children admitted to hospital and children not admitted to hospital because of an infection in the first year of life [p = 0.87]. There was no difference in hospital admission rate between anti-TNF types. Furthermore, there was no difference in hospital admissions because of a severe infection between infants exposed to combination therapy [n = 2, 8%] and infants exposed to anti-TNF monotherapy [n = 6, 9%] [p = 1.00]. 3.10. Allergies Eight infants [9%] suffered from an allergy, of which three [38%] were exposed to IFX and five [62%] to ADA. The following types of allergies were reported: cow milk allergy [n = 4], antibiotics [n = 2], allergic rhinitis [n = 1], and a sun allergy that resolved completely shortly after diagnosis [n = 1]. There was no correlation between anti-TNF type and allergies. 3.11. Adverse reaction to vaccinations Life vaccinations were avoided in cases in which anti-TNF levels were >3 µg/mL in the offspring. In The Netherlands, the first life vaccination is administered at the age of 14 months. None of the infants had anti-TNF levels >3 µg/mL at 14 months of age; moreover, none of the infants had anti-TNF levels exceeding 1 µg/mL at 6 months of age. Furthermore, none of the infants in our cohort had an adverse reaction to a vaccination. 4. Discussion We developed a linear regression model to demonstrate the effect of anti-TNF cessation during pregnancy on foetal exposure, for IFX and ADA separately. Anti-TNF concentrations in cord blood and maternal blood were higher in the IFX group than in the ADA group. Our linear regression shows that IFX transportation over the placenta increases exponentially during the third trimester of pregnancy. However, ADA transportation over the placenta is lower and increases in a linear fashion. Therefore, ADA may be continued longer during pregnancy than IFX without leading to higher anti-TNF concentrations in the newborn. In cases of disease activity in women with a current or future pregnancy, and in pregnant women who need to step-up to anti-TNF therapy, ADA may therefore be preferred over IFX. Furthermore, we did not observe significant differences in disease course, maternal outcomes, or birth outcomes between women using IFX and women using ADA during pregnancy. Continuing ADA longer during pregnancy may avoid low maternal ADA levels and subsequently an increased relapse risk in mothers. In addition, a shorter anti-TNF drug holiday may reduce the risk of an adverse event after drug re-initiation, such as an allergic reaction, or loss of response. We did not observe significant differences between the anti-TNF types regarding relapse rate or adverse events after drug re-initiation. However, our study may be underpowered, and therefore further evaluation in larger prospective studies is needed. Anti-TNF concentrations in cord blood varied widely between individuals, as is the case in non-pregnant patients.22,25 This variation is possibly due to several factors influencing the pharmacokinetics of anti-TNF drugs, such as anti-drug antibody formation, concomitant immunosuppressive therapy, serum CRP concentration, BMI, and serum albumin concentration.22,26,27 In addition, physiological changes during pregnancy may also alter the pharmacokinetics of anti-TNF drugs. The latter was demonstrated in a recent study showing a significant increase in the maternal anti-TNF level during pregnancy in women using IFX with a fixed dosing schedule, irrespective of albumin level or BMI.28 The underlying mechanism for this finding remains unknown and needs further evaluation. Because of the relatively small sample size, this study may be underpowered to demonstrate an association between potential predictor variables and anti-TNF concentration in cord blood. However, despite the small sample size, we did find a very strong association between anti-TNF concentration in cord blood and the variables anti-TNF type and stop week. These robust findings indicate that these variables are of utmost importance when predicting anti-TNF concentration in cord blood, which underlines the large pharmacokinetic differences between IFX and ADA. One-year health outcomes, such as growth, infection rate, hospitalization because of an infection, allergies, chronic diseases, adverse reactions to vaccinations, and the presence of eczema were similar between IFX-exposed and ADA-exposed infants. One or more infections were documented in 31% of infants, which is in line with a non-controlled follow-up study assessing the health outcomes of 25 anti-TNF–exposed children, of whom 32% were treated for an infection in the first year of life.29 The infection rate in our cohort is also in line with that of the overall Dutch population.30 However, the infection rate was higher in infants from non-IBD controls from the same geographic region, namely 40%.17 It should be noted that infection data are biased because parents of infants with a cord blood concentration of 3 µg/mL or higher were advised not to bring their child to day-care, to be extra cautious of infectious sources, and to postpone all life vaccinations before the repeated anti-TNF measurement was below 3 µg/mL. Therefore, the actual infection risk in the first year in anti-TNF–exposed infants may be higher than shown in our study. The cut-off level of 3µg/mL is, however, arbitrary and was initially based on adult studies showing an association between an IFX level of >3µg/mL and response to treatment.31 Subsequent studies showed that higher trough levels may be needed for response in the case of ADA treatment. However, we conservatively continued to use the lower cut-off value, based on the pharmacokinetics of IFX, in order to minimize health risks for the newborns. The top three indications for which antibiotics are prescribed in the general Dutch population are respiratory tract infections [45%], ear infections [20%], and urinary tract infections [10%]30, which resembled the indications in our study population: ear infections [48%], upper respiratory infections [33%], and urinary tract infections [6%]. It should be noted that this cohort received stringent counselling and follow-up before and during pregnancy. This strict follow-up has a beneficial effect on pregnancy outcomes and should be taken into account when comparing the results with those of other studies.32 In addition, disease activity during pregnancy could not be assessed in a standard manner. During pregnancy, some clinical scores and laboratory work-up are of limited value. Pregnant women often experience abdominal complaints, regardless of their underlying IBD, and clinical scores such as hematocrit and body weight to assess disease activity are of little value because pregnant women often become anemic and most women gain weight during pregnancy. An endoscopy to assess disease activity was only performed in cases where there was a strong indication. Furthermore, cord blood samples were not obtained from all pregnancies because anti-TNF measurements have only been performed since 2010 at our clinic, and there were samples missing because of logistic problems; however, missing samples were missing at random. In addition, we did not find a correlation between anti-TNF cord blood levels and the impact on the developing immune system of the child. However, this study may be underpowered to demonstrate a correlation, and therefore further prospective studies on this topic are needed. In conclusion, ADA may be continued longer during pregnancy than IFX because of the lower placental transmission. Continuing ADA longer during pregnancy may reduce relapse risk of the mother without increasing foetal anti-TNF exposure. Funding None Conflict of Interest Shannon L. Kanis: none; Alison de Lima-Karagiannis: none; Cokkie van der Ent: none; Dimitris Rizopoulos: none; C. Janneke van der Woude: has served as a speaker and a consultant for Abbot, Abbvie, and MSD, as a consultant for Shire, and has received funding from Janssen Biologics BV. Author Contributions Shannon L. Kanis: data collection, literature search, data analysis, data interpretation, drafting the article; Alison de Lima-Karagiannis: data collection, data interpretation, revising the article; Cokkie van der Ent: data collection, revising the article; Dimitris Rizopoulos: data analysis, figure, data interpretation, revising the article; C. Janneke van der Woude: study design, data interpretation, revising the article. All authors have read and approved this version as submitted. Acknowledgments Results from this study were presented at the 12th Congress of ECCO, February 17, 2017. References 1. Bröms G , Granath F , Linder M , Stephansson O , Elmberg M , Kieler H . Birth outcomes in women with inflammatory bowel disease: effects of disease activity and drug exposure . Inflamm Bowel Dis 2014 ; 20 : 1091 – 8 . Google Scholar PubMed 2. Ujihara M , Ando T , Ishiguro K , et al. Importance of appropriate pharmaceutical management in pregnant women with ulcerative colitis . BMC Res Notes 2013 ; 6 : 210 . Google Scholar CrossRef Search ADS PubMed 3. Reddy D , Murphy SJ , Kane SV , Present DH , Kornbluth AA . Relapses of inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes . Am J Gastroenterol 2008 ; 103 : 1203 – 9 . Google Scholar CrossRef Search ADS PubMed 4. Nørgård B , Hundborg HH , Jacobsen BA , Nielsen GL , Fonager K . Disease activity in pregnant women with Crohn’s disease and birth outcomes: a regional Danish cohort study . Am J Gastroenterol 2007 ; 102 : 1947 – 54 . Google Scholar CrossRef Search ADS PubMed 5. van der Woude CJ , Ardizzone S , Bengtson MB , et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease . J Crohns Colitis 2015 ; 9 : 107 – 24 . Google Scholar CrossRef Search ADS PubMed 6. Nguyen GC , Seow CH , Maxwell C , et al. The Toronto Consensus Statements for the management of inflammatory bowel disease in pregnancy . Gastroenterology 2016 ; 150 : 734 – 57 . Google Scholar CrossRef Search ADS PubMed 7. Malek A , Sager R , Kuhn P , Nicolaides KH , Schneider H . Evolution of maternofetal transport of immunoglobulins during human pregnancy . Am J Reprod Immunol 1996 ; 36 : 248 – 55 . Google Scholar CrossRef Search ADS PubMed 8. Palmeira P , Quinello C , Silveira-Lessa AL , Zago CA , Carneiro-Sampaio M . IgG placental transfer in healthy and pathological pregnancies . Clin Dev Immunol 2012 ; 2012 : 985646 . Google Scholar CrossRef Search ADS PubMed 9. Zelinkova Z , de Haar C , de Ridder L , et al. High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy . Aliment Pharmacol Ther 2011 ; 33 : 1053 – 8 . Google Scholar CrossRef Search ADS PubMed 10. Mahadevan U , Wolf DC , Dubinsky M , et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease . Clin Gastroenterol Hepatol 2013 ; 11 : 286 – 92 ; quiz e24. Google Scholar CrossRef Search ADS PubMed 11. Simister NE . Placental transport of immunoglobulin G . Vaccine 2003 ; 21 : 3365 – 9 . Google Scholar CrossRef Search ADS PubMed 12. Narula N , Al-Dabbagh R , Dhillon A , Sands BE , Marshall JK . Anti-TNFα therapies are safe during pregnancy in women with inflammatory bowel disease: a systematic review and meta-analysis . Inflamm Bowel Dis 2014 ; 20 : 1862 – 9 . Google Scholar CrossRef Search ADS PubMed 13. Shihab Z , Yeomans ND , De Cruz P . Anti-tumour necrosis factor alpha therapies and inflammatory bowel disease pregnancy outcomes: a meta-analysis . J Crohns Colitis 2016 ; 10 : 979 – 88 . Google Scholar CrossRef Search ADS PubMed 14. Schnitzler F , Fidder H , Ferrante M , et al. Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy . Inflamm Bowel Dis 2011 ; 17 : 1846 – 54 . Google Scholar CrossRef Search ADS PubMed 15. Mahadevan U , Kane S , Sandborn WJ , et al. Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn’s disease . Aliment Pharmacol Ther 2005 ; 21 : 733 – 8 . Google Scholar CrossRef Search ADS PubMed 16. Diav-Citrin O , Otcheretianski-Volodarsky A , Shechtman S , Ornoy A . Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: a prospective, comparative, observational study . Reprod Toxicol 2014 ; 43 : 78 – 84 . Google Scholar CrossRef Search ADS PubMed 17. de Lima A , Zelinkova Z , van der Ent C , Steegers EA , van der Woude CJ . Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety . Gut 2016 ; 65 : 1261 – 8 . Google Scholar CrossRef Search ADS PubMed 18. Guiddir T , Fremond ML , Triki TB , et al. Anti-TNF-alpha therapy may cause neonatal neutropenia . Pediatrics 2014 ; 134 : 1189 – 93 . Google Scholar CrossRef Search ADS 19. Cheent K , Nolan J , Shariq S , Kiho L , Pal A , Arnold J . Case report: fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease . J Crohns Colitis 2010 ; 4 : 603 – 5 . Google Scholar CrossRef Search ADS PubMed 20. Julsgaard M , Christensen LA , Gibson PR , et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection . Gastroenterology 2016 ; 151 : 110 – 9 . Google Scholar CrossRef Search ADS PubMed 21. Mahadevan U MC , Sandler RS . PIANO, a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy . Gastroenterology 2012 ; 142 . 22. Lie MR , Peppelenbosch MP , West RL , Zelinkova Z , van der Woude CJ . Adalimumab in Crohn’s disease patients: pharmacokinetics in the first 6 months of treatment . Aliment Pharmacol Ther 2014 ; 40 : 1202 – 8 . Google Scholar CrossRef Search ADS PubMed 23. Visser GHA , Eilers PHC , Elferink-Stinkens PM , Merkus HMWM , Wit JM . New Dutch reference curves for birthweight by gestational age . Early Hum Dev 2009 ; 85 : 737 – 44 . Google Scholar CrossRef Search ADS PubMed 24. Hozo SP , Djulbegovic B , Hozo I . Estimating the mean and variance from the median, range, and the size of a sample . BMC Med Res Methodol 2005 ; 5 : 13 . Google Scholar CrossRef Search ADS PubMed 25. Steenholdt C , Bendtzen K , Brynskov J , Ainsworth MA . Optimizing treatment with TNF inhibitors in inflammatory bowel disease by monitoring drug levels and antidrug antibodies . Inflamm Bowel Dis 2016 ; 22 : 1999 – 2015 . Google Scholar CrossRef Search ADS PubMed 26. Vermeire S , Noman M , Van Assche G , Baert F , D’Haens G , Rutgeerts P . Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease . Gut 2007 ; 56 : 1226 – 31 . Google Scholar CrossRef Search ADS PubMed 27. Ordas I , Feagan BG , Sandborn WJ . Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease . Clin Gastroenterol Hepatol 2012 ; 10 : 1079 – 87 . Google Scholar CrossRef Search ADS PubMed 28. Seow CH , Leung Y , Vande Casteele N , et al. The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease . Aliment Pharmacol Ther 2017 ; 45 : 1329 – 38 . Google Scholar CrossRef Search ADS PubMed 29. Bortlik M , Duricova D , Machkova N , et al. Impact of anti-tumor necrosis factor alpha antibodies administered to pregnant women with inflammatory bowel disease on long-term outcome of exposed children . Inflamm Bowel Dis 2014 ; 20 : 495 – 501 . Google Scholar CrossRef Search ADS PubMed 30. Otters HB , van der Wouden JC , Schellevis FG , van Suijlekom-Smit LW , Koes BW . Trends in prescribing antibiotics for children in Dutch general practice . J Antimicrob Chemother 2004 ; 53 : 361 – 6 . Google Scholar CrossRef Search ADS PubMed 31. Vande Casteele N , Khanna R , Levesque BG , et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease . Gut 2015 ; 64 : 1539 – 45 . Google Scholar CrossRef Search ADS PubMed 32. de Lima A , Zelinkova Z , Mulders AG , van der Woude CJ . Preconception care reduces relapse of inflammatory bowel disease during pregnancy . Clin Gastroenterol Hepatol 2016 ; 14 : 1285 – 92.e1 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Anti-TNF Levels in Cord Blood at Birth are Associated with Anti-TNF Type

Loading next page...
 
/lp/ou_press/anti-tnf-levels-in-cord-blood-at-birth-are-associated-with-anti-tnf-bFsxn6gNm0
Publisher
Elsevier Science
Copyright
Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
ISSN
1873-9946
eISSN
1876-4479
D.O.I.
10.1093/ecco-jcc/jjy058
Publisher site
See Article on Publisher Site

Abstract

Abstract Background and aims Pregnancy guidelines for women with inflammatory bowel disease [IBD] provide recommendations regarding anti-TNF cessation during pregnancy, in order to limit foetal exposure. Although infliximab [IFX] leads to higher anti-TNF concentrations in cord blood than adalimumab [ADA], the recommendations are similar. We aimed to demonstrate the effect of anti-TNF cessation during pregnancy on foetal exposure, for IFX and ADA separately. Methods We conducted a prospective single-center cohort study. Women with IBD, using IFX or ADA, were followed-up during pregnancy. In case of sustained disease remission, anti-TNF was stopped in the third trimester. At the birth, the anti-TNF concentration was measured in the cord blood. A linear regression model was developed to demonstrate anti-TNF concentration in cord blood at birth. In addition, outcomes such as disease activity, pregnancy outcomes and 1-year health outcomes of infants were collected. Results We included 131 pregnancies that resulted in a live birth [73 IFX, 58 ADA]. At birth, 94 cord blood samples were obtained [52 IFX, 42 ADA], showing significantly higher levels of IFX than ADA [p < 0.0001]. Anti-TNF type and stop week were used in the linear regression model. During the third trimester, IFX transportation over the placenta increased exponentially; however, ADA transportation was limited and increased in a linear fashion. Overall, health outcomes were comparable. Conclusions Our linear regression model shows that ADA may be continued longer during pregnancy, because transportation over the placenta is lower than for IFX. This may reduce relapse risk of the mother, without increasing foetal anti-TNF exposure. Infliximab, adalimumab, pregnancy 1. Introduction Active inflammatory bowel disease [IBD] during conception and pregnancy has been associated with adverse pregnancy outcomes such as spontaneous abortion, intrauterine growth restriction, preterm birth and low birth weight.1–4 Current pregnancy guidelines therefore advise conception during a time of disease remission.5,6 In order to maintain disease remission, anti-TNF IgG1 monoclonal antibodies such as infliximab [IFX] and adalimumab [ADA] are increasingly being used. These drugs, however, are actively transported over the placenta to the foetus.7,8 The transportation of IgG1 antibodies over the placenta increases exponentially during the third trimester, resulting in higher foetal levels than maternal levels at term.9–11 Previous studies among women suffering from IBD have suggested that the use of IFX and ADA during pregnancy is not related to adverse pregnancy outcomes, nor to adverse health outcomes of children until 1 year of age.12–17 However, a case series reported severe neutropenia at birth in four IFX-exposed children18; also, a case of a fatal disseminated Bacille Calmette-Guerin [BCG] infection of an IFX-exposed child has been reported.19 In addition, an increased infection risk has been seen in children exposed in utero to a combination of an immunomodulator and either IFX or ADA,20,21 and it should be noted that long-term health outcomes of anti-TNF–exposed infants have scarcely been studied. In view of this data, the safety of in utero exposure to high levels of anti-TNF is difficult to take for granted and should preferably be avoided. Current pregnancy guidelines provide recommendations on how to balance the limiting of drug exposure in utero to avoid health risks for the foetus with maintaining maternal disease remission. If women are not in sustained disease remission, it is advised to continue anti-TNF treatment throughout the entire pregnancy, because active IBD increases the risk of adverse pregnancy outcomes. However, in the case of women in sustained disease remission, anti-TNF treatment cessation may be considered in the third trimester to minimize foetal drug exposure. Anti-TNF cessation in the third trimester seems feasible in this latter group because it does not lead to an increased relapse risk.17 These current pregnancy guidelines, however, do not differentiate between IFX and ADA, although different pharmacokinetics are expected. A recent study, comparing anti-TNF levels in cord blood and the time of infant drug clearance between IFX-exposed infants and ADA-exposed infants, found significantly higher anti-TNF levels in cord blood and a longer time to anti-TNF clearance in IFX-exposed infants than in ADA-exposed infants.20 This suggests that it may be possible to extend ADA treatment longer during the third trimester of pregnancy than IFX treatment, without increasing anti-TNF levels in the newborn. The primary aim of our study was to illustrate the effect of gestational anti-TNF cessation on foetal drug exposure in a linear regression model for IFX and ADA separately. The secondary aims were to assess disease course during pregnancy, birth outcomes, adverse events after anti-TNF re-initiation, and infants’ health outcomes at 1 year for IFX and ADA separately. 2. Material and Methods 2.1. Study design All IBD women treated with either IFX or ADA who visited the preconception outpatient clinic at the Erasmus University Medical Center Rotterdam, a tertiary health centre, from December 2008 through June 2016 were prospectively enrolled. If patients did not attend follow-up visits at our clinic and/or if the pregnancy outcomes could not be retraced, they were excluded from analyses. This cohort consisted partly of women from a previously published cohort17 and partly of additional follow-up information. During visits at our IBD outpatient clinic, patients were counselled before pregnancy and seen bi-monthly during pregnancy by an experienced IBD physician. In case of disease activity, women were seen every second week at the outpatient clinic. Patients were counselled on medication use, folic acid intake, life style habits [e.g. smoking, alcohol use] and the importance of achieving and maintaining disease remission before conception and during pregnancy. Data regarding disease activity, medication adherence, smoking, alcohol use, folic acid intake and obstetric complications were collected during each visit. Disease activity was assessed based on clinical symptoms. (Harvey Bradshaw Index [HBI] or Simplified Clinical Colitis Activity Index [SCCAI], blood analysis, fecal calprotectin [FCP] measurement and an endoscopy was performed when necessary.) In case of disease relapse at any time from 6 months before conception until Gestational Week 20, anti-TNF treatment would be continued during the entire pregnancy. In case of sustained disease remission from 6 months before conception until Gestational Week 20, the option of discontinuing anti-TNF treatment in the third trimester was discussed in a multidisciplinary team, including the gynaecologist and the patient. All patients were additionally informed by an experienced IBD nurse regarding anti-TNF measurements in cord blood and peripheral maternal blood at birth. During this consult, patients received written instructions on how to obtain the blood samples at birth, which they handed over to their gynaecologist. During delivery, blood samples were collected by the gynaecologist and sent directly to the Laboratory of Gastroenterology at the Erasmus University Medical Center. Birth outcomes such as gestational age at birth, birth weight, and the presence of congenital abnormalities were noted during the first visit after delivery. After 1 year, health outcomes from infants were obtained through telephonic questionnaire with mothers and/or by obtaining medical information from the general practitioner after the consent of both parents. The 1-year outcomes included growth, infections for which systemic antibiotic treatment were needed, hospitalization for an infection, allergies, chronic diseases, adverse reactions to vaccinations, and the presence of eczema. 2.2. Outcome measurements Anti-TNF serum level measurements were performed since 2010 at our clinic. These measurements were done by ELISA from peripheral blood, as described in previous papers.9,22 2.3. Definitions Abnormal growth is defined as a growth or height for age and gender deviating >2 standard deviations [SD] from the mean Dutch growth chart. Preterm birth is defined as a delivery before 37 weeks of gestation. Small for gestational age [SGA] is a weight below the 2 SD for gestational age according to the Dutch reference curve.23 The presence of disease activity was assessed by the treating physician and based on the combination of clinical symptoms [HBI > 5 or SCCAI > 2], C-reactive protein [CRP] > 9.0 mgL, FCP measurement > 200 µg/g and when strongly indicated, an endoscopy was performed. The standard dose of anti-TNF treatment is 5 mg/kg intravenously every 8 weeks for IFX and 40 mg subcutaneously every 2 weeks for ADA. 2.4. Study size The primary aim was to assess the difference in anti-TNF cord blood concentrations between IFX and ADA and subsequently use the anti-TNF cord blood concentrations as a dependent variable in a linear regression model. The null hypothesis assumed no difference in anti-TNF cord blood concentration between IFX users and ADA users. We used the median anti-TNF level in cord blood and the range from a previous study20 and estimated the mean and SD according to the method devised by Hozo et al.24 We expected the mean anti-TNF concentration of ADA users to be lower than the mean anti-TNF concentration of IFX users; therefore, a one-sided test with alpha of 2.5% was used. To detect a lower mean anti-TNF concentration in cord blood of 3.5 µg/mL in ADA users, with a power of 90%, the estimated sample size was 31 per arm. 2.5. Statistical considerations All analyses were performed using IBM SPSS statistics [version 21.0 Chicago III, USA]. Descriptive statistics of continuous data are displayed as median with interquartile ranges [IQRs] or means with SDs, and compared using Students t-tests or Mann–Whitney U tests. Categorical data are shown as absolute numbers with percentages, and compared using Fisher’s exact tests. The tests were performed two-tailed, unless stated differently, and tested at a significance level of 0.05. Univariate and multivariate analysis are shown with a 95% confidence interval [CI]. Anti-TNF cord blood data was normalized by log transformation. Simple linear regression analyses were performed to determine the association between variables and anti-TNF concentration in cord blood at birth. All possible predictors [i.e. maternal age, diagnosis, pre-pregnancy body mass index [BMI], pre-pregnancy weight, anti-TNF stop week, smoking, type of anti-TNF, thiopurine use, steroid use, gestational age at birth, birth weight, bowel resection prior to pregnancy, anti-TNF dose, and disease relapse during pregnancy] were considered. Subsequently, only variables with a p-value < 0.20 in the univariate analysis and variables based on clinician’s rationale [i.e. disease activity during pregnancy, anti-TNF dose, and concomitant thiopurine use] were considered for the multiple linear regression model. These variables were carefully weighted to create the most favorable model. In the final multivariate model, interactions were tested between the independent variables and were included when significant [p < 0.01]. 2.6. Ethical statement This study was approved by the local ethics committee of the Erasmus University Medical Center [Rotterdam, The Netherlands]. Legal guardians of the children signed informed consent before data was collected from the general practitioner. 3. Results A total of 416 pregnancies were recorded at our outpatient clinic; during 170 [41%] pregnancies, mothers were treated with anti-TNF. Of these pregnancies, 136 [80%] resulted in a live birth, 28 [16%] resulted in spontaneous abortion, 5 [3%] were pregnant at the time of analyses, and 1 [1%] pregnancy was terminated by an elective abortion. 3.1. Live births We included 136 live births from 102 mothers (82 [80%] with Crohn’s disease [CD], 19 [19%] with ulcerative colitis [UC] and 1 [1%] with IBD unclassified). During conception and/or pregnancy, 76 [56%] infants were exposed to IFX and 60 [44%] were exposed to ADA in utero. There were 5 women who stopped anti-TNF treatment before the second trimester [3 IFX, 2 ADA], which was advised by a physician other than a gastroenterologist. These women were excluded from further analyses. Baseline characteristics per pregnancy are shown in Table 1. In our cohort, women with CD more often used ADA, and women with UC more often used IFX. In addition, IFX was more often prescribed in the case of extensive CD and in combination with a thiopurine. There were no other differences in the baseline characteristics between IFX users and ADA users. Table 1 Baseline characteristics per pregnancy [n = 131]. IFX [n = 73] ADA [n = 58] p value Median maternal age during conception [IQR] 30 [27–33] 30 [28–33] 0.59 Education level [%] High 27 [43] 18 [35] 0.44 Middle 34 [55] 33 [65] 0.34 Low 1 [2] 0 [0] 1.00 Diagnosis [%] Crohn’s disease 54 [74] 51 [88] 0.05 Ulcerative colitis 18 [25] 6 [10] 0.04 IBD unclassified 1 [1] 1 [2] 1.00 Disease location CD [Montreal] [%]  L1 Ileal 10 [19] 15 [30] 0.25  L2 Colonic 8 [15] 15 [30] 0.10  L3 Ileocolonic 35 [66] 20 [40] 0.01 Disease behaviour CD [Montreal] [%]  B1 Non-stricturing non-penetrating 44 [61] 28 [51] 0.28  B2 Stricturing 2 [3] 4 [7] 0.40  B3 Penetrating 14 [19] 14 [26] 0.52  B2 + B3 Stricturing and penetrating 12 [17] 9 [16] 1.00 P Perianal fistulizing disease [%] 20 [28] 19 [33] 0.57 Disease extent UC/IBDU [Montreal] [%]  E1 Proctitis 0 [0] 0 [0] 1.00  E2 Left-sided colitis 4 [21] 4 [57] 0.15  E3 Pancolitis 15 [79] 3 [43] 0.15 Disease duration in years [IQR] 7 [3–11] 7 [5–11] 0.58 Duration of anti-TNF treatment in months [IQR] 24 [8–40] 23 [8–38] 0.74 Anti-TNF dose [%]  Standard dose 50 [69] 47 [81] 0.11  Increased dose 3 [4] 0 [0] 0.13  Increased frequency 19 [26] 11 [19] 0.30  Increased dose and frequency 1 [1] 0 [0] 1.00 Co-medication  Mesalazine 5 [7] 5 [9] 0.75  Steroids [systemic] 9 [12] 10 [17] 0.46  Thiopurine 29 [40] 5 [9] 0.0001 IBD surgery [%]  Abdominal surgery 14 [19] 14 [25] 0.52  Perianal surgery 13 [19] 12 [22] 0.82 EIM prior to pregnancy [%] 15 [22] 14 [26] 0.68 Parity [%]  Nulliparous 47 [65] 30 [54] 0.21  Multiparous 24 [34] 26 [46] 0.20 Median pre-pregnancy BMI [IQR] 25 [22–27] 23 [21–27] 0.25 Disease relapse in the preceding year [%] 20 [29] 22 [47] 0.08 Folic acid intake [%] 55 [83] 45 [83] 1.00 Smoking [%] 5 [7] 6 [11] 0.53 Fertility treatment [%] 3 [4] 5 [9] 0.47 IFX [n = 73] ADA [n = 58] p value Median maternal age during conception [IQR] 30 [27–33] 30 [28–33] 0.59 Education level [%] High 27 [43] 18 [35] 0.44 Middle 34 [55] 33 [65] 0.34 Low 1 [2] 0 [0] 1.00 Diagnosis [%] Crohn’s disease 54 [74] 51 [88] 0.05 Ulcerative colitis 18 [25] 6 [10] 0.04 IBD unclassified 1 [1] 1 [2] 1.00 Disease location CD [Montreal] [%]  L1 Ileal 10 [19] 15 [30] 0.25  L2 Colonic 8 [15] 15 [30] 0.10  L3 Ileocolonic 35 [66] 20 [40] 0.01 Disease behaviour CD [Montreal] [%]  B1 Non-stricturing non-penetrating 44 [61] 28 [51] 0.28  B2 Stricturing 2 [3] 4 [7] 0.40  B3 Penetrating 14 [19] 14 [26] 0.52  B2 + B3 Stricturing and penetrating 12 [17] 9 [16] 1.00 P Perianal fistulizing disease [%] 20 [28] 19 [33] 0.57 Disease extent UC/IBDU [Montreal] [%]  E1 Proctitis 0 [0] 0 [0] 1.00  E2 Left-sided colitis 4 [21] 4 [57] 0.15  E3 Pancolitis 15 [79] 3 [43] 0.15 Disease duration in years [IQR] 7 [3–11] 7 [5–11] 0.58 Duration of anti-TNF treatment in months [IQR] 24 [8–40] 23 [8–38] 0.74 Anti-TNF dose [%]  Standard dose 50 [69] 47 [81] 0.11  Increased dose 3 [4] 0 [0] 0.13  Increased frequency 19 [26] 11 [19] 0.30  Increased dose and frequency 1 [1] 0 [0] 1.00 Co-medication  Mesalazine 5 [7] 5 [9] 0.75  Steroids [systemic] 9 [12] 10 [17] 0.46  Thiopurine 29 [40] 5 [9] 0.0001 IBD surgery [%]  Abdominal surgery 14 [19] 14 [25] 0.52  Perianal surgery 13 [19] 12 [22] 0.82 EIM prior to pregnancy [%] 15 [22] 14 [26] 0.68 Parity [%]  Nulliparous 47 [65] 30 [54] 0.21  Multiparous 24 [34] 26 [46] 0.20 Median pre-pregnancy BMI [IQR] 25 [22–27] 23 [21–27] 0.25 Disease relapse in the preceding year [%] 20 [29] 22 [47] 0.08 Folic acid intake [%] 55 [83] 45 [83] 1.00 Smoking [%] 5 [7] 6 [11] 0.53 Fertility treatment [%] 3 [4] 5 [9] 0.47 IBD, inflammatory bowel disease; IQR, interquartile range; IFX, infliximab; ADA, adalimumab; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, IBD unclassified; EMI, extra-intestinal manifestation; BMI, body mass index. View Large Table 1 Baseline characteristics per pregnancy [n = 131]. IFX [n = 73] ADA [n = 58] p value Median maternal age during conception [IQR] 30 [27–33] 30 [28–33] 0.59 Education level [%] High 27 [43] 18 [35] 0.44 Middle 34 [55] 33 [65] 0.34 Low 1 [2] 0 [0] 1.00 Diagnosis [%] Crohn’s disease 54 [74] 51 [88] 0.05 Ulcerative colitis 18 [25] 6 [10] 0.04 IBD unclassified 1 [1] 1 [2] 1.00 Disease location CD [Montreal] [%]  L1 Ileal 10 [19] 15 [30] 0.25  L2 Colonic 8 [15] 15 [30] 0.10  L3 Ileocolonic 35 [66] 20 [40] 0.01 Disease behaviour CD [Montreal] [%]  B1 Non-stricturing non-penetrating 44 [61] 28 [51] 0.28  B2 Stricturing 2 [3] 4 [7] 0.40  B3 Penetrating 14 [19] 14 [26] 0.52  B2 + B3 Stricturing and penetrating 12 [17] 9 [16] 1.00 P Perianal fistulizing disease [%] 20 [28] 19 [33] 0.57 Disease extent UC/IBDU [Montreal] [%]  E1 Proctitis 0 [0] 0 [0] 1.00  E2 Left-sided colitis 4 [21] 4 [57] 0.15  E3 Pancolitis 15 [79] 3 [43] 0.15 Disease duration in years [IQR] 7 [3–11] 7 [5–11] 0.58 Duration of anti-TNF treatment in months [IQR] 24 [8–40] 23 [8–38] 0.74 Anti-TNF dose [%]  Standard dose 50 [69] 47 [81] 0.11  Increased dose 3 [4] 0 [0] 0.13  Increased frequency 19 [26] 11 [19] 0.30  Increased dose and frequency 1 [1] 0 [0] 1.00 Co-medication  Mesalazine 5 [7] 5 [9] 0.75  Steroids [systemic] 9 [12] 10 [17] 0.46  Thiopurine 29 [40] 5 [9] 0.0001 IBD surgery [%]  Abdominal surgery 14 [19] 14 [25] 0.52  Perianal surgery 13 [19] 12 [22] 0.82 EIM prior to pregnancy [%] 15 [22] 14 [26] 0.68 Parity [%]  Nulliparous 47 [65] 30 [54] 0.21  Multiparous 24 [34] 26 [46] 0.20 Median pre-pregnancy BMI [IQR] 25 [22–27] 23 [21–27] 0.25 Disease relapse in the preceding year [%] 20 [29] 22 [47] 0.08 Folic acid intake [%] 55 [83] 45 [83] 1.00 Smoking [%] 5 [7] 6 [11] 0.53 Fertility treatment [%] 3 [4] 5 [9] 0.47 IFX [n = 73] ADA [n = 58] p value Median maternal age during conception [IQR] 30 [27–33] 30 [28–33] 0.59 Education level [%] High 27 [43] 18 [35] 0.44 Middle 34 [55] 33 [65] 0.34 Low 1 [2] 0 [0] 1.00 Diagnosis [%] Crohn’s disease 54 [74] 51 [88] 0.05 Ulcerative colitis 18 [25] 6 [10] 0.04 IBD unclassified 1 [1] 1 [2] 1.00 Disease location CD [Montreal] [%]  L1 Ileal 10 [19] 15 [30] 0.25  L2 Colonic 8 [15] 15 [30] 0.10  L3 Ileocolonic 35 [66] 20 [40] 0.01 Disease behaviour CD [Montreal] [%]  B1 Non-stricturing non-penetrating 44 [61] 28 [51] 0.28  B2 Stricturing 2 [3] 4 [7] 0.40  B3 Penetrating 14 [19] 14 [26] 0.52  B2 + B3 Stricturing and penetrating 12 [17] 9 [16] 1.00 P Perianal fistulizing disease [%] 20 [28] 19 [33] 0.57 Disease extent UC/IBDU [Montreal] [%]  E1 Proctitis 0 [0] 0 [0] 1.00  E2 Left-sided colitis 4 [21] 4 [57] 0.15  E3 Pancolitis 15 [79] 3 [43] 0.15 Disease duration in years [IQR] 7 [3–11] 7 [5–11] 0.58 Duration of anti-TNF treatment in months [IQR] 24 [8–40] 23 [8–38] 0.74 Anti-TNF dose [%]  Standard dose 50 [69] 47 [81] 0.11  Increased dose 3 [4] 0 [0] 0.13  Increased frequency 19 [26] 11 [19] 0.30  Increased dose and frequency 1 [1] 0 [0] 1.00 Co-medication  Mesalazine 5 [7] 5 [9] 0.75  Steroids [systemic] 9 [12] 10 [17] 0.46  Thiopurine 29 [40] 5 [9] 0.0001 IBD surgery [%]  Abdominal surgery 14 [19] 14 [25] 0.52  Perianal surgery 13 [19] 12 [22] 0.82 EIM prior to pregnancy [%] 15 [22] 14 [26] 0.68 Parity [%]  Nulliparous 47 [65] 30 [54] 0.21  Multiparous 24 [34] 26 [46] 0.20 Median pre-pregnancy BMI [IQR] 25 [22–27] 23 [21–27] 0.25 Disease relapse in the preceding year [%] 20 [29] 22 [47] 0.08 Folic acid intake [%] 55 [83] 45 [83] 1.00 Smoking [%] 5 [7] 6 [11] 0.53 Fertility treatment [%] 3 [4] 5 [9] 0.47 IBD, inflammatory bowel disease; IQR, interquartile range; IFX, infliximab; ADA, adalimumab; CD, Crohn’s disease; UC, ulcerative colitis; IBDU, IBD unclassified; EMI, extra-intestinal manifestation; BMI, body mass index. View Large 3.2. Maternal outcomes Maternal outcomes are displayed in Table 2. There were no differences regarding weight gain during pregnancy, anti-TNF stop week, disease relapse during pregnancy, or successful treatment of the relapse between IFX users and ADA users. In addition, we observed no differences in adverse events after restarting anti-TNF post-partum, such as allergic reactions, loss of response, or disease relapse within 3 months post-partum between these groups. Table 2 Maternal and pregnancy outcomes [n = 131]. IFX [n = 73] ADA [n = 58] p value Median weight gain in kilograms during pregnancy [IQR] 12 [10–18] 12 [10–15] 0.90 Anti-TNF stopped during pregnancy <Week 25 [%] 37 [52] 33 [57] 0.60 Median anti-TNF stop week during pregnancy [IQR] 23 [21–32] 23 [22–37] 0.19 Total disease activity during pregnancy [%] 19 [26] 19 [35] 0.33 Activity ongoing from conception [%] 7 [10] 8 [15] 0.42 New relapse during pregnancy [%] 12 [16] 11 [20] 0.65 Successful relapse treatment before delivery [%] 14 [78] 11 [58] 0.30 Median anti-TNF restart week postpartum [IQR] 3 [1–4] 2 [0–3.5] 0.20 Allergic reaction at restart anti-TNF [%] 2 [3]a 1 [2]b 1.00 Loss of response after restart anti-TNF [%] 1 [1]c 1 [2]d 1.00 Disease relapse within 3 months postpartum [%] 7 [12] 8 [19] 0.40 Median birthweight in kilograms [IQR] 3.3 [3.0–3.7] 3.4 [3.1–3.6] 0.50 Low birth weight [%] 6 [9] 4 [7] 1.00 Median gestational age [IQR] 39 [38–40] 39 [38–40] 0.75 Preterm birth [%] 7 [10] 2 [3] 0.18 Small for gestational age [SGA] [%] 3 [4] 1 [2] 0.63 Major congenital abnormalities [%] 3 [4.7]e 0 [0] 0.25 Breastfeeding >2 weeks [%] 18 [30] 16 [33] 0.68 Mode of delivery [%] Vaginal delivery 32 [48] 34 [61] 0.21 Caesarean section 35 [52] 22 [39] 0.21 IFX [n = 73] ADA [n = 58] p value Median weight gain in kilograms during pregnancy [IQR] 12 [10–18] 12 [10–15] 0.90 Anti-TNF stopped during pregnancy <Week 25 [%] 37 [52] 33 [57] 0.60 Median anti-TNF stop week during pregnancy [IQR] 23 [21–32] 23 [22–37] 0.19 Total disease activity during pregnancy [%] 19 [26] 19 [35] 0.33 Activity ongoing from conception [%] 7 [10] 8 [15] 0.42 New relapse during pregnancy [%] 12 [16] 11 [20] 0.65 Successful relapse treatment before delivery [%] 14 [78] 11 [58] 0.30 Median anti-TNF restart week postpartum [IQR] 3 [1–4] 2 [0–3.5] 0.20 Allergic reaction at restart anti-TNF [%] 2 [3]a 1 [2]b 1.00 Loss of response after restart anti-TNF [%] 1 [1]c 1 [2]d 1.00 Disease relapse within 3 months postpartum [%] 7 [12] 8 [19] 0.40 Median birthweight in kilograms [IQR] 3.3 [3.0–3.7] 3.4 [3.1–3.6] 0.50 Low birth weight [%] 6 [9] 4 [7] 1.00 Median gestational age [IQR] 39 [38–40] 39 [38–40] 0.75 Preterm birth [%] 7 [10] 2 [3] 0.18 Small for gestational age [SGA] [%] 3 [4] 1 [2] 0.63 Major congenital abnormalities [%] 3 [4.7]e 0 [0] 0.25 Breastfeeding >2 weeks [%] 18 [30] 16 [33] 0.68 Mode of delivery [%] Vaginal delivery 32 [48] 34 [61] 0.21 Caesarean section 35 [52] 22 [39] 0.21 aInfusion reaction, both treated with hydrocortisone and clemastine; bItch after ADA administration, treated with antihistamine; cDecreased effect of IFX after restart, switched to ADA after 5 months; dDecreased effect of ADA, switched to vedolizumab after 5 months; eVSD [n = 1], cleft palate [n = 1] and polydactyly [n = 1]. IQR, interquartile range. View Large Table 2 Maternal and pregnancy outcomes [n = 131]. IFX [n = 73] ADA [n = 58] p value Median weight gain in kilograms during pregnancy [IQR] 12 [10–18] 12 [10–15] 0.90 Anti-TNF stopped during pregnancy <Week 25 [%] 37 [52] 33 [57] 0.60 Median anti-TNF stop week during pregnancy [IQR] 23 [21–32] 23 [22–37] 0.19 Total disease activity during pregnancy [%] 19 [26] 19 [35] 0.33 Activity ongoing from conception [%] 7 [10] 8 [15] 0.42 New relapse during pregnancy [%] 12 [16] 11 [20] 0.65 Successful relapse treatment before delivery [%] 14 [78] 11 [58] 0.30 Median anti-TNF restart week postpartum [IQR] 3 [1–4] 2 [0–3.5] 0.20 Allergic reaction at restart anti-TNF [%] 2 [3]a 1 [2]b 1.00 Loss of response after restart anti-TNF [%] 1 [1]c 1 [2]d 1.00 Disease relapse within 3 months postpartum [%] 7 [12] 8 [19] 0.40 Median birthweight in kilograms [IQR] 3.3 [3.0–3.7] 3.4 [3.1–3.6] 0.50 Low birth weight [%] 6 [9] 4 [7] 1.00 Median gestational age [IQR] 39 [38–40] 39 [38–40] 0.75 Preterm birth [%] 7 [10] 2 [3] 0.18 Small for gestational age [SGA] [%] 3 [4] 1 [2] 0.63 Major congenital abnormalities [%] 3 [4.7]e 0 [0] 0.25 Breastfeeding >2 weeks [%] 18 [30] 16 [33] 0.68 Mode of delivery [%] Vaginal delivery 32 [48] 34 [61] 0.21 Caesarean section 35 [52] 22 [39] 0.21 IFX [n = 73] ADA [n = 58] p value Median weight gain in kilograms during pregnancy [IQR] 12 [10–18] 12 [10–15] 0.90 Anti-TNF stopped during pregnancy <Week 25 [%] 37 [52] 33 [57] 0.60 Median anti-TNF stop week during pregnancy [IQR] 23 [21–32] 23 [22–37] 0.19 Total disease activity during pregnancy [%] 19 [26] 19 [35] 0.33 Activity ongoing from conception [%] 7 [10] 8 [15] 0.42 New relapse during pregnancy [%] 12 [16] 11 [20] 0.65 Successful relapse treatment before delivery [%] 14 [78] 11 [58] 0.30 Median anti-TNF restart week postpartum [IQR] 3 [1–4] 2 [0–3.5] 0.20 Allergic reaction at restart anti-TNF [%] 2 [3]a 1 [2]b 1.00 Loss of response after restart anti-TNF [%] 1 [1]c 1 [2]d 1.00 Disease relapse within 3 months postpartum [%] 7 [12] 8 [19] 0.40 Median birthweight in kilograms [IQR] 3.3 [3.0–3.7] 3.4 [3.1–3.6] 0.50 Low birth weight [%] 6 [9] 4 [7] 1.00 Median gestational age [IQR] 39 [38–40] 39 [38–40] 0.75 Preterm birth [%] 7 [10] 2 [3] 0.18 Small for gestational age [SGA] [%] 3 [4] 1 [2] 0.63 Major congenital abnormalities [%] 3 [4.7]e 0 [0] 0.25 Breastfeeding >2 weeks [%] 18 [30] 16 [33] 0.68 Mode of delivery [%] Vaginal delivery 32 [48] 34 [61] 0.21 Caesarean section 35 [52] 22 [39] 0.21 aInfusion reaction, both treated with hydrocortisone and clemastine; bItch after ADA administration, treated with antihistamine; cDecreased effect of IFX after restart, switched to ADA after 5 months; dDecreased effect of ADA, switched to vedolizumab after 5 months; eVSD [n = 1], cleft palate [n = 1] and polydactyly [n = 1]. IQR, interquartile range. View Large 3.3. Disease relapse Overall, 42 [32%] women had a disease relapse in the year before conception, and 38 [30%] women experienced disease activity during pregnancy, of which, 15 [40%] were ongoing from conception and 23 [60%] were new relapses. The types of disease activity were as follows: 33 [87%] women had luminal disease activity, 4 [10%] women had an active perianal fistula, and 1 [3%] woman had an active extra-intestinal manifestation [EIM]. Active perianal fistula and EIM were diagnosed during clinical physical examination. Luminal disease activity was diagnosed by endoscopy [n = 12, 37%], abdominal ultrasound [n = 1, 3%], or based on clinical symptoms and laboratory work-up [CRP and/or FCP measurement] [n = 20, 60%]. Disease activity was treated as follows: in 6 cases anti-TNF was restarted or never discontinued because of disease activity, 11 women were treated with corticosteroids, 2 women were treated with antibiotics, and 1 woman was treated by means of nasogastric feeding. In other cases, the delivery was advanced or activity was not treated, as requested bythe patient. Treatment was successful in 25 [68%] cases before delivery. As advised by current pregnancy guidelines, women discontinued anti-TNF treatment before the third trimester in the case of sustained disease remission. Overall, there were 37 [52%] women using IFX and 33 [57%] women using ADA who discontinued treatment between Gestational Weeks 12 and 25 [p = 0.60]. In those cases in which women stopped treatment between Gestational Weeks 12 and 25, the rate of new relapses during pregnancy was 4 [11%] for women using IFX and 3 [10%] for women using ADA; this difference was not statistically significant [p = 1.00]. In those cases in which women continued anti-TNF after Gestational Week 25, the rate of new relapses during pregnancy was 8 [24%] for women using IFX and 8 [33%] for women using ADA; however, this difference was also not statistically significant [p = 0.55]. 3.4. Pregnancy outcomes No differences were observed in terms of birth weight, gestational age at birth, the presence of congenital abnormalities, or mode of delivery between IFX-exposed infants and ADA-exposed infants [Table 2]. Three children were born with a congenital abnormality. Two of the 3 mothers did not use folic acid at the time of conception. In addition, the mother of the child born with a polydactyly used methotrexate at the time of conception. She stopped the methotrexate and started folic acid after she discovered her pregnancy. The other mothers did not use teratogenic medication. 3.5. Drug concentration in cord blood and maternal blood At birth, cord blood samples in which anti-TNF concentration was measured were obtained from 94 mothers; 52 used IFX and 42 used ADA during pregnancy. The results are shown in Table 3. Anti-TNF levels in cord blood, and the ratio of cord blood level / maternal level were both higher in IFX users than in ADA users. In addition, anti-TNF levels in maternal blood were higher in IFX users than in ADA users [p = 0.05]. There were no other differences between women using IFX and women using ADA regarding anti-TNF stop week during pregnancy, duration of anti-TNF treatment before conception, relapse rate, or number of women using the standard dose. Table 3 Outcomes for mother–newborn pairs with anti-TNF measurement in cord blood [n = 94]. IFX [n = 52] ADA [n = 42] p value Median anti-TNF concentration in cord blood [µg/mL] [IQR] 4.9 [1.9–14.7] 1.1 [0.4–37.0] 0.0001 Median anti-TNF level in maternal blood at birth [µg/mL] [IQR] 1.7 [0.4–6.9] 0.6 [0.3–3.6] 0.05 Median ratio of cord blood level / maternal level [IQR] 2.63 [1.67–4.03] 1.36 [1.00–2.08] 0.0001 Median anti-TNF stop week [IQR] 25 [21–32] 23 [22–37] 0.56 Anti-TNF stopped during pregnancy before gestational Week 25 [%] 26 [50] 26 [62] 0.30 Disease relapse during pregnancy [%] 15 [29] 14 [36] 0.50 Median duration of anti-TNF treatment in months before pregnancy [IQR] 24 [8–40] 22 [8–38] 0.73 Standard dose anti-TNF [%] 35 [67] 33 [79] 0.25 IFX [n = 52] ADA [n = 42] p value Median anti-TNF concentration in cord blood [µg/mL] [IQR] 4.9 [1.9–14.7] 1.1 [0.4–37.0] 0.0001 Median anti-TNF level in maternal blood at birth [µg/mL] [IQR] 1.7 [0.4–6.9] 0.6 [0.3–3.6] 0.05 Median ratio of cord blood level / maternal level [IQR] 2.63 [1.67–4.03] 1.36 [1.00–2.08] 0.0001 Median anti-TNF stop week [IQR] 25 [21–32] 23 [22–37] 0.56 Anti-TNF stopped during pregnancy before gestational Week 25 [%] 26 [50] 26 [62] 0.30 Disease relapse during pregnancy [%] 15 [29] 14 [36] 0.50 Median duration of anti-TNF treatment in months before pregnancy [IQR] 24 [8–40] 22 [8–38] 0.73 Standard dose anti-TNF [%] 35 [67] 33 [79] 0.25 Italic values signifies that all test were performed two-tailed unless stated differently and tested at a significant level of 0.05 as stated in the statistical considerations. IQR, interquartile range; IFX, infliximab; ADA, adalimumab. View Large Table 3 Outcomes for mother–newborn pairs with anti-TNF measurement in cord blood [n = 94]. IFX [n = 52] ADA [n = 42] p value Median anti-TNF concentration in cord blood [µg/mL] [IQR] 4.9 [1.9–14.7] 1.1 [0.4–37.0] 0.0001 Median anti-TNF level in maternal blood at birth [µg/mL] [IQR] 1.7 [0.4–6.9] 0.6 [0.3–3.6] 0.05 Median ratio of cord blood level / maternal level [IQR] 2.63 [1.67–4.03] 1.36 [1.00–2.08] 0.0001 Median anti-TNF stop week [IQR] 25 [21–32] 23 [22–37] 0.56 Anti-TNF stopped during pregnancy before gestational Week 25 [%] 26 [50] 26 [62] 0.30 Disease relapse during pregnancy [%] 15 [29] 14 [36] 0.50 Median duration of anti-TNF treatment in months before pregnancy [IQR] 24 [8–40] 22 [8–38] 0.73 Standard dose anti-TNF [%] 35 [67] 33 [79] 0.25 IFX [n = 52] ADA [n = 42] p value Median anti-TNF concentration in cord blood [µg/mL] [IQR] 4.9 [1.9–14.7] 1.1 [0.4–37.0] 0.0001 Median anti-TNF level in maternal blood at birth [µg/mL] [IQR] 1.7 [0.4–6.9] 0.6 [0.3–3.6] 0.05 Median ratio of cord blood level / maternal level [IQR] 2.63 [1.67–4.03] 1.36 [1.00–2.08] 0.0001 Median anti-TNF stop week [IQR] 25 [21–32] 23 [22–37] 0.56 Anti-TNF stopped during pregnancy before gestational Week 25 [%] 26 [50] 26 [62] 0.30 Disease relapse during pregnancy [%] 15 [29] 14 [36] 0.50 Median duration of anti-TNF treatment in months before pregnancy [IQR] 24 [8–40] 22 [8–38] 0.73 Standard dose anti-TNF [%] 35 [67] 33 [79] 0.25 Italic values signifies that all test were performed two-tailed unless stated differently and tested at a significant level of 0.05 as stated in the statistical considerations. IQR, interquartile range; IFX, infliximab; ADA, adalimumab. View Large 3.6. Linear regression model The simple linear regression analyses, assessing the association between variables and anti-TNF concentration in cord blood at birth, are shown in Table 4. Only the variables anti-TNF stop week and type of anti-TNF were strongly associated with anti-TNF concentration in cord blood. There was no significant correlation between these two variables. No other variables improved the model. Therefore, in the final multiple linear regression model, anti-TNF stop week and type of anti-TNF were used as independent variables, and anti-TNF cord blood concentration at birth as a dependent variable [Figure 1]. This model shows that IFX transportation over the placenta increases exponentially during the third trimester of pregnancy. However, ADA transportation over the placenta is significantly lower than IFX and increases in a linear fashion. Table 4 Simple linear regression analyses: assessing association between variables and anti-TNF cord blood concentration. Independent variables Standardized β coefficients p value Maternal age 0.031 0.71 Diagnosis –0.078 0.41 Pre-pregnancy BMI –0.174 0.35 Pre-pregnancy weight –0.004 0.98 Anti-TNF stop week 0.738 0.0001 Smoking –0.071 0.39 Type anti-TNF –0.510 0.0001 Thiopurine –0.020 0.81 Steroids 0.027 0.77 Gestational age –0.113 0.27 Birth weight 0.053 0.56 Prior bowel resection 0.012 0.89 Standard anti-TNF dose 0.003 0.97 Relapse during pregnancy –0.118 0.24 Mode of delivery 0.05 0.58 Independent variables Standardized β coefficients p value Maternal age 0.031 0.71 Diagnosis –0.078 0.41 Pre-pregnancy BMI –0.174 0.35 Pre-pregnancy weight –0.004 0.98 Anti-TNF stop week 0.738 0.0001 Smoking –0.071 0.39 Type anti-TNF –0.510 0.0001 Thiopurine –0.020 0.81 Steroids 0.027 0.77 Gestational age –0.113 0.27 Birth weight 0.053 0.56 Prior bowel resection 0.012 0.89 Standard anti-TNF dose 0.003 0.97 Relapse during pregnancy –0.118 0.24 Mode of delivery 0.05 0.58 Italic values signifies that all test were performed two-tailed unless stated differently and tested at a significant level of 0.05 as stated in the statistical considerations. BMI, body mass index. View Large Table 4 Simple linear regression analyses: assessing association between variables and anti-TNF cord blood concentration. Independent variables Standardized β coefficients p value Maternal age 0.031 0.71 Diagnosis –0.078 0.41 Pre-pregnancy BMI –0.174 0.35 Pre-pregnancy weight –0.004 0.98 Anti-TNF stop week 0.738 0.0001 Smoking –0.071 0.39 Type anti-TNF –0.510 0.0001 Thiopurine –0.020 0.81 Steroids 0.027 0.77 Gestational age –0.113 0.27 Birth weight 0.053 0.56 Prior bowel resection 0.012 0.89 Standard anti-TNF dose 0.003 0.97 Relapse during pregnancy –0.118 0.24 Mode of delivery 0.05 0.58 Independent variables Standardized β coefficients p value Maternal age 0.031 0.71 Diagnosis –0.078 0.41 Pre-pregnancy BMI –0.174 0.35 Pre-pregnancy weight –0.004 0.98 Anti-TNF stop week 0.738 0.0001 Smoking –0.071 0.39 Type anti-TNF –0.510 0.0001 Thiopurine –0.020 0.81 Steroids 0.027 0.77 Gestational age –0.113 0.27 Birth weight 0.053 0.56 Prior bowel resection 0.012 0.89 Standard anti-TNF dose 0.003 0.97 Relapse during pregnancy –0.118 0.24 Mode of delivery 0.05 0.58 Italic values signifies that all test were performed two-tailed unless stated differently and tested at a significant level of 0.05 as stated in the statistical considerations. BMI, body mass index. View Large Figure 1 View largeDownload slide Multiple linear regression model predicting IFX and ADA cord blood concentration at birth, based on gestational stop week. The means are represented by the continuous lines, and the 95% confidence intervals are represented by the dotted lines. Figure 1 View largeDownload slide Multiple linear regression model predicting IFX and ADA cord blood concentration at birth, based on gestational stop week. The means are represented by the continuous lines, and the 95% confidence intervals are represented by the dotted lines. 3.7. One-year health outcomes of infants exposed to anti-TNF in utero Out of all live births, health outcomes until 1 year of age were obtained from 93 infants [71%]. These results are shown separately [Table 5]. Information was not obtained if infants did not yet reach the age of 1, or if we were unable to contact the mother for a telephonic questionnaire. There were no differences regarding growth, infection rate, hospitalization because of an infection, allergies, chronic diseases, adverse reactions to vaccinations, or the presence of eczema between IFX-exposed infants and ADA-exposed infants. Table 5 Health outcomes of infants at 1 year [n = 93]. IFX [n = 50] ADA [n = 43] p value Growth [%]  Normal 49 [98] 42 [98] 1.00  Abnormal 1 [2]a 1 [2]b 1.00 Number of infections treated with antibiotics [%]  0 35 [76] 31 [71] 0.82  1–2 10 [22] 10 [23] 0.48  3 1 [2] 3 [7] 0.35 Hospitalization because of infection [%] 5 [10] 3 [7] 0.72 Allergies [%] 3 [7] 5 [11] 0.48 Chronic diseases [%] 0 [0] 1 [2]c 1.00 Adverse reaction to vaccination [%] 0 [0] 0 [0] 1.00 Eczema [%] 12 [26] 6 [14] 0.20 IFX [n = 50] ADA [n = 43] p value Growth [%]  Normal 49 [98] 42 [98] 1.00  Abnormal 1 [2]a 1 [2]b 1.00 Number of infections treated with antibiotics [%]  0 35 [76] 31 [71] 0.82  1–2 10 [22] 10 [23] 0.48  3 1 [2] 3 [7] 0.35 Hospitalization because of infection [%] 5 [10] 3 [7] 0.72 Allergies [%] 3 [7] 5 [11] 0.48 Chronic diseases [%] 0 [0] 1 [2]c 1.00 Adverse reaction to vaccination [%] 0 [0] 0 [0] 1.00 Eczema [%] 12 [26] 6 [14] 0.20 aSecondary growth failure; bprimary growth failure; ccystic fibrosis. View Large Table 5 Health outcomes of infants at 1 year [n = 93]. IFX [n = 50] ADA [n = 43] p value Growth [%]  Normal 49 [98] 42 [98] 1.00  Abnormal 1 [2]a 1 [2]b 1.00 Number of infections treated with antibiotics [%]  0 35 [76] 31 [71] 0.82  1–2 10 [22] 10 [23] 0.48  3 1 [2] 3 [7] 0.35 Hospitalization because of infection [%] 5 [10] 3 [7] 0.72 Allergies [%] 3 [7] 5 [11] 0.48 Chronic diseases [%] 0 [0] 1 [2]c 1.00 Adverse reaction to vaccination [%] 0 [0] 0 [0] 1.00 Eczema [%] 12 [26] 6 [14] 0.20 IFX [n = 50] ADA [n = 43] p value Growth [%]  Normal 49 [98] 42 [98] 1.00  Abnormal 1 [2]a 1 [2]b 1.00 Number of infections treated with antibiotics [%]  0 35 [76] 31 [71] 0.82  1–2 10 [22] 10 [23] 0.48  3 1 [2] 3 [7] 0.35 Hospitalization because of infection [%] 5 [10] 3 [7] 0.72 Allergies [%] 3 [7] 5 [11] 0.48 Chronic diseases [%] 0 [0] 1 [2]c 1.00 Adverse reaction to vaccination [%] 0 [0] 0 [0] 1.00 Eczema [%] 12 [26] 6 [14] 0.20 aSecondary growth failure; bprimary growth failure; ccystic fibrosis. View Large 3.8. Growth There were 2 infants [2%] with an abnormal growth [1 IFX, 1 ADA]. One infant, diagnosed with cystic fibrosis [CF], had a primary growth failure. The second infant had a secondary growth failure; however, the cause was still unknown at the time of analyses. 3.9. Infections In total, 25 infants [27%] received one or more antibiotic treatments in the first year of life, of whom 12 [48%] were exposed to IFX. None of the infants received more than three antibiotic treatments. Anti-TNF type was not associated with the number of antibiotic-treated infections. A total of 33 oral antibiotic treatments were prescribed for the following types of infections: acute otitis media [n = 16], upper respiratory infections [n = 11], urinary tract infection [n = 2], infected toe [n = 1], paronychia [n = 1], impetigo [n = 1], and furuncles [n = 1]. Information regarding anti-TNF cord blood level and infection rate was collected from 55 mother–child pairs. The correlation between cord blood level at birth and infection rate is demonstrated in Figure 2. The median cord blood level of children who did not receive antibiotics for an infection [n = 38] was 2.0 µg/mL [IQR 1.0–7.8], of children who had one antibiotic-treated infection [n = 13] was 3.1 µg/mL [IQR 0.4–10.6], and of children who received two or more antibiotic treatments for an infection [n = 4] was 3.9 µg/mL [IQR 0.1–18.7]. There was no statistically significant difference regarding anti-TNF cord blood level between children without antibiotic-treated infections, children with one antibiotic-treated infection, and children with two or more antibiotic-treated infections. Figure 2 View largeDownload slide Anti-TNF cord blood levels compared with infection rates. Boxplot showing the association between anti-TNF cord blood level and infections rate within 1 year. One extreme outlier in the 1 infection group is not shown. One child–mother couple had an anti-TNF cord blood level of 56.0. The mother used 10 mg/kg IFX every 7 weeks. This pregnancy was complicated by preeclampsia with preterm birth after 35.5 gestational weeks. The last infusion was given 36 days before delivery. Figure 2 View largeDownload slide Anti-TNF cord blood levels compared with infection rates. Boxplot showing the association between anti-TNF cord blood level and infections rate within 1 year. One extreme outlier in the 1 infection group is not shown. One child–mother couple had an anti-TNF cord blood level of 56.0. The mother used 10 mg/kg IFX every 7 weeks. This pregnancy was complicated by preeclampsia with preterm birth after 35.5 gestational weeks. The last infusion was given 36 days before delivery. The rate of children who received at least one antibiotic treatment was similar for infants who were exposed to combination treatment of anti-TNF and an immunomodulator [n = 6, 26%] and infants exposed to anti-TNF monotherapy [n = 17, 30%] [p = 1.00]. There were eight infants [9%] admitted to hospital because of a severe infection. The indications for hospital admission were as follows: respiratory infections [n = 4], respiratory syncytial virus [RS-virus] [n = 2], furuncles [n = 1], and staphylococcal infection of the skin [n = 1]. There were four children exposed to IFX [50%]. The median cord blood level at birth of children admitted to hospital was 3.5 µg/mL [IQR 0.3–8.9], and the median cord blood level at birth of children not admitted to hospital was 2.0 µg/mL [IQR 0.9–7.8]. There was no statistically significant difference regarding anti-TNF cord blood level between children admitted to hospital and children not admitted to hospital because of an infection in the first year of life [p = 0.87]. There was no difference in hospital admission rate between anti-TNF types. Furthermore, there was no difference in hospital admissions because of a severe infection between infants exposed to combination therapy [n = 2, 8%] and infants exposed to anti-TNF monotherapy [n = 6, 9%] [p = 1.00]. 3.10. Allergies Eight infants [9%] suffered from an allergy, of which three [38%] were exposed to IFX and five [62%] to ADA. The following types of allergies were reported: cow milk allergy [n = 4], antibiotics [n = 2], allergic rhinitis [n = 1], and a sun allergy that resolved completely shortly after diagnosis [n = 1]. There was no correlation between anti-TNF type and allergies. 3.11. Adverse reaction to vaccinations Life vaccinations were avoided in cases in which anti-TNF levels were >3 µg/mL in the offspring. In The Netherlands, the first life vaccination is administered at the age of 14 months. None of the infants had anti-TNF levels >3 µg/mL at 14 months of age; moreover, none of the infants had anti-TNF levels exceeding 1 µg/mL at 6 months of age. Furthermore, none of the infants in our cohort had an adverse reaction to a vaccination. 4. Discussion We developed a linear regression model to demonstrate the effect of anti-TNF cessation during pregnancy on foetal exposure, for IFX and ADA separately. Anti-TNF concentrations in cord blood and maternal blood were higher in the IFX group than in the ADA group. Our linear regression shows that IFX transportation over the placenta increases exponentially during the third trimester of pregnancy. However, ADA transportation over the placenta is lower and increases in a linear fashion. Therefore, ADA may be continued longer during pregnancy than IFX without leading to higher anti-TNF concentrations in the newborn. In cases of disease activity in women with a current or future pregnancy, and in pregnant women who need to step-up to anti-TNF therapy, ADA may therefore be preferred over IFX. Furthermore, we did not observe significant differences in disease course, maternal outcomes, or birth outcomes between women using IFX and women using ADA during pregnancy. Continuing ADA longer during pregnancy may avoid low maternal ADA levels and subsequently an increased relapse risk in mothers. In addition, a shorter anti-TNF drug holiday may reduce the risk of an adverse event after drug re-initiation, such as an allergic reaction, or loss of response. We did not observe significant differences between the anti-TNF types regarding relapse rate or adverse events after drug re-initiation. However, our study may be underpowered, and therefore further evaluation in larger prospective studies is needed. Anti-TNF concentrations in cord blood varied widely between individuals, as is the case in non-pregnant patients.22,25 This variation is possibly due to several factors influencing the pharmacokinetics of anti-TNF drugs, such as anti-drug antibody formation, concomitant immunosuppressive therapy, serum CRP concentration, BMI, and serum albumin concentration.22,26,27 In addition, physiological changes during pregnancy may also alter the pharmacokinetics of anti-TNF drugs. The latter was demonstrated in a recent study showing a significant increase in the maternal anti-TNF level during pregnancy in women using IFX with a fixed dosing schedule, irrespective of albumin level or BMI.28 The underlying mechanism for this finding remains unknown and needs further evaluation. Because of the relatively small sample size, this study may be underpowered to demonstrate an association between potential predictor variables and anti-TNF concentration in cord blood. However, despite the small sample size, we did find a very strong association between anti-TNF concentration in cord blood and the variables anti-TNF type and stop week. These robust findings indicate that these variables are of utmost importance when predicting anti-TNF concentration in cord blood, which underlines the large pharmacokinetic differences between IFX and ADA. One-year health outcomes, such as growth, infection rate, hospitalization because of an infection, allergies, chronic diseases, adverse reactions to vaccinations, and the presence of eczema were similar between IFX-exposed and ADA-exposed infants. One or more infections were documented in 31% of infants, which is in line with a non-controlled follow-up study assessing the health outcomes of 25 anti-TNF–exposed children, of whom 32% were treated for an infection in the first year of life.29 The infection rate in our cohort is also in line with that of the overall Dutch population.30 However, the infection rate was higher in infants from non-IBD controls from the same geographic region, namely 40%.17 It should be noted that infection data are biased because parents of infants with a cord blood concentration of 3 µg/mL or higher were advised not to bring their child to day-care, to be extra cautious of infectious sources, and to postpone all life vaccinations before the repeated anti-TNF measurement was below 3 µg/mL. Therefore, the actual infection risk in the first year in anti-TNF–exposed infants may be higher than shown in our study. The cut-off level of 3µg/mL is, however, arbitrary and was initially based on adult studies showing an association between an IFX level of >3µg/mL and response to treatment.31 Subsequent studies showed that higher trough levels may be needed for response in the case of ADA treatment. However, we conservatively continued to use the lower cut-off value, based on the pharmacokinetics of IFX, in order to minimize health risks for the newborns. The top three indications for which antibiotics are prescribed in the general Dutch population are respiratory tract infections [45%], ear infections [20%], and urinary tract infections [10%]30, which resembled the indications in our study population: ear infections [48%], upper respiratory infections [33%], and urinary tract infections [6%]. It should be noted that this cohort received stringent counselling and follow-up before and during pregnancy. This strict follow-up has a beneficial effect on pregnancy outcomes and should be taken into account when comparing the results with those of other studies.32 In addition, disease activity during pregnancy could not be assessed in a standard manner. During pregnancy, some clinical scores and laboratory work-up are of limited value. Pregnant women often experience abdominal complaints, regardless of their underlying IBD, and clinical scores such as hematocrit and body weight to assess disease activity are of little value because pregnant women often become anemic and most women gain weight during pregnancy. An endoscopy to assess disease activity was only performed in cases where there was a strong indication. Furthermore, cord blood samples were not obtained from all pregnancies because anti-TNF measurements have only been performed since 2010 at our clinic, and there were samples missing because of logistic problems; however, missing samples were missing at random. In addition, we did not find a correlation between anti-TNF cord blood levels and the impact on the developing immune system of the child. However, this study may be underpowered to demonstrate a correlation, and therefore further prospective studies on this topic are needed. In conclusion, ADA may be continued longer during pregnancy than IFX because of the lower placental transmission. Continuing ADA longer during pregnancy may reduce relapse risk of the mother without increasing foetal anti-TNF exposure. Funding None Conflict of Interest Shannon L. Kanis: none; Alison de Lima-Karagiannis: none; Cokkie van der Ent: none; Dimitris Rizopoulos: none; C. Janneke van der Woude: has served as a speaker and a consultant for Abbot, Abbvie, and MSD, as a consultant for Shire, and has received funding from Janssen Biologics BV. Author Contributions Shannon L. Kanis: data collection, literature search, data analysis, data interpretation, drafting the article; Alison de Lima-Karagiannis: data collection, data interpretation, revising the article; Cokkie van der Ent: data collection, revising the article; Dimitris Rizopoulos: data analysis, figure, data interpretation, revising the article; C. Janneke van der Woude: study design, data interpretation, revising the article. All authors have read and approved this version as submitted. Acknowledgments Results from this study were presented at the 12th Congress of ECCO, February 17, 2017. References 1. Bröms G , Granath F , Linder M , Stephansson O , Elmberg M , Kieler H . Birth outcomes in women with inflammatory bowel disease: effects of disease activity and drug exposure . Inflamm Bowel Dis 2014 ; 20 : 1091 – 8 . Google Scholar PubMed 2. Ujihara M , Ando T , Ishiguro K , et al. Importance of appropriate pharmaceutical management in pregnant women with ulcerative colitis . BMC Res Notes 2013 ; 6 : 210 . Google Scholar CrossRef Search ADS PubMed 3. Reddy D , Murphy SJ , Kane SV , Present DH , Kornbluth AA . Relapses of inflammatory bowel disease during pregnancy: in-hospital management and birth outcomes . Am J Gastroenterol 2008 ; 103 : 1203 – 9 . Google Scholar CrossRef Search ADS PubMed 4. Nørgård B , Hundborg HH , Jacobsen BA , Nielsen GL , Fonager K . Disease activity in pregnant women with Crohn’s disease and birth outcomes: a regional Danish cohort study . Am J Gastroenterol 2007 ; 102 : 1947 – 54 . Google Scholar CrossRef Search ADS PubMed 5. van der Woude CJ , Ardizzone S , Bengtson MB , et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease . J Crohns Colitis 2015 ; 9 : 107 – 24 . Google Scholar CrossRef Search ADS PubMed 6. Nguyen GC , Seow CH , Maxwell C , et al. The Toronto Consensus Statements for the management of inflammatory bowel disease in pregnancy . Gastroenterology 2016 ; 150 : 734 – 57 . Google Scholar CrossRef Search ADS PubMed 7. Malek A , Sager R , Kuhn P , Nicolaides KH , Schneider H . Evolution of maternofetal transport of immunoglobulins during human pregnancy . Am J Reprod Immunol 1996 ; 36 : 248 – 55 . Google Scholar CrossRef Search ADS PubMed 8. Palmeira P , Quinello C , Silveira-Lessa AL , Zago CA , Carneiro-Sampaio M . IgG placental transfer in healthy and pathological pregnancies . Clin Dev Immunol 2012 ; 2012 : 985646 . Google Scholar CrossRef Search ADS PubMed 9. Zelinkova Z , de Haar C , de Ridder L , et al. High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy . Aliment Pharmacol Ther 2011 ; 33 : 1053 – 8 . Google Scholar CrossRef Search ADS PubMed 10. Mahadevan U , Wolf DC , Dubinsky M , et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease . Clin Gastroenterol Hepatol 2013 ; 11 : 286 – 92 ; quiz e24. Google Scholar CrossRef Search ADS PubMed 11. Simister NE . Placental transport of immunoglobulin G . Vaccine 2003 ; 21 : 3365 – 9 . Google Scholar CrossRef Search ADS PubMed 12. Narula N , Al-Dabbagh R , Dhillon A , Sands BE , Marshall JK . Anti-TNFα therapies are safe during pregnancy in women with inflammatory bowel disease: a systematic review and meta-analysis . Inflamm Bowel Dis 2014 ; 20 : 1862 – 9 . Google Scholar CrossRef Search ADS PubMed 13. Shihab Z , Yeomans ND , De Cruz P . Anti-tumour necrosis factor alpha therapies and inflammatory bowel disease pregnancy outcomes: a meta-analysis . J Crohns Colitis 2016 ; 10 : 979 – 88 . Google Scholar CrossRef Search ADS PubMed 14. Schnitzler F , Fidder H , Ferrante M , et al. Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy . Inflamm Bowel Dis 2011 ; 17 : 1846 – 54 . Google Scholar CrossRef Search ADS PubMed 15. Mahadevan U , Kane S , Sandborn WJ , et al. Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn’s disease . Aliment Pharmacol Ther 2005 ; 21 : 733 – 8 . Google Scholar CrossRef Search ADS PubMed 16. Diav-Citrin O , Otcheretianski-Volodarsky A , Shechtman S , Ornoy A . Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: a prospective, comparative, observational study . Reprod Toxicol 2014 ; 43 : 78 – 84 . Google Scholar CrossRef Search ADS PubMed 17. de Lima A , Zelinkova Z , van der Ent C , Steegers EA , van der Woude CJ . Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety . Gut 2016 ; 65 : 1261 – 8 . Google Scholar CrossRef Search ADS PubMed 18. Guiddir T , Fremond ML , Triki TB , et al. Anti-TNF-alpha therapy may cause neonatal neutropenia . Pediatrics 2014 ; 134 : 1189 – 93 . Google Scholar CrossRef Search ADS 19. Cheent K , Nolan J , Shariq S , Kiho L , Pal A , Arnold J . Case report: fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease . J Crohns Colitis 2010 ; 4 : 603 – 5 . Google Scholar CrossRef Search ADS PubMed 20. Julsgaard M , Christensen LA , Gibson PR , et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection . Gastroenterology 2016 ; 151 : 110 – 9 . Google Scholar CrossRef Search ADS PubMed 21. Mahadevan U MC , Sandler RS . PIANO, a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy . Gastroenterology 2012 ; 142 . 22. Lie MR , Peppelenbosch MP , West RL , Zelinkova Z , van der Woude CJ . Adalimumab in Crohn’s disease patients: pharmacokinetics in the first 6 months of treatment . Aliment Pharmacol Ther 2014 ; 40 : 1202 – 8 . Google Scholar CrossRef Search ADS PubMed 23. Visser GHA , Eilers PHC , Elferink-Stinkens PM , Merkus HMWM , Wit JM . New Dutch reference curves for birthweight by gestational age . Early Hum Dev 2009 ; 85 : 737 – 44 . Google Scholar CrossRef Search ADS PubMed 24. Hozo SP , Djulbegovic B , Hozo I . Estimating the mean and variance from the median, range, and the size of a sample . BMC Med Res Methodol 2005 ; 5 : 13 . Google Scholar CrossRef Search ADS PubMed 25. Steenholdt C , Bendtzen K , Brynskov J , Ainsworth MA . Optimizing treatment with TNF inhibitors in inflammatory bowel disease by monitoring drug levels and antidrug antibodies . Inflamm Bowel Dis 2016 ; 22 : 1999 – 2015 . Google Scholar CrossRef Search ADS PubMed 26. Vermeire S , Noman M , Van Assche G , Baert F , D’Haens G , Rutgeerts P . Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease . Gut 2007 ; 56 : 1226 – 31 . Google Scholar CrossRef Search ADS PubMed 27. Ordas I , Feagan BG , Sandborn WJ . Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease . Clin Gastroenterol Hepatol 2012 ; 10 : 1079 – 87 . Google Scholar CrossRef Search ADS PubMed 28. Seow CH , Leung Y , Vande Casteele N , et al. The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease . Aliment Pharmacol Ther 2017 ; 45 : 1329 – 38 . Google Scholar CrossRef Search ADS PubMed 29. Bortlik M , Duricova D , Machkova N , et al. Impact of anti-tumor necrosis factor alpha antibodies administered to pregnant women with inflammatory bowel disease on long-term outcome of exposed children . Inflamm Bowel Dis 2014 ; 20 : 495 – 501 . Google Scholar CrossRef Search ADS PubMed 30. Otters HB , van der Wouden JC , Schellevis FG , van Suijlekom-Smit LW , Koes BW . Trends in prescribing antibiotics for children in Dutch general practice . J Antimicrob Chemother 2004 ; 53 : 361 – 6 . Google Scholar CrossRef Search ADS PubMed 31. Vande Casteele N , Khanna R , Levesque BG , et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease . Gut 2015 ; 64 : 1539 – 45 . Google Scholar CrossRef Search ADS PubMed 32. de Lima A , Zelinkova Z , Mulders AG , van der Woude CJ . Preconception care reduces relapse of inflammatory bowel disease during pregnancy . Clin Gastroenterol Hepatol 2016 ; 14 : 1285 – 92.e1 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Crohn's and ColitisOxford University Press

Published: May 15, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off