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Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: A prospective, comparative, observational study
Reproductive Toxicology 43 (2014) 78–84
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Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: A prospective, comparative, observational study Orna Diav-Citrin a,b,∗ , Anna Otcheretianski-Volodarsky c , Svetlana Shechtman a , Asher Ornoy a,b a
The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel The Hebrew University Hadassah Medical School, Jerusalem, Israel c The Division of Clinical Pharmacy, the Hebrew University of Jerusalem, Israel b
a r t i c l e
i n f o
Article history: Received 2 May 2013 Received in revised form 29 October 2013 Accepted 14 November 2013 Available online 24 November 2013 Keywords: Anti-TNF-␣ Infliximab Etanercept Adalimumab Autoimmune diseases Pregnancy Congenital anomalies
a b s t r a c t Objective: To evaluate pregnancy safety of anti-TNF-␣ medications. Design: Prospective, comparative, observational study done at the Israeli Teratology Information Service between 2002 and 2011. Results: 83 anti-TNF-␣-exposed-pregnancies (97.6% in the first trimester, T1) were followed-up and compared with 86 disease-matched (DM) and 341 non-teratogenic-exposed (NTE) pregnancies. The anti-TNF-␣ group consisted of 35 infliximab-, 25 etanercept-, and 23 adalimumab-exposed pregnancies. The rate of major congenital anomalies did not significantly differ between the three groups [3/65 (4.6%) (anti-TNF-␣, T1), 5/79 (6.3%) (DM), 8/336 (2.4%) (NTE)], even after excluding genetic or cytogenetic anomalies [3/65 (4.6%) (anti-TNF-␣, T1), 4/79 (5.1%) (DM), 6/336 (1.8%) (NTE)]. There were no cases of VATER/VACTERL association. Conclusion: The present study suggests that anti-TNF-␣ treatment does not pose a major teratogenic risk in humans. This conclusion is based on relatively small numbers of exposed pregnancies and should be interpreted with caution. Larger studies are needed to establish anti-TNF-␣ pregnancy safety. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Infliximab, etanercept, and adalimumab are tumor necrosis factor-␣ inhibitors (anti-TNF-␣) produced by genetic engineering. Infliximab is a mouse-human chimeric monoclonal IgG1 antibody, etanercept is a TNF receptor-IgG1 fusion human protein, and adalimumab is a fully human monoclonal antibody. Anti-TNF␣ medications have led to a vast improvement in the treatment of inflammatory conditions. These new biopharmaceuticals target inflammatory cytokines, and are used in the treatment of autoimmune diseases including rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and inflammatory bowel diseases. Many of these illnesses are more common in women and occur during reproductive age. When anti mouse TNF␣ monoclonal antibody was administered to pregnant mice, there were no teratogenic effects [1]. The three anti-TNF-␣ antibodies,
∗ Corresponding author at: The Israeli Teratology Information Service Israel Ministry of Health, P.O. Box 1176, Jerusalem 9446724, Israel. Tel.: +972 2 5080441; fax: +972 2 6474822. E-mail address: [email protected] (O. Diav-Citrin). 0890-6238/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.reprotox.2013.11.004
infliximab, etanercept, and adalimumab, have a large molecular weight of approximately 149 kDa, and are, therefore, not expected to cross the human placenta in significant concentration in the first trimester of pregnancy. It is hypothesized, however, that the Fab’ fragment may passively cross the placenta in low levels in the first trimester during the period of organogenesis. Placental transfer of infliximab, etanercept, and adalimumab close to term has been documented [2–5]. The terminal elimination half-lives of these molecules are relatively long: 4 days for etanercept [6], 19 days for infliximab [7], and 15–19 days for adalimumab [8]. Human pregnancy experience with these medications is rather limited. It is based mostly on case reports, small case series, regulatory agency records, manufacturer’s registries, and preliminary data presented at scientific meetings published as abstracts. Human pregnancy data on infliximab specifically [9] and on anti-TNF-␣ medications in general [10] has been summarized in two recent review articles. Carter et al. [11] published a case report describing VATER association in a neonate born to a mother who was treated with etanercept during pregnancy. They reviewed the TNF-␣antagonists use in pregnancy report to the US Food and Drug Administration. They reported that 24 of the 41 children with congenital anomalies born to mothers who took infliximab or
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etanercept during pregnancy had one or more anomalies that are part of the VACTERL association [12]. They concluded that maternal treatment with TNF antagonists pose an increased risk for VATER or VACTERL association. A critical editorial [13] and a letter to the editor [14] published in the same journal raised questions and pointed out numerous methodological problems in this study. The analysis suffers from selection bias, is based on voluntary reports lacking a denominator of total number or pregnancies with maternal antiTNF-␣ treatment and, therefore, cannot be used for risk calculation. Sporadic reports of isolated anomalies that could be a part of the VACTERL association do not establish this diagnosis. The diagnosis requires a constellation of anomalies in the same patient. The study did not address potential confounders. In addition, placental transmission of these molecules during the first trimester of pregnancy, covering the period of organ formation, is not expected in significant amounts, and makes the suggested causation between VACTERL association and anti-TNF-␣ medications, unlikely. Contrary to the reports by Carter et al. [11,12], human pregnancy experience with TNF-␣ antagonists has been mostly reassuring [5,15–28]. A summary of the reports of pregnancies with exposure to anti-TNF-␣ medications is presented in Table 1. The primary objective of the present study was to prospectively evaluate the rate of major congenital anomalies after maternal treatment with TNF-␣-antagonists (infliximab, etanercept, or adalimumab) during pregnancy compared with two comparison groups: (1) pregnant women with autoimmune diseases not treated with anti-TNF-␣ medications during pregnancy (disease matched), (2) pregnant women counseled for non-teratogenic exposure. Secondary endpoints of interest were pregnancy outcome, birth weight, and gestational age at delivery.
2. Materials and methods Pregnant women counseled by the Israeli Teratology Information Service (TIS), Jerusalem, in regard to the TNF-␣-antagonists, infliximab, etanercept, or adalimumab, between the years 2002 and 2011, were enrolled in the present prospective comparative observational study. Exposure during the first trimester of pregnancy was defined when the pregnant woman received an anti-TNF-␣ before pregnancy, but conception occurred within 5 elimination half-lives from medication administration, or if the woman was treated during pregnancy before 13 completed weeks from her last menstrual period. Outcome was compared with two comparison groups in a similar time frame: (1) pregnant women with similar autoimmune diseases not treated with anti-TNF-␣ medications during pregnancy at a 1:1 ratio. This disease matched (DM) group was selected according to their disease from the Israeli TIS database and was either treated with medications other than antiTNF-␣ excluding methotrexate, or untreated during pregnancy; (2) pregnant women counseled for non-teratogenic exposure (NTE) at a 1:4 ratio. This group was randomly selected from the Israeli TIS database according to their exposure and included women counseled during pregnancy in regard to exposures known to be non-teratogenic or fetal toxic such as analgesics like paracetamol, low dose diagnostic radiation, topical preparations with negligible systemic exposure, antibiotics (penicillins or cephalosporins), oral contraceptives taken no longer than the 5th week of pregnancy, hair dye or house-cleaning agents. Pregnancies of women who have chronic diseases were not included in the NTE group. Details of exposure were collected during pregnancy, at the initial contact with the TIS and before pregnancy outcome was known, using a structured questionnaire. Verbal consent to participate in the study was given by the woman at initial contact. Since the study was observational no Institutional Review Board approval was required. In addition, the following information was recorded at the initial
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contact: maternal demographics, medical and obstetrical histories, and exposure details (dose, duration, and timing in pregnancy, additional exposures). Retrospective cases were not included in the study. Pregnant women who contacted the TIS after an anomaly had been identified on prenatal testing were also excluded. Pregnancy outcome was actively sought after the expected date of delivery in the exposed and comparison groups. Follow-up was conducted by a telephone interview with the woman to obtain details on the pregnancy outcome, gestational age at delivery, birth weight, congenital anomalies and neonatal complications. In cases of anomalies an attempt to obtain medical records was made. In addition, all exposures were ascertained. It was verified that the exposure/s the woman was counseled for indeed occurred during pregnancy. Details on any dose modifications during pregnancy, exact timing and duration of treatment, and additional exposures during pregnancy were also ascertained. The vast majority of infants in Israel are delivered in hospital. Each neonate in Israel undergoes at least two physical examinations before being discharged from the hospital. All neonates in the present study were delivered in hospital. The interview was conducted after these physical examinations. Data collection methods were similar in the exposed and comparison groups. Major anomalies were defined as structural abnormalities in the offspring that have serious medical, surgical or cosmetic consequences. The focus of the study was on anomalies that occur during the period of organogenesis in the first trimester of pregnancy. Therefore, an inguinal hernia in a term infant, as well as cryptorchidism, that occur later in pregnancy, were not considered major anomalies. Children with minor anomalies or functional problems without any morphological changes (e.g. ankyloglossia, umbilical hernia that spontaneously closed, systolic heart murmur with normal echocardiography) or infants with complications of preterm delivery were not considered as having major anomalies. Cardiac septal defects are structural anomalies of the heart, and are considered major anomalies in the present study, even if spontaneously resolved, unless the closure occurred during the neonatal period. Any ventricular septal defect carries a risk of infectious endocarditis and may require prophylactic antibiotics before invasive procedures. Horseshoe kidney is classified as a major anomaly because it carries a risk for renal cancer especially Wilms’ tumor, renal calculi and obstructive uropathy. Primary congenital hypothyroidism is considered a major anomaly in the present study because it requires lifelong replacement therapy. In addition, its etiology in the majority of cases, is either thyroid ectopy or athyreosis, both resulting from first trimester events. Abnormalities detected by prenatal ultrasonography (if verified postnatally or by autopsy) were included in our study, since antenatal screening for major anomalies is routinely performed in Israel. The classification of anomalies was done by a certified pediatrician blinded to the exposure group. An international expert was consulted in case of classification difficulty. Thus, the analysis of major congenital anomalies was performed among live-born infants, pregnancy losses with confirmed anomalies, and elective terminations of pregnancy due to prenatally diagnosed anomalies. In the case of multiple births, each live-born offspring was included in the analysis. Gestational age was defined from the last menstrual period. Miscarriage was defined as spontaneous pregnancy loss before or at 20 completed weeks, whereas stillbirth was defined as spontaneous pregnancy loss beyond 20 completed weeks. Preterm delivery was defined as birth before 37 completed weeks. All co-authors had access to the study data and had reviewed and approved the final manuscript. 2.1. Statistical analysis Categorical data were compared using 2 or Fisher exact tests and are expressed as ratios or percentages. Continuous data are
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Table 1 Summary of reports of pregnancies with exposure to anti-TNF-␣ medications. Reference
Medication
n (n T1)
Anomalies
Design
Katz et al., [15]
Infliximab
96 (58)
Chambers et al. [16]
29 4 10 (9)
Manufacturer’s data retrospective voluntary reports compared to National health statistics Prospective comparative OTIS study (abstract)
Mahadevan et al. [17]
Etanercept Infliximab Infliximab
- Tetralogy of Fallot - Intestinal malrotation - Trisomy 18 None
Retrospective international chart review
Lichtenstein et al. [18,19]
Infliximab
117*
Roux et al. [20]
Etanercept Adalimumab
2 (2) 1 (1)
- VSD* - Anencephaly* None
Prospective observational multicenter registry in North American patients with CD TREAT Prospective small case series
Berthelot et al. [21]
Infliximab Adalimumab Etanercept Etanercept Infliximab
3 (1) 2 (1) 10 (10) 22 19
None
French rheumatologist website questionnaire
Review of malformed and exposed in FDA Adverse Event Reporting System
Rump and Schönborn [22]
Etanercept
8
24/41 had one or more anomalies that are part of the VACTERL association - Megacolon
Zelinkova et al. [3]
Infliximab
4 (4)
- Polydactyly Lt hand
Case series
Verstappen et al. [23]
Infliximab Etanercept Adalimumab Infliximab Adalimumab Infliximab Adalimumab
61 (61) [3 anti-TNF-]
- CDH - Pyloric stenosis
British Society for Rheumatology Biologics Register (prospective)
35 (35) 7 (7) 25 (25) 28 (28)
- Trisomy 18
Belgian comparative observational study Prospective uncontrolled cohort, Berlin TIS (abstract)
Hultzsch et al. [26]
Etanercept
26 (26)
Chambers et al. [27]
Adalimumab
66 (66)
Viktil et al. [28]
Etanercept Adalimumab Infliximab Adalimumab Certolizumab
22 (20) 3 (3) 11 (11) 10 (10) 10 (7)
- Neurofibromatosis - VSD - Growing hemangiomas - Renal agenesis - Hypoplastic Lt heart & hypospadias - Wolf Parkinson White Syndrome Major anomalies in 3.1%, no evidence of pattern None
Carter et al. [12]
Schnitzler et al. [24] Weber-Schoendorfer et al. [25]
Mahadevan et al. [5]
None
Case series
Prospective uncontrolled cohort, Berlin TIS (abstract)
Prospective comparative OTIS study (abstract)
Norway Medical Birth Registry linked to prescription database comparative study Prospective PIANO Registry
n – exposed pregnancies; (n T1) – pregnancies exposed in the first trimester; when available; * – cited by Chambers et al. [10]; VSD – ventricular septal defect; Lt – left; CDH – congenital dysplasia of hip; OTIS – Organization of Teratology Information Specialists; CD – Crohn’s Disease; TREAT – Therapy, Resource, Evaluation, and Assessment Tool; FDA – Food and Drug Administration; TIS – Teratology Information Service; PIANO – Pregnancy IBD And Neonatal Outcomes.
presented using mean ± SD or median with interquartile range (IQR), and compared using the ANOVA or Kruskal–Wallis test, depending on whether they followed normal distribution, or not, for three groups, or using Student-t or Mann–Whitney tests, for two groups. The p-values presented in the tables are for a comparison between the three groups. For pair-wise comparisons Bonferroni method was applied. Statistical calculations were done using SPSS Version 19 or Epi InfoTM software (Center for Disease Control and Prevention, Atlanta Epidemiology Program Office, Atlanta, GA, USA). 3. Results A total of 83 TNF-␣-antagonist-exposed pregnancies, 86 pregnancies of women with autoimmune diseases not treated with anti-TNF-␣ medications during pregnancy, and 341 pregnancies of women counseled for non-teratogenic exposure, were prospectively followed-up. The anti-TNF-␣ group consisted of 35 (42.2%) infliximab, 25 (31.1%) etanercept, and 23 (27.7%) adalimumab exposed pregnancies. Exposure to an anti-TNF-␣ medication at least in the first trimester of pregnancy occurred in 81 of 83 (97.6%) pregnancies. In the two remaining pregnancies the anti-TNF-␣ was
administered only later in pregnancy, starting in the second or third trimesters. The median gestational week of treatment discontinuation was 9 (IQR 4–28). The median infliximab dose per infusion was 300 mg (IQR 255–300) with a median interval of 8 weeks between infusions (IQR 4–8), whereas the median weekly dose was 50 mg (IQR 50–50) for etanercept, and 20 mg (IQR 20–20) for adalimumab. Concurrent medications during pregnancy in addition to the anti-TNF-␣ were taken by 43.4% of the women and are presented in Table 2. Co-administration of methotrexate within 1 Table 2 Distribution of medications in the anti-TNF-␣ (concurrent) and the DM groups. Medications
Anti-TNF-␣ (%)
DM (%)
Steroids nb-DMARDs Blood thinners Steroids and nb-DMARDs nb-DMARDs and blood thinners Steroids, nb-DMARDs and blood thinners
10.8 20.5 3.6 4.8 2.4 1.2
3.5 64.0 18.6 3.5
nb-DMARDs – non-biologic disease modifying antirheumatic drugs; azathioprine, 6-mercaptopurine, methotrexate (only in the anti-TNF-␣ group), mesalamine, sulfasalazine, or hydroxychloroquine; Blood thinners: low dose aspirin or low molecular weight heparin.
O. Diav-Citrin et al. / Reproductive Toxicology 43 (2014) 78–84 Table 3 Distribution of diseases in the anti-TNF-␣ and DM comparison groups. Disease
Anti-TNF-␣ group (%)
DM comparison group (%)
Crohn’s disease Rheumatoid arthritis Ulcerative colitis Unspecified arthritis Psoriatic arthritis Ankylosing spondylitis Behc¸et’s disease
36.3 21.3 12.5 12.5 11.3 5.0 1.3
41.7 10.7a 33.3 14.3
a
one also with ulceratve colitis.
month before the last menstrual period was reported in 6 women in the anti-TNF-␣ group; however, it was discontinued before the last menstrual period in 5 of the women. One woman in the antiTNF-␣ group, whose pregnancy resulted in a miscarriage, received IV methotrexate 17.5 mg/week till the 10th gestational week when her pregnancy was diagnosed. The reported indications for treatment with anti-TNF-␣ medications and the distribution of diseases in the DM comparison group are presented in Table 3. Medications for the underlying disease were administered during pregnancy in 89.5% of the DM group and are presented in Table 2. A comparison of maternal characteristics and obstetrical history between the three groups is presented in Table 4. The women in the anti-TNF-␣ group called at a significantly earlier median gestational age compared with the women in the DM and NTE groups. Similarly, the women in the DM group called at a significantly earlier median gestational age compared with the NTE group. No significant differences were observed between the groups in maternal age, obstetrical history, or smoking status. A comparison of pregnancy outcome between the three groups is presented in Tables 5 and 6. A higher proportion of pregnancies resulted either in a miscarriage or in an elective termination of pregnancy in the anti-TNF-␣ group compared with the NTE group. Three of the five women who decided to terminate their pregnancy in the anti-TNF-␣ group reported that the reason for their decision was fear of the unknown possible effect of these medications, whereas the other two reported that their termination was due to social reasons. No anomalies were detected in the five
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fetuses whose pregnancy was terminated in the anti-TNF-␣ group. However, there were elective terminations of pregnancy due to prenatally diagnosed anomalies in both the DM and NTE groups. In the DM group three women terminated their pregnancy, two due to prenatally diagnosed anomalies (Turner syndrome in one case and vermis cerebelli agenesis in another), and one due to evidence of cytomegalovirus infection on amniocentesis. In the NTE group, three women terminated their pregnancy, all due to prenatally diagnosed anomalies (Down syndrome in one case, agenesis of corpus callosum in another case, and diagnosis of osteogenesis imperfecta in another). The latter five pregnancy terminations due to prenatally diagnosed anomalies are included in the initial analysis of major anomalies. The rate of major anomalies did not significantly differ between the three groups when the analysis was limited to pregnancies exposed to anti-TNF-␣ medications during the first trimester. In a re-analysis after excluding genetic or cytogenetic anomalies the differences in the rate of major anomalies remained insignificant. Follow-up was performed at a median offspring age four months older in the DM group compared with the NTE group. However, all the anomalies found in the anti-TNF-␣ and DM groups were diagnosed prenatally or perinatally. The median gestational age at delivery was a week earlier in the anti-TNF-␣ group compared with the NTE group, with a 3.4-fold increase in the rate of preterm deliveries. The median birth weight was 285 g lower in the anti-TNF-␣ group compared with the DM group, and 180 g lower compared with the NTE group. The mean birth weight was 210 g lower in the anti-TNF-␣ group compared with the DM group, but did not significantly differ from the mean birth weight in the NTE group, when the analysis was limited to full-term infants. Significant differences in mode of delivery were not found between the groups. To evaluate the relative contribution of various predictors to the differences in the miscarriage rate, logistic regression was performed. The following predictors were entered into the model: maternal age, history of miscarriage, smoking status (none, <10 cigarettes/day, or ≥10 cigarettes/day), gestational age at initial contact, exposure group, and exposure to methotrexate within 1 month before the last menstrual period. The only significant predictors were gestational age at initial contact (with a higher miscarriage
Table 4 Comparison of maternal characteristics and obstetrical history. Anti-TNF-␣ n = 83
DM n = 86
NTE n = 341
p value
Maternal age mean ±SD (y)
31.4 ± 5.1
30.9 ± 4.5
31.3 ± 4.4
0.720
Pregnancy order, n (%) 1 2–4 ≥5
21/74 (28.4) 47/74 (63.5) 6/74 (8.1)
30/86 (34.9) 48/86 (55.8) 8/86 (9.3)
122/328 (37.2) 179/328 (54.6) 27/328 (8.2)
0.356 0.374 0.946
Parity, n (%) 0 1–3 ≥4
28/79 (35.4) 49/79 (62.0) 2/79 (2.5)
36/88 (40.9) 48/88 (54.5) 4/88 (4.5)
144/328 (43.9) 171/328 (52.1) 13/328 (4.0)
0.382 0.284 0.779
Past miscarriages, n (%) 0 1 ≥2 Past ETOP, n (%) GA at initial contact, w median (IQR)
55/75 (73.3) 12/75 (16.0) 8/75 (10.7) 6/74 (8.1) 7a , b (5–10)
71/86 (82.6) 10/86 (11.6) 5/86 (5.8) 6/86 (7.0) 8a (6–15)
276/329 (83.9) 38/329 (11.6) 15/329 (4.6) 15/329 (4.6) 12 (7–19)
0.098 0.559 0.121 0.390 <0.001
Cigarette smoking None <10cigarettes/d ≥10cigarettes/d
74/78 (94.9) 4/78 (5.1) 0
78/82 (95.1) 2/82 (2.4) 2/82 (2.4)
313/324 (96.6) 8/324 (2.5) 3/324 (0.9)
0.691 0.437 0.296
p < 0.05 marked in bold. SD – standard deviation; y – years; ETOP – elective termination of pregnancy; GA – gestational age; w – weeks; IQR – interquartile range; Anti-TNF-␣ – anti-tumor necrosis factor ␣; DM – disease matched; NTE – non-teratogenic exposure. a Significant difference in comparison to the NTE group. b Significant difference in comparison to the DM group.
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Table 5 Comparison of pregnancy outcome.
Multiple gestations Delivery of live-born infant, n (%) Miscarriage, n (%) ETOP, n (%) Stillbirth, n (%) Ectopic pregnancy, n (%) Major anomalies, n (%) Major anomalies, excluding genetic or cytogenetic anomalies, n (%)
Anti-TNF-␣ n = 83
DM n = 86
NTE n = 341
0 67/83 (80.7)a 9/83 (10.8)a 5/83 (6.0)a 1/83 (1.2) 1/83 (1.2) 3/65* (4.6) 3/65* (4.6)
0 77/86 (89.5) 5/86 (5.8) 3/86 (3.5) 1/86 (1.2) 0 5/79 (6.3) 4/79 (5.1)
6 twin sets 328/341 (96.2) 10/341 (2.9) 3/341 (0.9) 0 0 8/336 (2.4) 6/336 (1.8)
ETOP – elective termination of pregnancy; Anti-TNF-␣ – anti-tumor necrosis factor ␣; DM – disease matched; NTE – non-teratogenic exposure; a Significant difference in comparison to the NTE group. * Among women treated with anti-TNF-␣ medications during the first trimester of pregnancy. Table 6 Comparison of age at follow-up, mode and time of delivery, and birth weight.
Age at F/U, m median (IQR) Mode of delivery Vaginal uncomplicated, n (%) Cesarean section, n (%) Vacuum delivery, n (%) GA at delivery, w median (IQR) Preterm delivery, <37 w, n (%) Birth weight, g median (IQR) Birth weight of full-term infants, g mean (±SD)
Anti-TNF-␣ n = 83
DM n = 86
NTE n = 341
p value
14 (5–35)
16a (4–42)
12 (6–19)
0.031
43/66 (65.2) 22/66 (33.3) 1/66 (1.5) 38a (37–40) 15/66a (22.7) 2975a,b (2528–3276) 3085b ± 520
50/76 (65.8) 19/76 (25.0) 7/76 (9.2) 39 (37–40) 11/77 (14.3) 3260 (2900–3475) 3295 ± 394
223/326 (68.4) 84/326 (25.8) 19/326 (5.8) 39 (38–40) 22/327 (6.7) 3155 (2853–3483) 3211 ± 456
0.823 0.419 0.146 <0.001 <0.001 0.002 0.049
p < 0.05 marked in bold. GA – gestational age; w – weeks; F/U – follow-up; m – months; IQR – interquartile range; g – grams; SD – standard deviation; Anti-TNF-␣ – anti-tumor necrosis factor ␣; DM – disease matched; NTE – non-teratogenic exposure. a Significant difference in comparison to the NTE group. b Significant difference in comparison to the DM group.
rate among women calling early during gestation) (p < 0.001) and smoking of less than 10 cigarettes/d (p = 0.010). The adjusted OR for miscarriages in the anti-TNF-␣ vs. NTE group was 1.96 (95%CI 0.64–5.96). The reported major anomalies and the details of exposures in the anti-TNF-␣ and DM groups are listed in Table 7.
4. Discussion The results of the present prospective comparative study suggest that treatment with the anti-TNF-␣ medications, infliximab, etanercept, or adalimumab, is not associated with an increased risk of major anomalies. These results, however, are consistent with
Table 7 Major congenital anomalies in the anti-TNF-␣ and DM groups. Group
Type of anomaly
Details of exposure, additional exposures, maternal illness
Pregnancy outcome, GA (w), sex, BW (g)
F/U comments
Anti-TNF-␣
VSD
Delivery, 40, F, 2075
Anti-TNF-␣
Unilateral renal agenesis Kaposiform hemangioendothelioma, Kasabach-Merritt syndrome, bilateral hydronephrosis
Adalimumab 40 mg/2 w TO pregnancy, azathioprine 50 mg/d till w 9, Crohn’s disease Infliximab 400 mg T1, azathioprine 50 mg/d, Crohn’s disease Etanercept 25 mgx2/w T1, prednisone 10 mg/d, HCQ 200 mg/d TO, MTX 2.5 mgx3/w till 1 m pre-LMP, enoxaparin, rheumatoid arthritis
Small VSD diagnosed on U/S at w 20, prenatal and postnatal echocardiography, spontaneously closed at 6 m Diagnosed on prenatal U/S
Anti-TNF-␣
DM
Turner syndrome*
DM
Horseshoe kidney
DM
Congenital primary hypothyroidism (permanent)
DM
Brain anomaly, vermis cerebelli agenesis Esophageal atresia with TE fistula
DM
Mercaptopurine 50 mg/d mesalamine 4 g/d, Crohn’s disease Mesalamine 4 g/d, azathioprine 150 mg/d, ulcerative colitis Mesalamine 1gx3/d, HCQ 200 mg/d, and azathioprine 100 mg/d TO, budesonide 3 mgx2/d till w 14, prednisone 10 mg/d fr w 14, SLE, Crohn’s disease Mesalamine 4 g/d, venlafaxine 75 mg/d, colitis None, ulcerative colitis, hereditary hemorrhagic telagiectasia
Delivery, 36, M, 3190 Delivery, 31, F, 2740
ETOP, 22 Delivery, 42, F, 3400 Delivery, 36, F, 1888
Fetal edema diagnosed on late U/S, DIC, thrombocytopenia, anemia, severe RDS, edema, ecchymosis, jaundice (phototherapy), PDA, renal failure, recurrent blood exchange, PLT/PC/FFP transfusions, ampicillin, gentamicin for 3d, vancomycin for 6d, TPN from 2nd d, died on 10th d pathologic diagnosis on PM Diagnosed on amniocentesis, maternal age 38 Diagnosed on prenatal U/S, normal kidney function till age 2.5 y Offspring treated with thyroxine, the mother was euthyroid in pregnancy
ETOP, 20
Diagnosed on prenatal U/S at w 14 and 20
Delivery, 37, F, 2600
Surgical correction on 2nd d of life
DM – disease matched; * – not included in the re-analysis excluding genetic or cytogenetic anomalies; VSD – ventricular septal defect; TE – tracheoesophageal; TO – throughout pregnancy; w – week; T1 – first trimester; HCQ – hydroxychloroquine; MTX – methotrexate; LMP – last menstrual period; SLE – systemic lupus erythematosus; F – female; M – male; ETOP – elective termination of pregnancy; F/U – follow-up; U/S – ultrasound; DIC – disseminated intravascular coagulation; RDS – respiratory distress syndrome; PDA – patent ductus arteriosus; PLT/PC/FFP – platelets/packed cells/fresh frozen plasma; TPN – total pareneteral nutrition; PM – post mortem.
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most human pregnancy experience with anti-TNF-␣ medications [5,15–28]. The rate of major anomalies in the present study did not significantly differ between the anti-TNF-␣, the DM, and the NTE groups. There was no specific pattern of anomalies in the offspring of women in the anti-TNF-␣ group, supporting lack of teratogenic effect. No case of VACTERL/VATER association was reported among the offspring of women treated with anti-TNF-␣ medications during pregnancy in the present study. A non-significant trend toward a higher risk of major anomalies in both groups with autoimmune diseases was observed in the present study. Inflammatory bowel disease has been inconsistently associated with increased risk of congenital anomalies. The risk of congenital anomalies among offspring of women with inflammatory bowel disease was found to be 2.37-fold increased (95% CI 1.47–3.82, p < 0.001) in a meta-analysis [29]. However, no increased risk of congenital anomalies was found in other relatively large studies [30,31]. The association between rheumatoid arthritis and congenital abnormalities has been even less consistent. Reed et al. [32] did not observe an increased risk for birth defects, while Nørgaard et al. [33] found an increased risk for congenital abnormalities in 1994–1997 [OR 2.57, (95% CI 1.59–4.16)], but not in 1998–2006. A sample size of 67 livebirths or elective terminations of pregnancy due to prenatally diagnosed anomalies in the anti-TNF-␣ group with a ratio of 1:4.9 to the NTE comparison group with 80% power, a baseline risk of 2.4% for major anomalies, enables detection of a 4.95-fold increase in the rate of major anomalies. The study is not powered to find a smaller increase in the overall rate of major anomalies or in the rate of specific rare anomalies. The higher rate of miscarriages found in the anti-TNF-␣ group was associated with an earlier gestational age at initial contact (with a higher miscarriage rate in women calling earlier in pregnancy), and to a lesser extent, with maternal smoking, but not with the exposure, as verified by the regression analysis. A 3.4fold increase in the rate of preterm deliveries in the anti-TNF-␣ group compared with the NTE group might be associated with the underlying diseases [29,34]. A lower median birth weight was found in the anti-TNF-␣ group compared with both the DM and NTE groups. The birth weight may be affected by the underlying disease activity [29,34,35], as well as by the use of concurrent immunosuppressive medications known to be associated with intrauterine growth restriction [36]. The median gestational week of anti-TNF-␣ medication discontinuation was 9 (4–28), before significant placental transfer of these molecules is expected. It should be kept in mind that women in the anti-TNF-␣ group probably had a more severe disease to become eligible for this treatment, and were more likely to be on concomitant immunosuppressive medications and steroids. Discontinuing their disease modifying anti-TNF-␣ treatment relatively early during pregnancy might have resulted in exacerbation of the disease, and subsequent higher rate of preterm deliveries and lower birth weight. The present study has certain limitations and advantages. It is based on TIS population, which may not represent the general population, but has two comparison groups from the same TIS. Other limitations of the study are: reliance on maternal interview as a source for outcome data in most cases, a nonrandomized design, using a group of three different anti-TNF-␣ medications, limited power for specific rare defects, and lack of data on periconceptional disease activity. However, applying the same procedure to the three arms of the study and the prospective nature minimize the potential biases. Due to ethical considerations randomized controlled trials are often not feasible in pregnancy. The fact that all data are from a single center also minimizes some potential biases. In addition, there were two comparison groups: a DM group with
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similar diseases without anti-TNF-␣ treatment and a group counseled for NTE. Medical records were available for most cases with anomalies including discharge letters, echocardiography results, or information from the child’s pediatrician. Another advantage of the present study is that data were available on elective terminations of pregnancies and were included in the analysis. In conclusion, the present prospective observational comparative cohort study suggests that the use of anti-TNF-␣ medications during pregnancy is not associated with an increased risk for major anomalies. One should keep in mind that this conclusion is based on relatively small numbers of exposed pregnancies, and should be interpreted with caution. Larger studies are needed to establish the pregnancy safety of anti-TNF-␣ medications. Further studies with exposure late in pregnancy are needed to address their potential effect on the infant’s developing immune system. Conflict of interest The authors have no conflict of interest to disclose. Acknowledgments This work is part of the Pharm D thesis in Clinical Pharmacy of the Hebrew University of Mrs. Anna Otcheretianski-Volodarsky. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.reprotox.2013. 11.004. References [1] Treacy G. Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for the humanized anti-TNF alpha monoclonal antibody. Hum Exp Toxicol 2000;19:226–8. [2] Vasiliauskas EA, Church JA, Silverman N, Barry M, Targan SR, Dubinsky MC. Case report: evidence for transplacental trasfer of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol 2006;4: 1255–8. [3] Zelinkova Z, de Haar C, de Ridder L, Pierik MJ, Kuipers EJ, Peppelenbosch MP, et al. High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy. Aliment Pharmacol Ther 2011;33:1053–8. [4] Murashima A, Watanabe N, Ozawa N, Saito H, Yamaguchi K. Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breastmilk and the infant’s serum [Letter]. Ann Rheum Dis 2009;68:1793–4. [5] Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11: 286–92. [6] Lee H, Kimko HC, Rogge M, Wang D, Nestorov I, Peck CC. Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis. Clin Pharmacol Ther 2003;73:348–65. [7] Ternant D, Aubourg A, Magdelaine-Beuzelin C, Degenne D, Watier H, Picon L, et al. Infliximab pharmacokinetics in inflammatory bowel disease patients. Ther Drug Monit 2008;30:523–9. [8] Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clin Ther 2003;25:1700–21. [9] Djokanovic N, Klieger-Grossman C, Pupco A, Koren G. Safety of infliximab use during pregnancy. Reprod Toxicol 2011;32:93–7. [10] Chambers CD, Johnson DL. Emerging data on the use of anti-tumor necrosis factor-alpha medications in pregnancy. Birth Defects Res A Clin Mol Teratol 2012;94:607–11. [11] Carter JD, Valeriano J, Vasey FB. Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol 2006;33:1014–7. [12] Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 2009;36:635–41. [13] Koren G, Inoue M. Do tumor necrosis factor inhibitors cause malformations in humans? [editorial]. J Rhematol 2009;36:465–6.
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[14] Winger EE, Reed JL. Was risk properly assessed in Carter, et al’s safety assessment of tumor necrosis factor antagonists during pregnancy? [Letter]. J Rheumatol 2009;36:2122. [15] Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment of Crohn’s disease and rheumatoid arthritis. Am J Gastroenterol 2004;99:2385–92. [16] Chambers CD, Johnson DL, Jones KL. Pregnancy outcome in women exposed to anti-TNF-alpha medications: the OTIS rheumatoid arthritis in pregnancy study [abstract]. Arthritis Rheumat 2004;50:S479–80. [17] Mahadevan U, Kane S, Sandborn WJ, Cohen RD, Hanson K, Terdiman JP, et al. International infliximab use during pregnancy for the induction or maintenance of remission in Crohn’s disease. Aliment Pharmacol Ther 2005;21: 733–8. [18] Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Chen DM, et al. Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry. Clin Gastroenterol Hepatol 2006;4:621–30. [19] Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Price S, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREATTM registry. Am J Gastroeneterol 2012;107:1409–22. [20] Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L. Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)-alpha therapy. Rheumatoloy (Oxford) 2007;46:695–8. [21] Berthelot JM, De Bandt M, Goupille P, Solau-Gervais E, Lioté F, Goeb V, et al. Exposition to anti-TNF drugs during pregnancy: outcome of 15 cases and review of the literature. Joint Bone Spine 2009;76:28–34. [22] Rump JA, Schönborn H. Conception and course of eight pregnancies in five women on TNF blocker etanercept treatment [German]. Z Rheumatol 2010;69:903–9. [23] Verstappen SM, King Y, Watson JD, Symmons DP, Hyrich KL, BSRBR Control Centre Consortium, BSR Biologics Register. Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823–6. [24] Schnitzler F, Fidder H, Ferrante M, Ballet V, Noman M, Van Assche G, et al. Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy. Inflamm Bowel Dis 2011;17:1846–54.
[25] Weber-Schoendorfer C, Fritzsche J, Schaefer C. Pregnancy outcome in women exposed to adalimumab or infliximab: the experience of the Berlin Institute for Clinical Teratology and Drug Risk Assessment [abstract]. Reprod Toxicol 2011;31:267–8. [26] Hultzsch S, Weber-Scoendorfer C, Schaefer C. Pregnancy outcomes after exposure to etanercept [abstract]. Reprod Toxicol 2011;31:260. [27] Chambers CD, Johnson DL, Jones KL, Luo Y, Xu R, Jimenez JL, et al. Pregnancy outcomes in women exposed to adalimumab for the treatment of rheumatoid arthritis: an update on the OTIS Autoimmune Diseases in Pregnancy Project [abstract]. Birth Defects Res A Clin Mol Teratol 2012;94:325. [28] Viktil KK, England A, Furi K. Outcomes after anti-rheumatic drug use before and during pregnancy: a cohort study among 150,000 pregnant women and expectant fathers. Scand J Rheumatol 2012;41:196–201. [29] Cornish J, Tan E, Teare J, Teoh TG, Rai R, Clark SK, et al. A meta-analysis on the influence of inflammatory bowel disease on pregnancy. Gut 2007;56:830–7. [30] Mahadevan U, Dandborn WJ, Li DK, Hakimian S, Kane S, Corley DA. Pregnancy outcomes in women with inflammatory bowel disease: a large communitybased study from Northern California. Gastroenterology 2007;133:1106–12. [31] Bortoli A, Pedersen N, Duricova D, D’Inca R, Gionchetti P, Panelli MR, et al. Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, 2003–2006. Aliment Pharmacol Ther 2011;34:724–34. [32] Reed SD, Vollan TA, Svec MA. Pregnancy outcomes in women with rheumatoid arthritis in Washington State. Matern Child Health J 2006;10:361–6. [33] Nørgaard M, Larsson H, Pedersen L, Granath F, Askling J, Kieler H, et al. Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study. J Intern Med 2012;268:329–37. [34] de Man YA, Hazes JM, van der Heide H, Willemsen SP, de Groot CJ, Steegers EA, et al. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheum 2009;60:3196–206. [35] Bowden AP, Barrett JH, Fallow W, Silman AJ. Women with inflammatory polyarthritis have babies of lower birth weight. J Rheumatol 2001;28:355–9. [36] Pirson Y, Van Lierde M, Ghysen J, Squifflet JP, Alexandre GP, van Ypersele de Strihou C. Retardation of fetal growth in patients receiving immunosuppressive therapy [Letter]. N Engl J Med 1985;313:328.
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Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: A prospective, comparative, observational study Orna Diav-Citrin a,b,∗ , Anna Otcheretianski-Volodarsky c , Svetlana Shechtman a , Asher Ornoy a,b a
The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel The Hebrew University Hadassah Medical School, Jerusalem, Israel c The Division of Clinical Pharmacy, the Hebrew University of Jerusalem, Israel b
a r t i c l e
i n f o
Article history: Received 2 May 2013 Received in revised form 29 October 2013 Accepted 14 November 2013 Available online 24 November 2013 Keywords: Anti-TNF-␣ Infliximab Etanercept Adalimumab Autoimmune diseases Pregnancy Congenital anomalies
a b s t r a c t Objective: To evaluate pregnancy safety of anti-TNF-␣ medications. Design: Prospective, comparative, observational study done at the Israeli Teratology Information Service between 2002 and 2011. Results: 83 anti-TNF-␣-exposed-pregnancies (97.6% in the first trimester, T1) were followed-up and compared with 86 disease-matched (DM) and 341 non-teratogenic-exposed (NTE) pregnancies. The anti-TNF-␣ group consisted of 35 infliximab-, 25 etanercept-, and 23 adalimumab-exposed pregnancies. The rate of major congenital anomalies did not significantly differ between the three groups [3/65 (4.6%) (anti-TNF-␣, T1), 5/79 (6.3%) (DM), 8/336 (2.4%) (NTE)], even after excluding genetic or cytogenetic anomalies [3/65 (4.6%) (anti-TNF-␣, T1), 4/79 (5.1%) (DM), 6/336 (1.8%) (NTE)]. There were no cases of VATER/VACTERL association. Conclusion: The present study suggests that anti-TNF-␣ treatment does not pose a major teratogenic risk in humans. This conclusion is based on relatively small numbers of exposed pregnancies and should be interpreted with caution. Larger studies are needed to establish anti-TNF-␣ pregnancy safety. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Infliximab, etanercept, and adalimumab are tumor necrosis factor-␣ inhibitors (anti-TNF-␣) produced by genetic engineering. Infliximab is a mouse-human chimeric monoclonal IgG1 antibody, etanercept is a TNF receptor-IgG1 fusion human protein, and adalimumab is a fully human monoclonal antibody. Anti-TNF␣ medications have led to a vast improvement in the treatment of inflammatory conditions. These new biopharmaceuticals target inflammatory cytokines, and are used in the treatment of autoimmune diseases including rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and inflammatory bowel diseases. Many of these illnesses are more common in women and occur during reproductive age. When anti mouse TNF␣ monoclonal antibody was administered to pregnant mice, there were no teratogenic effects [1]. The three anti-TNF-␣ antibodies,
∗ Corresponding author at: The Israeli Teratology Information Service Israel Ministry of Health, P.O. Box 1176, Jerusalem 9446724, Israel. Tel.: +972 2 5080441; fax: +972 2 6474822. E-mail address: [email protected] (O. Diav-Citrin). 0890-6238/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.reprotox.2013.11.004
infliximab, etanercept, and adalimumab, have a large molecular weight of approximately 149 kDa, and are, therefore, not expected to cross the human placenta in significant concentration in the first trimester of pregnancy. It is hypothesized, however, that the Fab’ fragment may passively cross the placenta in low levels in the first trimester during the period of organogenesis. Placental transfer of infliximab, etanercept, and adalimumab close to term has been documented [2–5]. The terminal elimination half-lives of these molecules are relatively long: 4 days for etanercept [6], 19 days for infliximab [7], and 15–19 days for adalimumab [8]. Human pregnancy experience with these medications is rather limited. It is based mostly on case reports, small case series, regulatory agency records, manufacturer’s registries, and preliminary data presented at scientific meetings published as abstracts. Human pregnancy data on infliximab specifically [9] and on anti-TNF-␣ medications in general [10] has been summarized in two recent review articles. Carter et al. [11] published a case report describing VATER association in a neonate born to a mother who was treated with etanercept during pregnancy. They reviewed the TNF-␣antagonists use in pregnancy report to the US Food and Drug Administration. They reported that 24 of the 41 children with congenital anomalies born to mothers who took infliximab or
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etanercept during pregnancy had one or more anomalies that are part of the VACTERL association [12]. They concluded that maternal treatment with TNF antagonists pose an increased risk for VATER or VACTERL association. A critical editorial [13] and a letter to the editor [14] published in the same journal raised questions and pointed out numerous methodological problems in this study. The analysis suffers from selection bias, is based on voluntary reports lacking a denominator of total number or pregnancies with maternal antiTNF-␣ treatment and, therefore, cannot be used for risk calculation. Sporadic reports of isolated anomalies that could be a part of the VACTERL association do not establish this diagnosis. The diagnosis requires a constellation of anomalies in the same patient. The study did not address potential confounders. In addition, placental transmission of these molecules during the first trimester of pregnancy, covering the period of organ formation, is not expected in significant amounts, and makes the suggested causation between VACTERL association and anti-TNF-␣ medications, unlikely. Contrary to the reports by Carter et al. [11,12], human pregnancy experience with TNF-␣ antagonists has been mostly reassuring [5,15–28]. A summary of the reports of pregnancies with exposure to anti-TNF-␣ medications is presented in Table 1. The primary objective of the present study was to prospectively evaluate the rate of major congenital anomalies after maternal treatment with TNF-␣-antagonists (infliximab, etanercept, or adalimumab) during pregnancy compared with two comparison groups: (1) pregnant women with autoimmune diseases not treated with anti-TNF-␣ medications during pregnancy (disease matched), (2) pregnant women counseled for non-teratogenic exposure. Secondary endpoints of interest were pregnancy outcome, birth weight, and gestational age at delivery.
2. Materials and methods Pregnant women counseled by the Israeli Teratology Information Service (TIS), Jerusalem, in regard to the TNF-␣-antagonists, infliximab, etanercept, or adalimumab, between the years 2002 and 2011, were enrolled in the present prospective comparative observational study. Exposure during the first trimester of pregnancy was defined when the pregnant woman received an anti-TNF-␣ before pregnancy, but conception occurred within 5 elimination half-lives from medication administration, or if the woman was treated during pregnancy before 13 completed weeks from her last menstrual period. Outcome was compared with two comparison groups in a similar time frame: (1) pregnant women with similar autoimmune diseases not treated with anti-TNF-␣ medications during pregnancy at a 1:1 ratio. This disease matched (DM) group was selected according to their disease from the Israeli TIS database and was either treated with medications other than antiTNF-␣ excluding methotrexate, or untreated during pregnancy; (2) pregnant women counseled for non-teratogenic exposure (NTE) at a 1:4 ratio. This group was randomly selected from the Israeli TIS database according to their exposure and included women counseled during pregnancy in regard to exposures known to be non-teratogenic or fetal toxic such as analgesics like paracetamol, low dose diagnostic radiation, topical preparations with negligible systemic exposure, antibiotics (penicillins or cephalosporins), oral contraceptives taken no longer than the 5th week of pregnancy, hair dye or house-cleaning agents. Pregnancies of women who have chronic diseases were not included in the NTE group. Details of exposure were collected during pregnancy, at the initial contact with the TIS and before pregnancy outcome was known, using a structured questionnaire. Verbal consent to participate in the study was given by the woman at initial contact. Since the study was observational no Institutional Review Board approval was required. In addition, the following information was recorded at the initial
79
contact: maternal demographics, medical and obstetrical histories, and exposure details (dose, duration, and timing in pregnancy, additional exposures). Retrospective cases were not included in the study. Pregnant women who contacted the TIS after an anomaly had been identified on prenatal testing were also excluded. Pregnancy outcome was actively sought after the expected date of delivery in the exposed and comparison groups. Follow-up was conducted by a telephone interview with the woman to obtain details on the pregnancy outcome, gestational age at delivery, birth weight, congenital anomalies and neonatal complications. In cases of anomalies an attempt to obtain medical records was made. In addition, all exposures were ascertained. It was verified that the exposure/s the woman was counseled for indeed occurred during pregnancy. Details on any dose modifications during pregnancy, exact timing and duration of treatment, and additional exposures during pregnancy were also ascertained. The vast majority of infants in Israel are delivered in hospital. Each neonate in Israel undergoes at least two physical examinations before being discharged from the hospital. All neonates in the present study were delivered in hospital. The interview was conducted after these physical examinations. Data collection methods were similar in the exposed and comparison groups. Major anomalies were defined as structural abnormalities in the offspring that have serious medical, surgical or cosmetic consequences. The focus of the study was on anomalies that occur during the period of organogenesis in the first trimester of pregnancy. Therefore, an inguinal hernia in a term infant, as well as cryptorchidism, that occur later in pregnancy, were not considered major anomalies. Children with minor anomalies or functional problems without any morphological changes (e.g. ankyloglossia, umbilical hernia that spontaneously closed, systolic heart murmur with normal echocardiography) or infants with complications of preterm delivery were not considered as having major anomalies. Cardiac septal defects are structural anomalies of the heart, and are considered major anomalies in the present study, even if spontaneously resolved, unless the closure occurred during the neonatal period. Any ventricular septal defect carries a risk of infectious endocarditis and may require prophylactic antibiotics before invasive procedures. Horseshoe kidney is classified as a major anomaly because it carries a risk for renal cancer especially Wilms’ tumor, renal calculi and obstructive uropathy. Primary congenital hypothyroidism is considered a major anomaly in the present study because it requires lifelong replacement therapy. In addition, its etiology in the majority of cases, is either thyroid ectopy or athyreosis, both resulting from first trimester events. Abnormalities detected by prenatal ultrasonography (if verified postnatally or by autopsy) were included in our study, since antenatal screening for major anomalies is routinely performed in Israel. The classification of anomalies was done by a certified pediatrician blinded to the exposure group. An international expert was consulted in case of classification difficulty. Thus, the analysis of major congenital anomalies was performed among live-born infants, pregnancy losses with confirmed anomalies, and elective terminations of pregnancy due to prenatally diagnosed anomalies. In the case of multiple births, each live-born offspring was included in the analysis. Gestational age was defined from the last menstrual period. Miscarriage was defined as spontaneous pregnancy loss before or at 20 completed weeks, whereas stillbirth was defined as spontaneous pregnancy loss beyond 20 completed weeks. Preterm delivery was defined as birth before 37 completed weeks. All co-authors had access to the study data and had reviewed and approved the final manuscript. 2.1. Statistical analysis Categorical data were compared using 2 or Fisher exact tests and are expressed as ratios or percentages. Continuous data are
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Table 1 Summary of reports of pregnancies with exposure to anti-TNF-␣ medications. Reference
Medication
n (n T1)
Anomalies
Design
Katz et al., [15]
Infliximab
96 (58)
Chambers et al. [16]
29 4 10 (9)
Manufacturer’s data retrospective voluntary reports compared to National health statistics Prospective comparative OTIS study (abstract)
Mahadevan et al. [17]
Etanercept Infliximab Infliximab
- Tetralogy of Fallot - Intestinal malrotation - Trisomy 18 None
Retrospective international chart review
Lichtenstein et al. [18,19]
Infliximab
117*
Roux et al. [20]
Etanercept Adalimumab
2 (2) 1 (1)
- VSD* - Anencephaly* None
Prospective observational multicenter registry in North American patients with CD TREAT Prospective small case series
Berthelot et al. [21]
Infliximab Adalimumab Etanercept Etanercept Infliximab
3 (1) 2 (1) 10 (10) 22 19
None
French rheumatologist website questionnaire
Review of malformed and exposed in FDA Adverse Event Reporting System
Rump and Schönborn [22]
Etanercept
8
24/41 had one or more anomalies that are part of the VACTERL association - Megacolon
Zelinkova et al. [3]
Infliximab
4 (4)
- Polydactyly Lt hand
Case series
Verstappen et al. [23]
Infliximab Etanercept Adalimumab Infliximab Adalimumab Infliximab Adalimumab
61 (61) [3 anti-TNF-]
- CDH - Pyloric stenosis
British Society for Rheumatology Biologics Register (prospective)
35 (35) 7 (7) 25 (25) 28 (28)
- Trisomy 18
Belgian comparative observational study Prospective uncontrolled cohort, Berlin TIS (abstract)
Hultzsch et al. [26]
Etanercept
26 (26)
Chambers et al. [27]
Adalimumab
66 (66)
Viktil et al. [28]
Etanercept Adalimumab Infliximab Adalimumab Certolizumab
22 (20) 3 (3) 11 (11) 10 (10) 10 (7)
- Neurofibromatosis - VSD - Growing hemangiomas - Renal agenesis - Hypoplastic Lt heart & hypospadias - Wolf Parkinson White Syndrome Major anomalies in 3.1%, no evidence of pattern None
Carter et al. [12]
Schnitzler et al. [24] Weber-Schoendorfer et al. [25]
Mahadevan et al. [5]
None
Case series
Prospective uncontrolled cohort, Berlin TIS (abstract)
Prospective comparative OTIS study (abstract)
Norway Medical Birth Registry linked to prescription database comparative study Prospective PIANO Registry
n – exposed pregnancies; (n T1) – pregnancies exposed in the first trimester; when available; * – cited by Chambers et al. [10]; VSD – ventricular septal defect; Lt – left; CDH – congenital dysplasia of hip; OTIS – Organization of Teratology Information Specialists; CD – Crohn’s Disease; TREAT – Therapy, Resource, Evaluation, and Assessment Tool; FDA – Food and Drug Administration; TIS – Teratology Information Service; PIANO – Pregnancy IBD And Neonatal Outcomes.
presented using mean ± SD or median with interquartile range (IQR), and compared using the ANOVA or Kruskal–Wallis test, depending on whether they followed normal distribution, or not, for three groups, or using Student-t or Mann–Whitney tests, for two groups. The p-values presented in the tables are for a comparison between the three groups. For pair-wise comparisons Bonferroni method was applied. Statistical calculations were done using SPSS Version 19 or Epi InfoTM software (Center for Disease Control and Prevention, Atlanta Epidemiology Program Office, Atlanta, GA, USA). 3. Results A total of 83 TNF-␣-antagonist-exposed pregnancies, 86 pregnancies of women with autoimmune diseases not treated with anti-TNF-␣ medications during pregnancy, and 341 pregnancies of women counseled for non-teratogenic exposure, were prospectively followed-up. The anti-TNF-␣ group consisted of 35 (42.2%) infliximab, 25 (31.1%) etanercept, and 23 (27.7%) adalimumab exposed pregnancies. Exposure to an anti-TNF-␣ medication at least in the first trimester of pregnancy occurred in 81 of 83 (97.6%) pregnancies. In the two remaining pregnancies the anti-TNF-␣ was
administered only later in pregnancy, starting in the second or third trimesters. The median gestational week of treatment discontinuation was 9 (IQR 4–28). The median infliximab dose per infusion was 300 mg (IQR 255–300) with a median interval of 8 weeks between infusions (IQR 4–8), whereas the median weekly dose was 50 mg (IQR 50–50) for etanercept, and 20 mg (IQR 20–20) for adalimumab. Concurrent medications during pregnancy in addition to the anti-TNF-␣ were taken by 43.4% of the women and are presented in Table 2. Co-administration of methotrexate within 1 Table 2 Distribution of medications in the anti-TNF-␣ (concurrent) and the DM groups. Medications
Anti-TNF-␣ (%)
DM (%)
Steroids nb-DMARDs Blood thinners Steroids and nb-DMARDs nb-DMARDs and blood thinners Steroids, nb-DMARDs and blood thinners
10.8 20.5 3.6 4.8 2.4 1.2
3.5 64.0 18.6 3.5
nb-DMARDs – non-biologic disease modifying antirheumatic drugs; azathioprine, 6-mercaptopurine, methotrexate (only in the anti-TNF-␣ group), mesalamine, sulfasalazine, or hydroxychloroquine; Blood thinners: low dose aspirin or low molecular weight heparin.
O. Diav-Citrin et al. / Reproductive Toxicology 43 (2014) 78–84 Table 3 Distribution of diseases in the anti-TNF-␣ and DM comparison groups. Disease
Anti-TNF-␣ group (%)
DM comparison group (%)
Crohn’s disease Rheumatoid arthritis Ulcerative colitis Unspecified arthritis Psoriatic arthritis Ankylosing spondylitis Behc¸et’s disease
36.3 21.3 12.5 12.5 11.3 5.0 1.3
41.7 10.7a 33.3 14.3
a
one also with ulceratve colitis.
month before the last menstrual period was reported in 6 women in the anti-TNF-␣ group; however, it was discontinued before the last menstrual period in 5 of the women. One woman in the antiTNF-␣ group, whose pregnancy resulted in a miscarriage, received IV methotrexate 17.5 mg/week till the 10th gestational week when her pregnancy was diagnosed. The reported indications for treatment with anti-TNF-␣ medications and the distribution of diseases in the DM comparison group are presented in Table 3. Medications for the underlying disease were administered during pregnancy in 89.5% of the DM group and are presented in Table 2. A comparison of maternal characteristics and obstetrical history between the three groups is presented in Table 4. The women in the anti-TNF-␣ group called at a significantly earlier median gestational age compared with the women in the DM and NTE groups. Similarly, the women in the DM group called at a significantly earlier median gestational age compared with the NTE group. No significant differences were observed between the groups in maternal age, obstetrical history, or smoking status. A comparison of pregnancy outcome between the three groups is presented in Tables 5 and 6. A higher proportion of pregnancies resulted either in a miscarriage or in an elective termination of pregnancy in the anti-TNF-␣ group compared with the NTE group. Three of the five women who decided to terminate their pregnancy in the anti-TNF-␣ group reported that the reason for their decision was fear of the unknown possible effect of these medications, whereas the other two reported that their termination was due to social reasons. No anomalies were detected in the five
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fetuses whose pregnancy was terminated in the anti-TNF-␣ group. However, there were elective terminations of pregnancy due to prenatally diagnosed anomalies in both the DM and NTE groups. In the DM group three women terminated their pregnancy, two due to prenatally diagnosed anomalies (Turner syndrome in one case and vermis cerebelli agenesis in another), and one due to evidence of cytomegalovirus infection on amniocentesis. In the NTE group, three women terminated their pregnancy, all due to prenatally diagnosed anomalies (Down syndrome in one case, agenesis of corpus callosum in another case, and diagnosis of osteogenesis imperfecta in another). The latter five pregnancy terminations due to prenatally diagnosed anomalies are included in the initial analysis of major anomalies. The rate of major anomalies did not significantly differ between the three groups when the analysis was limited to pregnancies exposed to anti-TNF-␣ medications during the first trimester. In a re-analysis after excluding genetic or cytogenetic anomalies the differences in the rate of major anomalies remained insignificant. Follow-up was performed at a median offspring age four months older in the DM group compared with the NTE group. However, all the anomalies found in the anti-TNF-␣ and DM groups were diagnosed prenatally or perinatally. The median gestational age at delivery was a week earlier in the anti-TNF-␣ group compared with the NTE group, with a 3.4-fold increase in the rate of preterm deliveries. The median birth weight was 285 g lower in the anti-TNF-␣ group compared with the DM group, and 180 g lower compared with the NTE group. The mean birth weight was 210 g lower in the anti-TNF-␣ group compared with the DM group, but did not significantly differ from the mean birth weight in the NTE group, when the analysis was limited to full-term infants. Significant differences in mode of delivery were not found between the groups. To evaluate the relative contribution of various predictors to the differences in the miscarriage rate, logistic regression was performed. The following predictors were entered into the model: maternal age, history of miscarriage, smoking status (none, <10 cigarettes/day, or ≥10 cigarettes/day), gestational age at initial contact, exposure group, and exposure to methotrexate within 1 month before the last menstrual period. The only significant predictors were gestational age at initial contact (with a higher miscarriage
Table 4 Comparison of maternal characteristics and obstetrical history. Anti-TNF-␣ n = 83
DM n = 86
NTE n = 341
p value
Maternal age mean ±SD (y)
31.4 ± 5.1
30.9 ± 4.5
31.3 ± 4.4
0.720
Pregnancy order, n (%) 1 2–4 ≥5
21/74 (28.4) 47/74 (63.5) 6/74 (8.1)
30/86 (34.9) 48/86 (55.8) 8/86 (9.3)
122/328 (37.2) 179/328 (54.6) 27/328 (8.2)
0.356 0.374 0.946
Parity, n (%) 0 1–3 ≥4
28/79 (35.4) 49/79 (62.0) 2/79 (2.5)
36/88 (40.9) 48/88 (54.5) 4/88 (4.5)
144/328 (43.9) 171/328 (52.1) 13/328 (4.0)
0.382 0.284 0.779
Past miscarriages, n (%) 0 1 ≥2 Past ETOP, n (%) GA at initial contact, w median (IQR)
55/75 (73.3) 12/75 (16.0) 8/75 (10.7) 6/74 (8.1) 7a , b (5–10)
71/86 (82.6) 10/86 (11.6) 5/86 (5.8) 6/86 (7.0) 8a (6–15)
276/329 (83.9) 38/329 (11.6) 15/329 (4.6) 15/329 (4.6) 12 (7–19)
0.098 0.559 0.121 0.390 <0.001
Cigarette smoking None <10cigarettes/d ≥10cigarettes/d
74/78 (94.9) 4/78 (5.1) 0
78/82 (95.1) 2/82 (2.4) 2/82 (2.4)
313/324 (96.6) 8/324 (2.5) 3/324 (0.9)
0.691 0.437 0.296
p < 0.05 marked in bold. SD – standard deviation; y – years; ETOP – elective termination of pregnancy; GA – gestational age; w – weeks; IQR – interquartile range; Anti-TNF-␣ – anti-tumor necrosis factor ␣; DM – disease matched; NTE – non-teratogenic exposure. a Significant difference in comparison to the NTE group. b Significant difference in comparison to the DM group.
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Table 5 Comparison of pregnancy outcome.
Multiple gestations Delivery of live-born infant, n (%) Miscarriage, n (%) ETOP, n (%) Stillbirth, n (%) Ectopic pregnancy, n (%) Major anomalies, n (%) Major anomalies, excluding genetic or cytogenetic anomalies, n (%)
Anti-TNF-␣ n = 83
DM n = 86
NTE n = 341
0 67/83 (80.7)a 9/83 (10.8)a 5/83 (6.0)a 1/83 (1.2) 1/83 (1.2) 3/65* (4.6) 3/65* (4.6)
0 77/86 (89.5) 5/86 (5.8) 3/86 (3.5) 1/86 (1.2) 0 5/79 (6.3) 4/79 (5.1)
6 twin sets 328/341 (96.2) 10/341 (2.9) 3/341 (0.9) 0 0 8/336 (2.4) 6/336 (1.8)
ETOP – elective termination of pregnancy; Anti-TNF-␣ – anti-tumor necrosis factor ␣; DM – disease matched; NTE – non-teratogenic exposure; a Significant difference in comparison to the NTE group. * Among women treated with anti-TNF-␣ medications during the first trimester of pregnancy. Table 6 Comparison of age at follow-up, mode and time of delivery, and birth weight.
Age at F/U, m median (IQR) Mode of delivery Vaginal uncomplicated, n (%) Cesarean section, n (%) Vacuum delivery, n (%) GA at delivery, w median (IQR) Preterm delivery, <37 w, n (%) Birth weight, g median (IQR) Birth weight of full-term infants, g mean (±SD)
Anti-TNF-␣ n = 83
DM n = 86
NTE n = 341
p value
14 (5–35)
16a (4–42)
12 (6–19)
0.031
43/66 (65.2) 22/66 (33.3) 1/66 (1.5) 38a (37–40) 15/66a (22.7) 2975a,b (2528–3276) 3085b ± 520
50/76 (65.8) 19/76 (25.0) 7/76 (9.2) 39 (37–40) 11/77 (14.3) 3260 (2900–3475) 3295 ± 394
223/326 (68.4) 84/326 (25.8) 19/326 (5.8) 39 (38–40) 22/327 (6.7) 3155 (2853–3483) 3211 ± 456
0.823 0.419 0.146 <0.001 <0.001 0.002 0.049
p < 0.05 marked in bold. GA – gestational age; w – weeks; F/U – follow-up; m – months; IQR – interquartile range; g – grams; SD – standard deviation; Anti-TNF-␣ – anti-tumor necrosis factor ␣; DM – disease matched; NTE – non-teratogenic exposure. a Significant difference in comparison to the NTE group. b Significant difference in comparison to the DM group.
rate among women calling early during gestation) (p < 0.001) and smoking of less than 10 cigarettes/d (p = 0.010). The adjusted OR for miscarriages in the anti-TNF-␣ vs. NTE group was 1.96 (95%CI 0.64–5.96). The reported major anomalies and the details of exposures in the anti-TNF-␣ and DM groups are listed in Table 7.
4. Discussion The results of the present prospective comparative study suggest that treatment with the anti-TNF-␣ medications, infliximab, etanercept, or adalimumab, is not associated with an increased risk of major anomalies. These results, however, are consistent with
Table 7 Major congenital anomalies in the anti-TNF-␣ and DM groups. Group
Type of anomaly
Details of exposure, additional exposures, maternal illness
Pregnancy outcome, GA (w), sex, BW (g)
F/U comments
Anti-TNF-␣
VSD
Delivery, 40, F, 2075
Anti-TNF-␣
Unilateral renal agenesis Kaposiform hemangioendothelioma, Kasabach-Merritt syndrome, bilateral hydronephrosis
Adalimumab 40 mg/2 w TO pregnancy, azathioprine 50 mg/d till w 9, Crohn’s disease Infliximab 400 mg T1, azathioprine 50 mg/d, Crohn’s disease Etanercept 25 mgx2/w T1, prednisone 10 mg/d, HCQ 200 mg/d TO, MTX 2.5 mgx3/w till 1 m pre-LMP, enoxaparin, rheumatoid arthritis
Small VSD diagnosed on U/S at w 20, prenatal and postnatal echocardiography, spontaneously closed at 6 m Diagnosed on prenatal U/S
Anti-TNF-␣
DM
Turner syndrome*
DM
Horseshoe kidney
DM
Congenital primary hypothyroidism (permanent)
DM
Brain anomaly, vermis cerebelli agenesis Esophageal atresia with TE fistula
DM
Mercaptopurine 50 mg/d mesalamine 4 g/d, Crohn’s disease Mesalamine 4 g/d, azathioprine 150 mg/d, ulcerative colitis Mesalamine 1gx3/d, HCQ 200 mg/d, and azathioprine 100 mg/d TO, budesonide 3 mgx2/d till w 14, prednisone 10 mg/d fr w 14, SLE, Crohn’s disease Mesalamine 4 g/d, venlafaxine 75 mg/d, colitis None, ulcerative colitis, hereditary hemorrhagic telagiectasia
Delivery, 36, M, 3190 Delivery, 31, F, 2740
ETOP, 22 Delivery, 42, F, 3400 Delivery, 36, F, 1888
Fetal edema diagnosed on late U/S, DIC, thrombocytopenia, anemia, severe RDS, edema, ecchymosis, jaundice (phototherapy), PDA, renal failure, recurrent blood exchange, PLT/PC/FFP transfusions, ampicillin, gentamicin for 3d, vancomycin for 6d, TPN from 2nd d, died on 10th d pathologic diagnosis on PM Diagnosed on amniocentesis, maternal age 38 Diagnosed on prenatal U/S, normal kidney function till age 2.5 y Offspring treated with thyroxine, the mother was euthyroid in pregnancy
ETOP, 20
Diagnosed on prenatal U/S at w 14 and 20
Delivery, 37, F, 2600
Surgical correction on 2nd d of life
DM – disease matched; * – not included in the re-analysis excluding genetic or cytogenetic anomalies; VSD – ventricular septal defect; TE – tracheoesophageal; TO – throughout pregnancy; w – week; T1 – first trimester; HCQ – hydroxychloroquine; MTX – methotrexate; LMP – last menstrual period; SLE – systemic lupus erythematosus; F – female; M – male; ETOP – elective termination of pregnancy; F/U – follow-up; U/S – ultrasound; DIC – disseminated intravascular coagulation; RDS – respiratory distress syndrome; PDA – patent ductus arteriosus; PLT/PC/FFP – platelets/packed cells/fresh frozen plasma; TPN – total pareneteral nutrition; PM – post mortem.
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most human pregnancy experience with anti-TNF-␣ medications [5,15–28]. The rate of major anomalies in the present study did not significantly differ between the anti-TNF-␣, the DM, and the NTE groups. There was no specific pattern of anomalies in the offspring of women in the anti-TNF-␣ group, supporting lack of teratogenic effect. No case of VACTERL/VATER association was reported among the offspring of women treated with anti-TNF-␣ medications during pregnancy in the present study. A non-significant trend toward a higher risk of major anomalies in both groups with autoimmune diseases was observed in the present study. Inflammatory bowel disease has been inconsistently associated with increased risk of congenital anomalies. The risk of congenital anomalies among offspring of women with inflammatory bowel disease was found to be 2.37-fold increased (95% CI 1.47–3.82, p < 0.001) in a meta-analysis [29]. However, no increased risk of congenital anomalies was found in other relatively large studies [30,31]. The association between rheumatoid arthritis and congenital abnormalities has been even less consistent. Reed et al. [32] did not observe an increased risk for birth defects, while Nørgaard et al. [33] found an increased risk for congenital abnormalities in 1994–1997 [OR 2.57, (95% CI 1.59–4.16)], but not in 1998–2006. A sample size of 67 livebirths or elective terminations of pregnancy due to prenatally diagnosed anomalies in the anti-TNF-␣ group with a ratio of 1:4.9 to the NTE comparison group with 80% power, a baseline risk of 2.4% for major anomalies, enables detection of a 4.95-fold increase in the rate of major anomalies. The study is not powered to find a smaller increase in the overall rate of major anomalies or in the rate of specific rare anomalies. The higher rate of miscarriages found in the anti-TNF-␣ group was associated with an earlier gestational age at initial contact (with a higher miscarriage rate in women calling earlier in pregnancy), and to a lesser extent, with maternal smoking, but not with the exposure, as verified by the regression analysis. A 3.4fold increase in the rate of preterm deliveries in the anti-TNF-␣ group compared with the NTE group might be associated with the underlying diseases [29,34]. A lower median birth weight was found in the anti-TNF-␣ group compared with both the DM and NTE groups. The birth weight may be affected by the underlying disease activity [29,34,35], as well as by the use of concurrent immunosuppressive medications known to be associated with intrauterine growth restriction [36]. The median gestational week of anti-TNF-␣ medication discontinuation was 9 (4–28), before significant placental transfer of these molecules is expected. It should be kept in mind that women in the anti-TNF-␣ group probably had a more severe disease to become eligible for this treatment, and were more likely to be on concomitant immunosuppressive medications and steroids. Discontinuing their disease modifying anti-TNF-␣ treatment relatively early during pregnancy might have resulted in exacerbation of the disease, and subsequent higher rate of preterm deliveries and lower birth weight. The present study has certain limitations and advantages. It is based on TIS population, which may not represent the general population, but has two comparison groups from the same TIS. Other limitations of the study are: reliance on maternal interview as a source for outcome data in most cases, a nonrandomized design, using a group of three different anti-TNF-␣ medications, limited power for specific rare defects, and lack of data on periconceptional disease activity. However, applying the same procedure to the three arms of the study and the prospective nature minimize the potential biases. Due to ethical considerations randomized controlled trials are often not feasible in pregnancy. The fact that all data are from a single center also minimizes some potential biases. In addition, there were two comparison groups: a DM group with
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similar diseases without anti-TNF-␣ treatment and a group counseled for NTE. Medical records were available for most cases with anomalies including discharge letters, echocardiography results, or information from the child’s pediatrician. Another advantage of the present study is that data were available on elective terminations of pregnancies and were included in the analysis. In conclusion, the present prospective observational comparative cohort study suggests that the use of anti-TNF-␣ medications during pregnancy is not associated with an increased risk for major anomalies. One should keep in mind that this conclusion is based on relatively small numbers of exposed pregnancies, and should be interpreted with caution. Larger studies are needed to establish the pregnancy safety of anti-TNF-␣ medications. Further studies with exposure late in pregnancy are needed to address their potential effect on the infant’s developing immune system. Conflict of interest The authors have no conflict of interest to disclose. Acknowledgments This work is part of the Pharm D thesis in Clinical Pharmacy of the Hebrew University of Mrs. Anna Otcheretianski-Volodarsky. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.reprotox.2013. 11.004. References [1] Treacy G. Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for the humanized anti-TNF alpha monoclonal antibody. Hum Exp Toxicol 2000;19:226–8. [2] Vasiliauskas EA, Church JA, Silverman N, Barry M, Targan SR, Dubinsky MC. Case report: evidence for transplacental trasfer of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol 2006;4: 1255–8. [3] Zelinkova Z, de Haar C, de Ridder L, Pierik MJ, Kuipers EJ, Peppelenbosch MP, et al. High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy. Aliment Pharmacol Ther 2011;33:1053–8. [4] Murashima A, Watanabe N, Ozawa N, Saito H, Yamaguchi K. Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breastmilk and the infant’s serum [Letter]. Ann Rheum Dis 2009;68:1793–4. [5] Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013;11: 286–92. [6] Lee H, Kimko HC, Rogge M, Wang D, Nestorov I, Peck CC. Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis. Clin Pharmacol Ther 2003;73:348–65. [7] Ternant D, Aubourg A, Magdelaine-Beuzelin C, Degenne D, Watier H, Picon L, et al. Infliximab pharmacokinetics in inflammatory bowel disease patients. Ther Drug Monit 2008;30:523–9. [8] Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clin Ther 2003;25:1700–21. [9] Djokanovic N, Klieger-Grossman C, Pupco A, Koren G. Safety of infliximab use during pregnancy. Reprod Toxicol 2011;32:93–7. [10] Chambers CD, Johnson DL. Emerging data on the use of anti-tumor necrosis factor-alpha medications in pregnancy. Birth Defects Res A Clin Mol Teratol 2012;94:607–11. [11] Carter JD, Valeriano J, Vasey FB. Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol 2006;33:1014–7. [12] Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 2009;36:635–41. [13] Koren G, Inoue M. Do tumor necrosis factor inhibitors cause malformations in humans? [editorial]. J Rhematol 2009;36:465–6.
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