Article

Risk of preterm delivery and small-for-gestational-age births in women with autoimmune disease using biologics before or during pregnancy: A population-based cohort study

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Abstract

Objectives To assess the risk of preterm delivery and small-for-gestational-age (SGA) births in women with autoimmune diseases using biologics before or during pregnancy. Methods Using population-based administrative data in British Columbia, Canada, women with one or more autoimmune diseases who had pregnancies between 1 January 2002 and 31 December 2012 were included. Exposure to biologics was defined as having at least one biologic prescription 3 months before or during pregnancy. Each exposed pregnancy was matched with five unexposed pregnancies using high-dimensional propensity scores (HDPS). Logistic regression modelling was used to evaluate the association between biologics use and preterm delivery and SGA. Results There were 6218 women with 8607 pregnancies who had an autoimmune disease diagnosis; of which 109 women with 120 pregnancies were exposed to biologics 3 months before or during pregnancy. In unadjusted analyses, the ORs for the association of biologics exposure with preterm deliveries were 1.64 (95% CI 1.02 to 2.63) and 1.34 (95% CI 0.72 to 2.51) for SGA. After HDPS matching with 600 unexposed pregnancies, the ORs for the association of biologics exposure and preterm deliveries were 1.13 (95% CI 0.67 to 1.90) and 0.91 (95% CI 0.46 to 1.78) for SGA. Sensitivity analyses using HDPS deciles, continuous HDPS covariate or longer exposure window did not result in marked changes in point estimates and CIs. Conclusions These population-based data suggest that the use of biologics before and during pregnancy is not associated with an increased risk of preterm delivery or SGA births.

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... We did not find evidence of heterogeneity across studies (Q statistic P ¼ 0.76, I 2 ¼ 0%) or publication bias ( Fig. 2A; Supplementary Fig. S1, available at Rheumatology online). Five studies reported risk estimates of the association between biologic exposure and congenital anomalies, after adjusting for confounders [20][21][22][23][24]. When pooling the adjusted risk estimates, the association was no longer significant (OR 1.18, 95% CI: 0.88, 1.57) (Fig. 2B). ...
... Sixteen studies examined preterm deliveries in women who were exposed (n ¼ 5198) and unexposed (n ¼ 45 022) to a biologic before or during pregnancy; 11 only reported crude proportions of preterm deliveries by exposure group, three only reported adjusted risk estimates, one reported both and one reported unadjusted risk estimates only (Table 1). Ten studies reported the definition for preterm delivery with eight using a threshold of delivering at <37 weeks gestation [18,21,22,[24][25][26][27][28], one at <36 weeks [29], and one at <35 weeks [30]. Despite different definitions, the OR of pooled crude rates of preterm deliveries was 1.61 (95% CI: 1.37, 1.89) when comparing pregnancies in women with inflammatory systemic disease exposed to a biologic (n ¼ 1428) to those unexposed (n ¼ 24 627) (Fig. 3A). ...
... (12.5%) babies born to mothers exposed to a biologic and 5/60 (8.3%) babies born to unexposed mothers [19]. Using the same SGA definition, a larger study by Tsao et al. applied high-dimension propensity score (HDPS) methods to address confounding by indication to report an adjusted OR of 0.91 (95% CI: 0.46, 1.78) [24]. Using a definition of less than the fifth percentile of gestational age specific weights (i.e. ...
Article
Objective: To determine the association between exposure to biologics in pregnant women with inflammatory systemic diseases and maternal and neonatal outcomes through a meta-analysis of findings from studies identified in a systematic review. Methods: We conducted a systematic review of Medline, Embase, and Cochrane Database of Systematic Reviews to identify observational studies assessing the perinatal impacts of biologic in women with inflammatory systemic disease. Findings were meta-analysed across included studies with random-effects models. Crude risk estimates and, where possible, adjusted risk estimates were pooled to determine the impact on results when confounding is addressed. Results: Overall, 24 studies were included in the meta-analysis. Meta-analyses of crude risk estimates resulted in pooled odds ratios (OR) for the association of biologic use during pregnancy and the following respective outcomes: congenital anomalies (1.30, 95% CI: 1.02, 1.67), preterm birth (OR 1.61, 95% CI: 1.37, 1.89), and low birth weight (OR 1.68, 95% CI: 1.21, 2.31). However, in pooled analyses of adjusted risk estimates we observed that the association between biologics use during pregnancy in disease-matched exposed and unexposed pregnant women was no longer statistically significant for congenital anomalies (adjusted OR 1.18, 95% CI: 0.88, 1.57). Conclusion: Pooled results from studies reporting adjusted risk estimates showed no increased risk of congenital anomalies associated with biologics use, suggesting that increased rates of adverse outcomes may be due to disease activity itself or other confounders.
... Therefore, for pragmatic reasons, our recommendations are applicable to equivalent licensed biosimilars. Five studies were identified that assessed the impact of biologic drugs as a whole on pregnancy outcomes [255][256][257][258][259]. These studies included a total of 379 pregnancies in women with autoimmune disease on predominantly anti-TNFa drugs, but also rituximab (RTX), abatacept (ABA), tocilizumab (TCZ), ustekinumab (UST) and anakinra. ...
... Overall, the authors of these studies found no increased risk of miscarriage, stillbirth or congenital anomalies in biologic-exposed patients. One study that reported outcomes for 120 pregnancies in women with autoimmune diseases (predominantly RA and IBD) found a slightly increased risk of prematurity and a trend towards low birth weight in the biologic-exposed group compared with those not exposed [257]. However, once statistical modelling had been performed to correct for confounding by indication and proxies of unmeasured confounders, no association was found between biologic exposure and birth weight or gestational age. ...
... TNFi exposure in pregnancy and with breastmilk exposure has been extensively studied since our last search. We identified an additional 50 studies, reporting 12 491 pregnancy exposures to TNFi, including INF (n 5377), ADA (n 2797), ETA (n 2210), CZP (n 776) and GOL (n 196) [37,[255][256][257][258][259]. Many studies reported combined outcomes for exposure to different TNFi agents. ...
... Overall, there were 35 4,9,[27][28][29][30][31][32][33][34][35][36]11,[37][38][39][40][41][42][43][44][45][46]20,[47][48][49][50][51][52][21][22][23][24][25][26] individual observational studies included in the meta-analysis, 24 cohort studies and 11 case series fulfilling the inclusion criteria. This review contains a total of 35 studies with 11172 pregnancies exposed to biologics, 17 studies with 39290 disease matched controls and 9 studies 2892933 chronic inflammatory disease free pregnancies used for the meta-analysis. ...
... 23 Tsao et al found an OR for the association between biologic exposure and SGA was 0.91 (95% CI 0.46 to 1.78). 34 The PIANO trial found no difference in LBW in those exposed to biologics after controlling for PTB and disease activity 11 . ...
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Background: Biologic medications, specifically the TNF-α inhibitors, have become increasingly prevalent in the treatment of chronic inflammatory disease (CID) in pregnancy. Objective: To determine pregnancy outcomes in women with CID exposed to biologics during pregnancy. Search strategy: PubMed and EMBASE databases were searched through January 1998-July 2021. Selection criteria: Peer reviewed, English language cohort, case-control, cross-sectional studies, and case series which contained original data. Data collection and analysis: Two authors independently conducted data extraction. A meta-analysis of proportions using a random-effects model was used to pool outcomes. Linear regression analysis was used to compare the mean of proportions of outcomes across exposure groups using the 'treated' group as the reference category. All studies were evaluated using an appropriate quality assessment tool described by McDonald et al. The GRADE approach was used to assess the overall certainty of evidence. Main results: 35 studies, 11172 pregnancies, were eligible for inclusion. Analysis showed pooled proportions for congenital malformations: treated 0.04(95% CI 0.03-0.04; I2 77) vs disease matched 0.04(0.03-0.05. I2 86) p=0.238. Preterm delivery treated 0.04(0.10-0.14. I2 88) vs disease matched 0.10(0.09-0.12. I2 87) p=0.250. Severe neonatal infection: treated 0.05(0.03-0.07. I2 88) vs disease matched 0.05(0.02-0.07. I2 94) p=0.970. Low birth weight: treated 0.10(0.07-0.12. I2 93) vs disease matched 0.08(0.07-0.09. I2 0) p=0.241. The pooled Miscarriage: treated 0.13(0.10-0.15. I2 77) vs disease matched 0.08(0.04-0.11. I2 5) p=0.078. Pre-eclampsia; treated 0.01(0.01-0.02. I2 0) vs disease matched 0.01(0.00-0.01. I2 0). p=0.193. No statistical differences in proportions were observed. GRADE certainty of findings were low to very low. Conclusion: We demonstrated comparable pregnancy outcomes in pregnancies exposed to biologics, disease matched controls and CID free pregnancies using the GRADE approach.
... Each woman was matched by 5 other women with autoimmune diseases who did not receive biologics during pregnancy (585 women and 600 pregnancies). It has been established that biologic therapy in pregnant women with autoimmune diseases does not increase the risk of preterm labour nor giving birth to a baby who is small for gestational age (SGA) compared to the control group [17]. ...
... The results of available studies suggest the safety of bDMARDs and tsDMARDs in pregnant women with autoimmune diseases and could contribute to more frequent use of these drugs during pregnancy and lactation [17]. It refers mainly to TNF-αi. ...
Article
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Chronic inflammatory diseases often affect women of childbearing age. Since biologic and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) are more available, their use during conception, pregnancy and lactation has become a matter of concern. Current studies prove the safety of innovative therapy in pregnant women and may contribute to its wider use than before in pregnancy and lactation. It mainly concerns tumour necrosis factor α (TNF-α) inhibitors. We searched PubMed using Medical Subject Headings (MeSH) terms and identified relevant studies and guidelines. We present up-to-date knowledge of bDMARDs and tsDMARDs safety in pregnant and breastfeeding women.
... Although many of these agents are known to cross the placenta at the end of the second trimester and after delivery, 12-14 use of biologics for the management of IBD during pregnancy is considered low risk, 15,16 with no evidence of an increased risk of unfavorable pregnancy outcomes. 17,18 The ongoing prospective, multicenter Pregnancy in IBD and Neonatal Outcomes (PIANO) registry, with an enrollment of approximately 1,500 women in the United States, is providing insight into the safety of biologic medicines in pregnant women with IBD. 19 Analyses from PIANO have reported that the use of vedolizumab, a biologic, was not associated with an increase in adverse pregnancy outcomes, such as congenital abnormalities or abnormal infant growth and development, or infant infection rates. ...
Article
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Vedolizumab, a humanized monoclonal antibody approved for the treatment of adults with moderately to severely active ulcerative colitis or Crohn disease, targets α 4 β 7 integrin and selectively blocks gut-specific lymphocyte trafficking. The potential effects of vedolizumab on development were assessed by standard preclinical toxicity studies in rabbits and cynomolgus monkeys. A single infusion of vedolizumab (0, 10, 30, or 100 mg/kg) was administered intravenously to pregnant rabbits on gestational day 7; rabbits were monitored to gestational day 29. Vedolizumab (0, 10, or 100 mg/kg) was administered intravenously every 2 weeks to pregnant cynomolgus monkeys beginning on gestational day 20 with the last dose on gestational day 132 (9 doses total). In rabbits, vedolizumab did not affect maternal net body weight or net gains, gravid uterine weights, or mean maternal food consumption, nor did it affect intrauterine growth or fetal survival. There were also no vedolizumab effects on embryo–fetal development compared to controls. In cynomolgus monkeys, there was no increase in prenatal loss/death or stillbirth and no maternal toxicity associated with vedolizumab. On day 28 postpartum, low levels of vedolizumab were detected in the breast milk of 3 of 11 monkeys in the 100 mg/kg group. No vedolizumab-related effects on the number of infants born, infant development, or animal hematology or clinical chemistry were noted. Administration of vedolizumab to pregnant rabbits and cynomolgus monkeys did not show any potential for maternal or developmental effects.
... Prolong inflammation can lead to placenta insufficiency and resulted in intrauterine growth restriction, miscarriage, preterm birth, pre-eclampsia and small for gestational age (SGA) [8,10,11]. Additionally, the use of disease-modifying anti-rheumatic drugs and biologics for disease control also raised the concern for pregnancy interruption [9,12]. Clear understanding of the potential adverse events not only provide patients with better preconceptional and prenatal counselling, but likely ease JIA mothers from inexplicable worries. ...
Article
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Backgrounds: In order to provide juvenile idiopathic arthritis (JIA) patients with better pre-conceptional and prenatal counselling, we investigated the obstetrical and neonatal outcomes among women with Asian descent. Methods: Through the linkage of Taiwan National Health Insurance database and National Birth Registry, we established a population-based birth cohort in Taiwan between 2004 and 2014. In a case control study design, first children born to mothers with JIA are identified and matched with 5 non-JIA controls by maternal age and birth year. Conditional logistic regression was used to calculate odds ratios for maternal and neonatal outcomes crude and with adjustment. Results: Of the 2,100,143 newborn, 778 (0.037%) were born to JIA mothers. Among them, 549 first-born children were included in this research. Our result suggested that babies born to mothers with JIA were more likely to have low birth body weight, with an adjusted OR of 1.35(95% CI: 1.02 to 1.79) when compared to babies born to mothers without. No differences were observed in other perinatal complications between women with and without JIA including stillbirth, prematurity, or small for gestational age. The rate of adverse obstetrical outcomes such as caesarean delivery, preeclampsia, gestational diabetes, postpartum hemorrhage and mortality were also similar between the two. Conclusions: Adverse obstetrical and neonatal outcomes were limited among Asian mothers with JIA. Intensive care may not be necessary for JIA mothers and their newborns.
... Several studies have not found increased risks of adverse birth outcomes. 31,32 Luu et al recently reported an increased risk for complications as a composite criterion, not specifying risk estimates for particular birth outcomes. 11 In other studies, risk estimates were slightly increased, or the prevalence of adverse birth outcomes differed between exposed and unexposed patients, but formal analyses were limited by few events. ...
Article
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Purpose: To study the risk of preterm birth, caesarean section, and small for gestational age after anti-tumor necrosis factor agent treatment (anti-TNF) in pregnancy. Methods: Population-based study including women with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis, and their infants born 2006 to 2013 from the national health registers in Denmark, Finland, and Sweden. Women treated with anti-TNF were compared with women with nonbiologic systemic treatment. Adalimumab, etanercept, and infliximab were compared pairwise. Continuation of treatment in early pregnancy was compared with discontinuation. Odds ratios with 95% confidence intervals were calculated in logistic regression models adjusted for country and maternal characteristics. Results: Among 1 633 909 births, 1027 infants were to women treated with anti-TNF and 9399 to women with nonbiologic systemic treatment. Compared with non-biologic systemic treatment, women with anti-TNF treatment had a higher risk of preterm birth, odds ratio 1.61 (1.29-2.02) and caesarean section, 1.57 (1.35-1.82). The odds ratio for small for gestational age was 1.36 (0.96-1.92). In pairwise comparisons, infliximab was associated with a higher risk of severely small for gestational age for inflammatory joint and skin diseases but not for inflammatory bowel disease. Discontinuation of anti-TNF had opposite effects on preterm birth for inflammatory bowel disease and inflammatory joint and skin diseases. Conclusions: Anti-TNF agents were associated with increased risks of preterm birth, caesarean section, and small for gestational age. However, the diverse findings across disease groups may indicate an association related to the underlying disease activity, rather than to agent-specific effects.
... pregnancy 13 . Furthermore, the recommendation to discontinue certain TNF inhibitors (TNFi) at 20-32 weeks of pregnancy also lacks sufficient data 8,14 . ...
Article
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Childbearing women with rheumatoid (RA) and psoriatic arthritis (PsA) have significant peripartum issues. A retrospective anonymous RedCAP survey of peripartum period in females with RA/PsA in the RAPPORT registry was performed. Completed analyses included descriptive statistics, Chi-square and Fisher’s exact test. 162 patients (133 RA/29 PsA) completed the survey (103 women having 234 pregnancies), 164 pregnancies occurring before and 70 pregnancies occurring after diagnosis. Pregnancy outcomes from 103 patients included: 96% live births, 1.9% stillbirths, 23% miscarriages, and 15% therapeutic abortions. A third of patients had fewer children than desired due to disease activity, medications and other reasons. For 63 pregnancies after diagnosis: (1) 49% of pregnancies received pre-conception counseling; (2) 65% described good disease control during pregnancy but 74% flared in the first 3 months postpartum; (3) 79% of pregnancies discontinued IA medications; (4) 35% of pregnancies occurred on biologic therapy at or prior to conception. Gestational age at time of delivery was 37–40 weeks in 58% (33/57) post-arthritis vs 66% (83/126) pre-arthritis pregnancies. No statistically significant differences occurred between pregnancies before or after RA/PsA diagnosis for: pregnancy planning, fertility treatment, pregnancy and labour/delivery complications, birth defect frequency or neonatal complications. Neonatal ICU admissions were significantly lower in pre- compared to post-arthritis pregnancies (3.2% vs 14.5%). No pregnancy complications were noted in 24/54 pregnancies on medications compared to 6/9 pregnancies not on medications. The impact of RA/PsA before, during and after pregnancy varied considerably in this cohort emphasizing the importance of informed-decision making at all stages.
... 06 particularly bDMARDs, with the aim of minimizing the possible maternal and foetal adverse events linked to the continuous use median dosages of steroids during pregnancy. No association was also found between cDMARDs and/or bDMARDs use and adverse pregnancy outcomes, confirming recent data (Tsao et al., 2018a). ...
Article
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Objectives: Women with Rheumatoid Arthritis (RA) can experience flares during pregnancy that might influence pregnancy outcomes. We aimed at assessing the disease course during pregnancy and identifying risk factors for flares. Methods: Data about prospectively-followed pregnancies in RA were retrospectively collected before conception, during each trimester and in the post-partum period. Clinical characteristics, disease activity (DAS28-CRP3), medication use, and pregnancy outcomes were analysed with regard to disease flares. Results: Among 73 women who had a live birth, 64 (88%) were in remission/low disease activity before conception. During pregnancy, a flare occurred in 27 (37%) patients, mainly during first and second trimester. Flares during pregnancy were associated with the discontinuation of bDMARDs at positive pregnancy test (55% of patients with flare vs . 30% of patients with no flare, p 0.034, OR 2.857, 95% CI 1.112–8.323) and a previous use of >1 bDMARDs (33% of patients with flare vs . 10% of patients with no flare, p 0.019, OR 4.1, 95%CI 1.204–13.966). Preterm pregnancies were characterised by higher values of CRP [10 mg/L (5–11) vs . 3 mg/L (2.5–5), p 0.01] and DAS28-CRP3 [4.2 (1.9–4.5) vs . 1.9 (1.7–2.6), p 0.01] during the first trimester as compared with pregnancies at term. Preterm delivery was associated with the occurrence of flare during pregnancy (flare 27% vs . no-flare 7%, p 0.034, OR 4.625, 95%CI 1.027–20.829). Conclusion: Preterm delivery in RA patients was associated with flares during pregnancy. Flares occurred more frequently after the discontinuation of bDMARDs at positive pregnancy test. Women with aggressive RA on treatment with bDMARDs should be considered as candidates for continuing bDMARDs during pregnancy in order to reduce the risk of flare and adverse pregnancy outcomes.
... M32.8, M32.9), at any time prior to the date of conception. 23 Given that the unit of analysis was individual pregnancy, each pregnancy had to satisfy the above criteria to be included in the analyses. ...
Article
Objectives This study aimed to characterize the patterns of medication use before, during and after pregnancy in a population-based cohort of women with systemic lupus erythematosus (SLE). Methods Using population-based administrative data in British Columbia, Canada, with valid information on start date of pregnancy, we identified women with SLE who had singleton pregnancies ending in deliveries between January 1, 2002, and December 31, 2012. We assessed the proportion of SLE pregnancies exposed to SLE medications – namely antimalarials and immunosuppressants – as well as glucocorticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs) 24 months before pregnancy, each trimester of pregnancy, and 12 months postpregnancy. We also assessed discontinuation of antimalarials and immunosuppressants, defined as no prescriptions in a given window following a prescription in a preceding window. Results Of 376 pregnancies (284 women) with SLE, 24.2% had one or more dispensing for antimalarials, 8.2% for azathioprine, 19.7% for glucocorticosteroids and 4.8% for NSAIDs during pregnancy. We observed a 16.7% discontinuation of antimalarials in the year prior to pregnancy, 29.8% in the first trimester, 9.7% in the second trimester, and 26.0% in the third trimester. We also observed a 29.2% discontinuation of azathioprine in the first trimester, 8.0% in the second trimester, and 9.1% in the third trimester. Conclusions These population-based data show frequent discontinuation of medications, particularly antimalarials, in SLE pregnancies. These findings suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy.
... In contrast to other studies [7,10], the current study did not suggest a higher risk of small for gestational age birth, as the rate of 4.7% did not exceed that of the general population (9.3%) [37]. Findings from a recent population-based study from Canada are also in accordance with our findings [40]. ...
Article
Objectives: To investigate the courses and outcomes of pregnancies involving JIA patients who were exposed to DMARDs. Methods: In the Juvenile arthritis MTX/Biologics long-term Observation study, pregnant patients or male patients with pregnant partners were identified. Standardized patient interviews were conducted, and the course and outcome of pregnancy were assessed. Prospectively collected physician- and patient-reported data were also considered in the analysis. Results: The study sample included 152 pregnancies in 98 women with JIA and 39 pregnancies involving 21 male patients as partners. The majority of patients had polyarticular-onset/-course JIA (61%). The average age of patients at first pregnancy was 24.1 (4.5) years, and their mean disease duration was 13.8 (5.9) years. Patients had been exposed to DMARDs for 9.5 (5.6) years, and 90% of these patients had received biologics before. Half of the pregnancies occurred during DMARD exposure, mostly with etanercept. Significant differences in pregnancy outcomes between DMARD-exposed and -unexposed pregnancies were not observed. Spontaneous abortion (13.1%) and congenital anomaly (3.6%) rates were not suggestive of increased risk compared with expected background rates. However, the rates of premature birth (12.3%) and caesarean section (37.7%) were slightly above those in the German birthing population. The disease activity of female patients remained relatively stable in pregnancy, with mean cJADAS-10 scores of 5.3, 7.1 and 5.6 in each trimester, respectively. Conclusion: Young adults with JIA often become pregnant or become fathers of children while still being treated with DMARDs. Data suggest no increased risk of major adverse pregnancy outcomes.
... High-quality studies showed a significantly increased OR compared to studies of low and acceptable quality for the analysis of preterm birth (OR 1.45, 95% CI = 1.14 to 1.83, p = 0.002) [22,23,25,27,30,33,35,42,44,46,48,[51][52][53][54][55]. ...
Article
Background Anti-TNFα is increasingly used as treatment for immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and psoriasis (PS). However, the impact of anti-TNFα during pregnancy on mother and newborn is under debate. This requires a sound knowledge of the effects of this treatment on pregnancy and neonatal outcomes. Objectives To assess pregnancy and neonatal outcomes after anti-TNFα therapy during pregnancy in women with IMID, specifically IBD, RA and PS. Methods We performed a systematic review and meta-analysis of 39 studies assessing pregnancy and neonatal outcomes of women with IMID exposed to anti-TNFα agents during pregnancy. We used a random-effects model to determine pooled outcome measures. Results An increased risk of preterm births (OR 1.45, 95% CI = 1.16 to 1.82, p = 0.001) and infections in newborns (OR 1.12, 95% CI = 1.00 to 1.27, p = 0.05)) was seen for women in the combined group of IMID exposed to anti-TNFα compared to diseased controls. Specifically for IBD patients exposed to anti-TNFα, the risk was increased for preterm birth (OR 1.66, 95% CI = 1.14 to 2.42, p = 0.009), and low birth weight (OR 1.49, 95% CI = 1.01 to 2.20, p = 0.047) compared to diseased controls. Combined data from studies of women with RA and PS, showed no increased risk for adverse pregnancy outcome after exposure to anti-TNFα. Most children of mothers with IMID received vaccination according to national vaccination schemes and only minor adverse events were reported. Conclusion Exposure to anti-TNFα agents during pregnancy is associated with increased risk of preterm birth and infections in newborns of women with IMID compared to diseased controls. The risk of preterm birth and low birth weight was increased in women with IBD specifically. The increased risk of infections in newborns underlines the importance of vaccination, which seems to be safe in children exposed to anti-TNFα. Delay of vaccination is therefore unnecessary in these children. These data may aid in balancing the continuing anti-TNFα therapy versus the risk of adverse pregnancy outcomes.
... 61 Studies of women with autoimmune diseases in British Columbia, using linked administrative health data and a perinatal registry, did not find associations between exposure to various biologics during pregnancy and infant outcomes, including risk of preterm birth, infections and congenital anomalies. [62][63][64] No serious safety signals have yet been reported with other biologics, such as tocilizumab, 65 canakinumab, 66 ustekinumab, 67 vedolizumab 59 or belimumab, 68 but the evidence is mainly from small retrospective observational studies and is of low quality. 3,16 ...
... 28 Tsao et al found an OR for the association between biologic exposure and SGA was 0.91 (95% CI 0.46 to 1.78). 29 The PIANO trial found no difference in LBW in those exposed to biologics after controlling for PTB and disease activity 20 . ...
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Background: Biologic medications, specifically the TNF-α inhibitors, have become increasingly prevalent in the treatment of chronic inflammatory disease (CID) in pregnancy. Objective: To determine pregnancy outcomes in women with CID exposed to biologics during pregnancy. Search strategy: PubMed and EMBASE databases were searched through January 1998-July 2021. Selection criteria: Peer reviewed, English language cohort, case-control, cross-sectional studies, and case series which contained original data. Data collection and analysis: Two authors independently conducted data extraction and assessed study quality. A meta-analysis of proportions using a random-effects model was used to pool outcomes. Linear regression analysis was used to compare the mean of proportions of outcomes across exposure groups using the ‘treated’ group as the reference category. All studies were evaluated using an appropriate quality assessment tool described by McDonald et al. Main Results: 35 studies, 11172 pregnancies, were eligible for inclusion. Analysis showed pooled proportions for congenital malformations: treated 4%(95% CI 0.03-0.4) vs disease matched 4%(0.03-0.05).Preterm delivery treated 12%(0.10-0.14) vs disease matched 10%(0.09-0.12) Severe neonatal infection: treated 5%(0.03-0.07) vs disease matched 5%(0.02-0.07) Low birth weight: treated 10%(0.07-0.12) vs disease matched 8%(0.07-0.09) The pooled Miscarriage: treated 13%(0.10-0.15) vs disease matched 8%(0.04-0.11) Pre-eclampsia; treated 1%(0.01-0.02) vs disease matched 1%(0.00-0.01). No statistical differences in proportions were observed. Conclusion: We demonstrated comparable pregnancy outcomes in pregnancies exposed to biologics, disease matched controls and CID free pregnancies. Overall, women receiving biologics in pregnancy may be reassured regarding their safety.
... Eine kanadische populationsbasierte Kohortenstudie zeigte, dass TNF-Inhibitoren in den 120 untersuchten Schwangerschaften nicht mit einem Frühgeburtsrisiko oder einem erniedrigten Geburtsgewicht von Neugeborenen assoziiert sind [27]. ...
Article
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Zusammenfassung Eine aktive chronisch entzündliche Rheumaerkrankung birgt in der Schwangerschaft Risiken für Mutter und Kind. Remission oder inaktive Erkrankung sind somit das Ziel, das im Hinblick auf die mütterliche Gesundheit und auf den Schwangerschaftsausgang zu verfolgen ist. Die antirheumatische Therapie sollte gemäß internationalen Empfehlungen bereits bei geplanter Schwangerschaft angepasst werden. Zu den erwiesenen teratogenen Antirheumatika zählen Mycophenolat, Methotrexat, Cyclophosphamid und Thalidomid, diese müssen ca. 3 Monate vor der Konzeption abgesetzt werden. Leflunomid ist ein schwaches humanes Teratogen, das vor einer Schwangerschaft abgesetzt und medikamentös ausgewaschen werden soll. Aufgrund einer unzureichenden Datenlage sollten Apremilast und JAK(Januskinase)-Inhibitoren sowie neuere Biologika in der Schwangerschaft vermieden werden. Als kompatibel mit einer Schwangerschaft gelten die Antirheumatika Hydroxychloroquin, Sulfasalazin, Azathioprin, Ciclosporin, Tacrolimus, Colchicum, nichtselektive NSAR (nichtsteroidale Antirheumatika), niedrig dosiertes Prednison/Prednisolon sowie TNF(Tumor-Nekrose-Faktor)-Hemmer. Auch in der Stillzeit sind diese Antirheumatika möglich, darüber hinaus auch andere Biologika wie Rituximab. In einem Beratungsgespräch bei Schwangerschaftsplanung sollten mit der Patientin der Nutzen sowie die internationalen Empfehlungen zur schwangerschaftskompatiblen Antirheumatikatherapie gegenüber den fetomaternalen Risiken einer aktiven Erkrankung besprochen werden, um eine gemeinsame Entscheidungsfindung zu ermöglichen.
... Des études sur les personnes atteintes de maladies autoimmunes en Colombie-Britannique, menées à partir de bases de données médico-administratives reliées et d'un registre périnatal, n'ont révélé aucun lien entre l'exposition à divers agents biologiques durant la grossesse et les résultats chez les nourrissons, y compris le risque de prématurité, d'infection et d'anomalie congénitale [62][63][64] . Aucune alerte majeure n'a été mentionnée avec d'autres agents biologiques, tels que le tocilizumab 65 , le canakinumab 66 , l'ustékinumab 67 , le védolizumab 59 ou le bélimumab 68 , mais les données probantes proviennent principalement de petites études rétrospectives observationnelles et sont de faible qualité 3,16 . ...
... Compared with the general population, birth defects, prematurity and spontaneous abortion were more common in pregnancies associated to autoimmune diseases. However, such an increased risk appears to be disease-related and independent of anti-TNF exposure [41,47,48]. ...
Article
Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are used in pregnant patients with rheumatic diseases. Long-term follow-up data about newborns exposed to bDMARDs during pregnancy are however scarce. Here we summarize the published evidence and available recommendations for use of bDMARDs during pregnancy. We analyse clinical features at birth and at follow-up of 84 children, including: 16 consecutive children born to mothers with autoimmune diseases exposed to bDMARDs in utero; 32 children born to mothers with autoimmune diseases who did not receive bDMARDs; 36 children born to healthy mothers. In our monocentric cohort, children born to mothers with autoimmune diseases had lower gestational age at birth compared to those born to healthy mothers, independently of exposure to bDMARDs. At multivariate analysis, prematurity was an independent predictor of the need for antibiotic treatment, but not for hospitalisation or neonatal intensive care unit (ICU) stay during the neonatal period. Exposure to bDMARDs during pregnancy does not seem to interfere with post-natal development up to infancy. Prospective studies are needed in larger cohorts of pregnant patients to confirm that bDMARDs do not have a negative impact on psychomotor achievements in newborns.
Article
The introduction of biological disease-modifying antirheumatic drug (bDMARD) treatments for various types of autoimmune arthritis, such as rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis, represents a new era of treatment for patients with a refractory response to conventional synthetic DMARDs (csDMARDs). Many new bDMARDs with different modalities or that target different pro-inflammatory molecules, likely cytokines, are rapidly emerging. Hence, physicians in the field may be confused about choosing appropriate bDMARDs for their patients. Considering the high cost of bDMARDs and the rapid destructive process of autoimmune arthritis in patients, the choice of optimal bDMARDs for patients who fail to respond or show an inadequate therapeutic response to csDMARDs designed to control the disease is very critical. Here, we summarize the strengths and weaknesses of bDMARDs and specifically focus on their uses in patients with comorbid conditions or with specific medical conditions, such as pregnancy. This commentary provides a solid up-to-date review on commercially available bDMARDs and very useful information for physicians to facilitate the choice of more appropriate bDMARDs to treat patients with autoimmune arthritis and for basic researchers to understand the current strategies of bDMARD usage and hopefully to develop more powerful bDMARDs with fewer safety concerns.
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Rheumatoid Arthritis (RA) is a frequent chronic inflammatory autoimmune condition, characterized by persistent inflammation of synovial joints. Managing RA during pregnancy is complex, considering the need for an appropriate balance between monitoring disease activity and mitigating symptoms with non-toxic but effective therapies. During pregnancy, a decrease in disease activity can be observed in 48 to 86% of patients. Some RA patients may develop flares, as well as pregnancy complications such as preterm labor, low birth weight and miscarriage. NSAIDs may increase the risk of subfertility in patients with RA. Hydroxychloroquine and sulfasalazine can be safely administered throughout pregnancy. Glucocorticoids at doses greater than 7.5mg/day prednisone or equivalent were associated with preterm delivery. During the first trimester of pregnancy, continuation of anti-TNF therapy is recommended. Both Leflunomide and Methotrexate should be discontinued when pregnancy is being planned.
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Background Inflammatory autoimmune diseases are chronic diseases that often affect women of childbearing age. Therefore, detailed knowledge of the safety profile of medications used for management of inflammatory autoimmune diseases during pregnancy is important. However, in many cases the potential harmful effects of medications (especially biologics) during pregnancy (and lactation) on mother and child have not been fully identified.Objective Our aim was to update the data on the occurrence of miscarriages and (major) congenital malformations when using biologics during pregnancy based on newly published articles. Additionally, we selected several different secondary outcomes that may be of interest for clinicians, especially information on adverse events in the use of a specific biologic during pregnancy.Material and MethodsA search was conducted from 1 January 2015 until 4 July 2019 in Embase.com, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar with specific search terms for each database. Selection of publications was based on title/abstract and followed by full text (double blinded, two researchers). An overview was made based on outcomes of interest. References of the included publications were reviewed to include and minimize the missing publications.ResultsA total of 143 publications were included. The total number of cases ranged from nine for canakinumab to 4276 for infliximab. The rates of miscarriages and major congenital malformations did not show relevant differences from those rates in the general population.Conclusion Despite limitations to our study, no major safety issues were reported and no trend could be identified in the reported malformations.
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Autoimmune thyroiditis (AIT) is a common organ-specific autoimmune disease with a high incidence among women of childbearing age. Recent studies have reported that women with AIT are more susceptible to infertility, miscarriage and preterm birth. It has been investigated that abnormal changes in maternal immune system and maternal–fetal interface can dampen the immune tolerance between mother and fetus, which underlie the pathogenesis of adverse pregnancy outcomes. Hence, we summarize the immunological changes related to adverse reproductive outcomes in AIT and highlight the respective contributions of both humoral and cellular immune dysfunctions to pregnancy failures. Moreover, the direct impacts of AIT on maternal–fetal immune activation and biological influences to trophoblasts are discussed as well. All these associations require confirmation in larger studies, and the pathogenic mechanisms need to be better understood, which might provide useful information for clinical diagnosis and therapy of AIT.
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High-dimensional propensity score analysis automatically selects independent variables for calculating propensity scores, using a vast amount of information from real-world health care databases. This technique can reduce confounding by indication or unmeasured confounders more precisely compared with conventional propensity score analysis. High-dimensional propensity score analysis assumes that proxy information for important unmeasured confounders can be obtained from the underlying data. The number of published studies using high-dimensional propensity score analysis has increased, with pharmacoepidemiology as the main area in which these studies have been published. This report explains the main assumption and the limitations of this analytical method and provides step-by-step procedures to implement the method.
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Introduction: Biological agents have radically changed the prognosis of rheumatic patients. Current evidence demonstrates that tight disease control during pregnancy is mandatory to minimize adverse outcome risk. As the new therapeutic tools are pivotal to maintain appropriate disease activity, it is timely to review available evidence about the safety of biologics and small molecules in pregnancy. Areas covered: A comprehensive literature review has been performed, reporting available data about the passage into breast milk, rate of pregnancy loss and foetal malformations and long-term complications due to in utero exposure to biological agents and small molecules. Expert Commentary: Data about the safety of agents against tumor necrosis factor in pregnancy are reassuring. Even rituximab, tocilizumab, belimumab, ustekinumab, secukinumab and abatacept have not been associated with an increased rate of foetal abnormalities or adverse pregnancy outcome. Experience with small molecules is too small to draw any conclusion. Even if further data are warranted to define the possible long-term effects of in utero biologic exposure on the infant immune system development, it is reasonable to speculate that in the next future the use of biologics during pregnancy will continue to expand, at least when maternal benefit justifies the potential risk to the foetus.
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Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell–mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a “feed forward” inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management.
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There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-β offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided essential information about their functions. Here we review recent developments on IL-1 to IL-38, TNF-α, TGF-β, and interferons. We highlight recent advances during the last few years in this area and extensively discuss their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases.
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Preterm birth (delivery before 37 weeks and 0/7 days of gestation) is a leading cause of infant morbidity and mortality in the United States. In 2013, 11.4% of the nearly 4 million U.S. live births were preterm; however, 36% of the 8,470 infant deaths were attributed to preterm birth (1). Infants born at earlier gestational ages, especially <32 0/7 weeks, have the highest mortality (Figure) and morbidity rates. Morbidity associated with preterm birth includes respiratory distress syndrome, necrotizing enterocolitis, and intraventricular hemorrhage; longer-term consequences include developmental delay and decreased school performance. Risk factors for preterm delivery include social, behavioral, clinical, and biologic characteristics (Box). Despite advances in medical care, racial and ethnic disparities associated with preterm birth persist. Reducing preterm birth, a national public health priority (2), can be accomplished by implementing and monitoring strategies that target modifiable risk factors and populations at highest risk, and by providing improved quality and access to preconception, prenatal, and interconception care through implementation of strategies with potentially high impact.
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Background Adalimumab has been used in patients with moderately to severely active rheumatoid arthritis (RA) for over 10 years and has a well-established safety profile across multiple indications. Objective To update adverse events (AEs) of special interest from global adalimumab clinical trials in patients with RA. Methods This analysis includes 15 132 patients exposed to adalimumab in global RA clinical trials. AEs of interest included overall infections, laboratory abnormalities and AEs associated with influenza vaccination. Pregnancy outcome data were collected from the Adalimumab Pregnancy Registry. Results Serious infections and tuberculosis occurred at a rate of 4.7 and 0.3 events/100 patient-years, respectively. Two patients experienced hepatitis B reactivation. No significant laboratory abnormalities were reported with adalimumab-plus-methotrexate compared with placebo-plus-methotrexate. Influenza-related AEs occurred in 5% of vaccinated patients compared with 14% of patients not vaccinated during the study. Relative risk of major birth defects and spontaneous abortions in adalimumab-exposed women were similar between that of unexposed women with RA and healthy women. Conclusions This analysis confirms and expands the known safety profile of adalimumab and reports no additional safety risk of laboratory abnormalities, hepatitis B reactivation and pregnancy outcomes, including spontaneous abortions and birth defects. The benefits of influenza vaccination are reinforced. Trial registration numbers NCT00195663, NCT00195702, NCT00448383, NCT00049751, NCT00234845, NCT00650390, NCT00235859, NCT00647920, NCT00649545, NCT00647491, NCT00649922, NCT00538902, NCT00420927, NCT00870467, NCT00650156, NCT00647270, NCT01185288, NCT01185301.
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The introduction of biolologic therapy (infliximab, adalimumab) has led to a deep transformation in the management of inflammatory bowel disease (Crohn's disease and ulcerative colitis). Despite their proven efficacy, open issues still remain about their long term safety profile and the optimization of their use; particularly as far as the personalization of the therapy is concerned.
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Background: Elevated maternal serum levels of interleukin-2 soluble receptor-alpha (IL-2 sRalpha), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) have been associated with pregnancy loss. The aim of our study was to evaluate the predictive value of these cytokines in the outcome of early IVF pregnancies. Methods: One hundred and fifty-nine consecutive IVF patients who were subsequently diagnosed to have a biochemical pregnancy (n = 23), a first-trimester miscarriage (n = 19) or a normal term delivery (n = 117) were included in this study. Serum was collected from the initial pregnancy test, 11 days after a day 3 embryo transfer, and all samples were analysed for IL-2 sRalpha, TNF-alpha and IFN-gamma by commercially available enzyme-linked immunosorbent assay (ELISA) kits. Results: IL-2 sRalpha levels were significantly higher in patients with an early pregnancy loss compared with patients with a normal term delivery (849.5 +/- 69.6 versus 693.5 +/- 31.2 pg/ml, P = 0.02), and a cut-off point of IL-2 sRalpha >1000 pg/ml predicted a poor pregnancy outcome (44.4 versus 22.7% pregnancy loss, IL-2 sRalpha >or=1000 versus IL-2 sRalpha <1000 pg/ml; P = 0.02). IFN-gamma-positive patients had twice the risk for poor IVF pregnancy outcome compared with IFN-gamma-negative subjects (40.8 versus 20.0%, respectively; P < 0.02), including a significantly lower implantation rate (37.6 +/- 0.05 versus 50.0 +/- 0.03%, respectively; P = 0.02). There was no difference in pregnancy outcome based upon serum levels, or the ability to detect the presence of TNF-alpha. No differences in levels of these cytokines were found based on the aetiology of the patients' infertility. Conclusions: Elevated maternal serum levels of IL-2 sRalpha and IFN-gamma as early as 11 days after embryo transfer are associated with poor IVF pregnancy outcome.
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The British Society for Rheumatology Biologics Register (BSRBR) has collected data on adverse events including pregnancies in patients with rheumatoid arthritis treated with anti-tumour necrosis factor (anti-TNF) therapy. The purpose of this report is to summarise the pregnancy outcomes in women treated with anti-TNF in the BSRBR. Patients were categorised according to anti-TNF exposure as follows: (1) exposure to anti-TNF and to methotrexate (MTX) and/or leflunomide (LEF) at conception (n=21 pregnancies); (2) exposure to anti-TNF at conception (n=50); (3) exposure to anti-TNF prior to conception (n=59); (4) no exposure to anti-TNF (control group; n=10). Eighty-eight live births in a total of 130 pregnancies were reported in patients who received anti-TNF before or during pregnancy. The rate of spontaneous abortion was highest among patients exposed to anti-TNF at the time of conception (with MTX/LEF 33% and without MTX/LEF 24%). This compared with 17% spontaneous abortions in those with prior exposure to anti-TNF and 10% spontaneous abortions in the control group. Ten terminations were performed. Although the results to date have been promising, no firm conclusions can be drawn about the safety of anti-TNF during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception cannot yet be changed.
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Adjusting for large numbers of covariates ascertained from patients' health care claims data may improve control of confounding, as these variables may collectively be proxies for unobserved factors. Here, we develop and test an algorithm that empirically identifies candidate covariates, prioritizes covariates, and integrates them into a propensity-score-based confounder adjustment model. We developed a multistep algorithm to implement high-dimensional proxy adjustment in claims data. Steps include (1) identifying data dimensions, eg, diagnoses, procedures, and medications; (2) empirically identifying candidate covariates; (3) assessing recurrence of codes; (4) prioritizing covariates; (5) selecting covariates for adjustment; (6) estimating the exposure propensity score; and (7) estimating an outcome model. This algorithm was tested in Medicare claims data, including a study on the effect of Cox-2 inhibitors on reduced gastric toxicity compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). In a population of 49,653 new users of Cox-2 inhibitors or nonselective NSAIDs, a crude relative risk (RR) for upper GI toxicity (RR = 1.09 [95% confidence interval = 0.91-1.30]) was initially observed. Adjusting for 15 predefined covariates resulted in a possible gastroprotective effect (0.94 [0.78-1.12]). A gastroprotective effect became stronger when adjusting for an additional 500 algorithm-derived covariates (0.88 [0.73-1.06]). Results of a study on the effect of statin on reduced mortality were similar. Using the algorithm adjustment confirmed a null finding between influenza vaccination and hip fracture (1.02 [0.85-1.21]). In typical pharmacoepidemiologic studies, the proposed high-dimensional propensity score resulted in improved effect estimates compared with adjustment limited to predefined covariates, when benchmarked against results expected from randomized trials.
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Despite the growing popularity of propensity score (PS) methods in epidemiology, relatively little has been written in the epidemiologic literature about the problem of variable selection for PS models. The authors present the results of two simulation studies designed to help epidemiologists gain insight into the variable selection problem in a PS analysis. The simulation studies illustrate how the choice of variables that are included in a PS model can affect the bias, variance, and mean squared error of an estimated exposure effect. The results suggest that variables that are unrelated to the exposure but related to the outcome should always be included in a PS model. The inclusion of these variables will decrease the variance of an estimated exposure effect without increasing bias. In contrast, including variables that are related to the exposure but not to the outcome will increase the variance of the estimated exposure effect without decreasing bias. In very small studies, the inclusion of variables that are strongly related to the exposure but only weakly related to the outcome can be detrimental to an estimate in a mean squared error sense. The addition of these variables removes only a small amount of bias but can increase the variance of the estimated exposure effect. These simulation studies and other analytical results suggest that standard model-building tools designed to create good predictive models of the exposure will not always lead to optimal PS models, particularly in small studies.
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Objectives: To characterize the patterns of biologics utilization and discontinuation before and during pregnancy in women with autoimmune diseases in British Columbia, Canada. Methods: Women with one or more autoimmune diseases identified by International Classification of Diseases 9(th) /10(th) revision codes that had pregnancies ending in deliveries between January 1st, 2002 and December 31st, 2012; and had at least one prescription for a biologic one year before, or during, pregnancy were included. We examined secular trends, patterns of biologics use, and risk of biologics discontinuation before and during pregnancy. Associations between drug discontinuations and various factors were investigated using multilevel logistic regression models, fitted with binomial generalized estimating equations. Results: Of 6,218 women (8,431 pregnancies) with autoimmune diseases, 131 women (144 pregnancies) were exposed to a biologic before or during pregnancy. Use of biologics in this cohort increased from 0% in 2002 to 5.7% by 2012 (p<0.001). Within the first trimester of pregnancy, 31% (34/110) of women discontinued their biologic and 38% (30/79) discontinued in the second trimester, while 98% (50/51) of those who were on treatment in the second trimester remained on treatment in the third trimester. Women with rheumatoid arthritis had three times higher odds (OR 3.40 [95%CI 1.33-8.71]) of discontinuing biologics during pregnancy, compared to those with inflammatory bowel disease. Conclusions: Given the increased utilization of biologics and high odds of discontinuation during pregnancy in certain populations, more research is needed to improve our understanding of the risks and benefits of biologics on fetal and maternal health. This article is protected by copyright. All rights reserved.
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Pro-inflammatory cytokines promote autoimmune inflammation and tissue damage, while anti-inflammatory cytokines help resolve inflammation and facilitate tissue repair. Over the past few decades, this general feature of cytokine-mediated events has offered a broad framework to comprehend the pathogenesis of autoimmune and other immune-mediated diseases, and to successfully develop therapeutic approaches for diseases such as rheumatoid arthritis (RA). Anti-tumor necrosis factor-α (TNF-α) therapy is a testimony in support of this endeavor. However, many patients with RA fail to respond to this or other biologics, and some patients may suffer unexpected aggravation of arthritic inflammation or other autoimmune effects. These observations combined with rapid advancements in immunology in regard to newer cytokines and T cell subsets have enforced a re-evaluation of the perceived pathogenic attribute of the pro-inflammatory cytokines. Studies conducted by others and us in experimental models of arthritis involving direct administration of IFN-γ or TNF-α; in vivo neutralization of the cytokine; the use of animals deficient in the cytokine or its receptor; and the impact of the cytokine or anti-cytokine therapy on defined T cell subsets have revealed paradoxical anti-inflammatory and immunoregulatory attributes of these two cytokines. Similar studies in other models of autoimmunity as well as limited studies in arthritis patients have also unveiled the disease-protective effects of these pro-inflammatory cytokines. A major mechanism in this regard is the altered balance between the pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells in favor of the latter. However, it is essential to consider that this aspect of the pro-inflammatory cytokines is context-dependent such that the dose and timing of intervention, the experimental model of the disease under study, and the differences in individual responsiveness can influence the final outcomes. Nevertheless, the realization that pro-inflammatory cytokines can also be immunoregulatory offers a new perspective in fully understanding the pathogenesis of autoimmune diseases and in designing better therapies for controlling them.
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The birth weight charts presented here are part of a series of British Columbia-specific charts that include body length, head circumference, ethnic group, geographic region, and neighborhood income quintile. Because birth weight charts can be used to identify infants who exhibit accelerated or retarded intrauterine growth compared with other infants in the same population, they are useful for evaluating nutritional status and postnatal growth. The gender-specific charts presented here provide physicians with additional clinically applicable references to supplement the newly approved overall British Columbia birth weight chart that will soon appear in hospitals. Data recording and analyses practices have assured the accuracy of these charts and allowed them to reflect the particular population mix in BC, the availability of medical care and other health-related services for infants, and the context in which those services are delivered.
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Fetal size and growth reflect critical dimensions of fetal health, and abnormal fetal growth is associated with perinatal death and neonatal morbidity. This chapter presents basic information on how to evaluate normal and abnormal fetal size and growth throughout gestation and at birth. This includes the use of ultrasound-based references for individual measurements and estimated fetal weight, more traditional birthweight-for-gestational age charts, individual segmental and/or planar measurements and ratios, such as femur length and abdominal circumference, and newer techniques for customizing the assessment of fetal growth and assessing fetal and neonatal body composition. Fetal size and growth are also discussed with regard to the main causes of poor or excessive fetal growth, the relationship between fetal growth and preterm delivery, and how fetal growth differs in twin pregnancies.
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Background Observational data so far suggest that biologic disease modifying antirheumatic drugs (bDMARDs) can be safely used in patients with rheumatoid arthritis (RA) until conception/awareness of pregnancy. However, little is known about the course of the disease during pregnancy in women who stopped bDMARDs in the first trimester, how to treat high disease activity (e.g. glucocorticoid use) and the influence of treatments on the birth outcome. Objectives To study the outcomes of pregnancies and the courses of disease activity in RA patients under different treatment regimens. Methods We analysed pregnancies and their outcomes that were reported to the German biologics register RABBIT until end of 2014, stratified by treatment at the time of conception. In a subgroup of patients with pregnancies reported between 2001 and 2011, data of the regular RABBIT study visits were complemented by telephone interviews with particular focus on the course of pregnancy as well as disease activity and treatment during pregnancy. Descriptive statistics were applied to study associations between pregnancy outcomes and exposure to bDMARDs, glucocorticoid use as well as the course of self-reported disease activity. Results In 1,715 female RA patients ≤45 years, 95 pregnancies in 78 patients were reported. At time of conception 51 pregnancies were exposed to bDMARDs (26x etanercept, 10x adalimumab, 4x tocilizumab, 4x certolizumab pegol, 3x rituximab, 2x abatacept, 1x infliximab, and 1x golimumab). Out of 44 women unexposed to bDMARDs at time of conception, 9 were biologic naive and 35 had received their last infusion or injection at least 4 weeks (rituximab 6 months) before conception (10x etanercept, 9x adalimumab, 2x tocilizumab, 1x infliximab, 13x rituximab). The rates of spontaneous abortions were similar across treatment regimens and in the range of the rates of the general population (∼ 15-20%). Induced abortions were reported in 4 out of 95 pregnancies (one due to trisomia 21 with cardiac defect). More than one third of patients (37%) exposed to bDMARDs at conception also required bDMARDs and/or ≥10 mg/d glucocorticoids later in pregnancy. All preterm births occurred in patients with ≥10 mg/d glucocorticoids. Table: Pregnancy outcomes in the cohort and the interviewed subgroup (the latter with course of disease and treatment during pregnancy). LI = last infusion/injection before conception, ADA = adalimumab, RTX = rituximab Conclusions Within this limited sample of pregnancies we confirmed previous reports and found no increased risk of malformations or other harmful consequences in patients exposed to biologic treatment around the time of conception. Acknowledgements The German Biologics Register RABBIT is supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, MSD Sharp&Dohme, Pfizer, Roche, and UCB. Disclosure of Interest None declared
Article
Background Anti-TNFα agents and Rituximab fall within the FDA category B concerning fetal risk. However numerous case series and registry data of pregnancies exposed to these therapies are available in the literature Objectives Aim of this study was to offer the contribution of our Centre Methods Data were collected from a prospective single-centre cohort of outpatients followed during pregnancy between 2006 and 2013. Women exposed to biological agent during pregnancy or in the 3 months before conception were included. Outcomes in the biological-exposed group are compared with those in a disease and age-matched group of pregnant women without biological agent exposure. Demographic and clinical data, obstetric outcome and neonatal complications were recorded Results 26 pregnancies in 21 patients,10 Rheumatoid Arthritis (RA),5 ankylosing spondilytis (SA),3 Psoriatic arthritis (PA),3 Undifferentiated spondyloarthritis (uSpA) exposed to a biologic agent (13 etanercept, 6 adalimumab, 3 infliximab, 4 RTX) were included. The median age was 33 (range 29-49 yrs),18 women were nulliparous. All patients a-TNF treated withdrew therapy in early pregnancy (≤10 weeks gestational age). A woman affected by RA became pregnant four times during RTX therapy, respectively 3 months after 3rd retreatment, 2 months after 4th retreatment and 1 month after 5th and 6th retreatment. Only 3 patients were also on DMARDs therapy at time of conceptions,2 with sulphasalazine (which was continued) and 1 with methotrexate which was immediately withdrawn.12 patients (6 RA,4 PA,2 SA) started or increased oral and/or intra-articular steroids during pregnancy because of disease flare. 28 pregnancy in 25 patients were enrolled as control group (12 RA, 9 uSpA,2 Juvanile Idiopatic Arthritis, 2 PA), median age 34 (range 23-39 yrs).15 patients were treated with DMARDs during pregnancy (sulphasalazine 7;hydroxycloroquine 7, cyclosporine 1). No other drugs were taken at the time of conception, apart from low dose of steroids in 15 cases.Pregnancy outcomes are summarized in tab.1. Therapeutic abortions were performed for extrauterine pregnancy occurred twice in the patient with RA which became pregnant four times during RTX treatment, after the 5th and the 6th retreatment. After the 4th retreatment she had an early spontaneous abortion. Previously, she delivered 2 healthy children after exposure to etanercept and 3th retreatment of RTX. No serious perinatal complication occurred excluding very preterm baby delivery at 28th weeks, who needed neonatal intensive care. No congenital malformations were observed. Klinefelter syndrome was diagnosed in 1 case. Conclusions Based on these findings, there are no significant differences about pregnancy outcome between biologic-exposed group and non-exposed control group. Additional data from larger numbers of pregnant women exposed to biological agents are required. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3342
Article
Rheumatic diseases (RDs) occur preferentially in women, often during the childbearing age. The interaction of pregnancy and the RD is varied, ranging from spontaneous improvement to aggravation of disease symptoms or life-threatening flares. Risks for the mother with RD and the child differ in regard to the presence of organ manifestations, organ damage, disease activity, presence of specific autoantibodies, and therapy. Pregnancy complications comprise hypertension, preeclampsia, premature delivery, and side effects of therapy. Adverse pregnancy outcomes include recurrent miscarriage, intrauterine growth restriction, and fetal demise, and they are frequently encountered in RD with organ manifestations and harmful autoantibodies. Because of the difference in the prevalence of RDs, knowledge on the gestational course of disease and pregnancy outcome is limited to the fairly common RDs such as rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome. Pregnancies in RD are connected with increased risks for mother and child and need interdisciplinary care and management. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Background The safety of anti-tumour necrosis factor (TNF) agents during pregnancy is a major concern for child-bearing women and physicians.AimTo assess the impact of anti-TNF therapy on adverse pregnancy and foetal outcomes in women with inflammatory bowel disease (IBD).Methods Pregnancies occurring during anti-TNF treatment or less than 3 months after its cessation in IBD patients followed in GETAID centres were recorded from January 2009 to December 2010. Ninety-nine pregnancies in women without anti-TNF treatment were identified from the CESAME registry. We compared pregnancy and neonatal outcomes by a case–control study.ResultsIn the 124 IBD patients followed, 133 pregnancies were reported. At the conception time, 23% of patients had active disease. Eighty-eight per cent (n = 117) of the 133 pregnancies followed until delivery resulted in 118 liveborns (one twin pregnancy). Complications were observed in 47 (35%) women and 24 (20%) newborns. In multivariate analysis, factors associated with pregnancy complications were: current smoking (P = 0.004), a B2 (stenotic) phenotype in CD women (P = 0.004), occurrence of a flare during pregnancy (P = 0.006) and a past history of complicated pregnancy (P = 0.007). Current smoking was the only factor associated with severe (i.e. potentially lethal) pregnancy complications (P = 0.02). Having IBD for more than 10 years prior to conception was associated with newborn complications (P = 0.007). No difference was found with the control group for any of the pregnancy and neonatal outcomes.Conclusion In our series, the safety profile of anti-TNF therapy during pregnancy and the neonatal period appears similar to control group of IBD women not treated with anti-TNF therapy.
Article
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation. It has been a worldwide health-care problem with a continually increasing incidence. It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut, catalyzed by the genetic susceptibility of the individual. Although the etiology of IBD remains largely unknown, it involves a complex interaction between the genetic, environmental or microbial factors and the immune responses. Of the four components of IBD pathogenesis, most rapid progress has been made in the genetic study of gut inflammation. The latest internationally collaborative studies have ascertained 163 susceptibility gene loci for IBD. The genes implicated in childhood-onset and adult-onset IBD overlap, suggesting similar genetic predispositions. However, the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD. Meanwhile, the adaptive immune response has been classically considered to play a major role in the pathogenesis of IBD, as new studies in immunology and genetics have clarified that the innate immune response maintains the same importance in inducing gut inflammation. Recent progress in understanding IBD pathogenesis sheds lights on relevant disease mechanisms, including the innate and adaptive immunity, and the interactions between genetic factors and microbial and environmental cues. In this review, we provide an update on the major advances that have occurred in above areas.
Article
To evaluate pregnancy safety of anti-TNF-α medications. Prospective, comparative, observational study done at the Israeli Teratology Information Service between 2002 and 2011. 83 anti-TNF-α-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-α 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-α, T1), 5/79 (6.3%) (DM), 8/336 (2.4%) (NTE)], even after excluding genetic or cytogenetic anomalies [3/65 (4.6%) (anti-TNF-α, T1), 4/79 (5.1%) (DM), 6/336 (1.8%) (NTE)]. There were no cases of VATER/VACTERL association. The present study suggests that anti-TNF-α 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-α pregnancy safety.
Article
Background: Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy. Methods: This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti-TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women. Results: Thirty-two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37-39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti-TNF treatment were not different from those in pregnancies before anti-TNF treatment or with indirect exposure to anti-TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis. Conclusions: Direct exposure to anti-TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall.
Article
During pregnancy, the fetus represents a natural allograft that is not normally rejected. While the maternal immune system retains the ability to respond to foreign antigens, tolerance mechanisms are up-regulated to protect the fetus from immunologic attacks by the mother. The profound immunologic adaptations during and after pregnancy do influence maternal autoimmune rheumatic diseases in several ways. One is triggering the onset of a rheumatic disease in the post partum period, the other influencing disease activity of established rheumatic disease. The review will discuss the mechanisms of increased susceptibility of rheumatoid arthritis (RA) in the first year post partum with a specific emphasis on the role of fetal cells or antigens persisting in the maternal circulation (so called microchimerism). Furthermore, the different influences of pregnancy on established rheumatic diseases will be highlighted. A marked beneficial effect of pregnancy is observed on RA whereas several other rheumatic diseases as ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) show either no particular effect or an aggravation of symptoms during pregnancy. Differences emerging in regard to modulation of disease symptoms during pregnancy seem related to response to hormones, the type of cytokine profile and immune response prevailing as well as further downstream interactions of molecular pathways that are important in disease pathogenesis.
Article
Women with Crohn's disease (CD) are considered to be at increased risk for adverse outcomes of pregnancy. However, the few studies assessing this risk have had small sample sizes and limitations. We examined outcomes of pregnancy among a large cohort of primiparous women with CD. Our population-based prevalence study utilized data from medical birth registries in Sweden and Denmark between 1994 and 2006. Linking birth registry data with national patient registries, we identified 2377 women with a hospital diagnosis of CD prior to delivery and 869,202 women with no diagnosis of CD. Using logistic regression analysis, we estimated relative risks with 95% confidence intervals (CI) for pre-eclampsia, preterm birth, 5-minute Apgar scores below 7, cesarean section, small for gestational age (SGA), stillbirth, and congenital malformations. Maternal CD was associated with increased risk of moderately and very preterm birth (prevalence odds ratio [POR], 1.76; 95% CI, 1.51-2.05; and POR, 1.86; 95% CI, 1.38-2.52, respectively). Maternal CD was also associated with increased risk for cesarean section (POR, 1.93; 95% CI, 1.76-2.12). The strongest associations with CD were observed for prelabor cesarean section and induced preterm delivery. Risk of small size for gestational age birth was slightly increased among women with CD, especially during the time period of 2002-2006 (POR, 1.43; 95% CI, 1.09-1.89). We found no increased risks for pre-eclampsia, low 5-minute Apgar score, stillbirth, or congenital malformations. Maternal CD is a risk factor for preterm birth, but not birth defects.
Article
Spurious effects from an extraneous variable are a troublesome problem in many areas of research in the biological and behavioral sciences. While investigators have recognized intuitively that there is a relationship between the size of an effect and its chance of being spurious, current textbooks do not contain any explicit statement of this relationship. In this paper one such statement, the Size Rule, is developed. The application of this rule to controversies in the medical area is discussed.
Article
Tumour necrosis factor-α (TNF-α) is a pleiotropic cytokine which stimulates the synthesis and release of prostaglandins (PGs) in several in vitro and in vivo models of preterm labour. While TNF-α-stimulated PG production has been described in decidual, amnion and myometrial cells, to date no studies have focused on the role of TNF-α in the stimulation of arachidonic acid metabolism in placental trophoblast cells. Cyclo-oxygenase-2 (COX-2) is the rate-limiting enzyme in PG biosynthesis and is expressed de novo during cellular activation by cytokines. To test whether TNF-α alters expression of COX-2, trophoblasts from first trimester chorionic villi were cultured as a continuous cell line and treated with TNF-α alone or with TNF-α and dexamethasone (Dex). Total RNA and protein were extracted from the trophoblasts and subjected to Northern and immunoblot analysis, respectively. Northern blots were hybridized with a ³²P-labelled probe encoding the COX-2 cDNA and immunoblots were incubated with anti-COX-2 antibodies. There was a time- and dose-dependent increase in COX-2 mRNA and protein expression in cells stimulated with TNF-α. The effect of TNF-α on COX-2 rnRNA and protein expression was inhibited by dexamethasone (Dex). To examine the production of PGE2 and PGF2α, specific RIAs were performed on culture media from similarly stimulated cells. PG accumulation after TNF-α-stimulation occurred in a time- and dose-dependent fashion with a similar inhibition of PG accumulation after Dex exposure. To be certain that TNF-α-stimulated PGE2 production was, indeed, a result of COX-2 induction, RIAs were carried out with the COX-2-selective inhibitor NS-398. Cells stimulated with the NS-398 after TNF-α exposure demonstrated suppression of TNF-α-stimulated PGE2 formation. The results suggest that TNF-α elicits part of its pathophysiologic effects in preterm labour via alterations in COX-2 gene expression within the placental microenvironment.
Article
Although the woman with IBD possesses a greater potential for a complicated pregnancy, the majority of patients will experience an uneventful normal pregnancy. It is important to educate the young patient with IBD when she is planning a family. Conception at a time when IBD is quiescent offers the greatest likelihood of an uncomplicated pregnancy. Physicians must recognize and inform their patients that most medications that are necessary to suppress the disease should be continued throughout pregnancy. Although generalities can be made regarding the management of pregnant women with IBD, the individual patient may need specifically tailored therapy for her individual case.
Article
The aim of this study was to evaluate the production of tumor necrosis factor (TNF) by peripheral blood cells during pregnancy, at the onset of labor and of spontaneous abortion (SA), as well as in non-pregnant women with and without a history of recurrent spontaneous abortions (RSA). The peripheral blood cells TNF production was evaluated in 28 women in the 1st trimester of pregnancy, 21 in the 2nd, and 30 in the 3rd, 47 at term labor; 43, at the onset of SA; 19 healthy and 19 RSA non-pregnant women. The statistical method used was the Mann-Whitney test. We observed (1) lack of TNF detection in the 1st gestational trimester; (2) increase of TNF production with gestational age, with the highest values being observed at labor (P<0.05); (3) high TNF production at the onset of SA; (4) no difference in the TNF production by healthy and RSA non-pregnant women. The suppression of TNF production during the 1st trimester of pregnancy seems to favor the normal development of pregnancy. It remains to be investigated whether the assessment of TNF production is a valuable prognostic parameter for the occurrence of abortion.
Article
To find out whether preterm labor is associated with raised maternal serum concentrations of interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) and whether the measurement of these cytokines can be used to detect early intrauterine infection in preterm labor. Cross-sectional study: 77 women in preterm labor, 47 controls of healthy preterm women not in labor and 19 women in term labor. The serum cytokines levels were measured by enzyme-linked immunosorbent assay (ELISA). The newborns of women who were in labor were followed up for evidence of infection. Differences between groups were tested using analysis of variance, Student's t-test and chi2-test. There was no significant difference in the concentration of all the cytokines measured between the different groups. No statistical difference was found in the concentration of the cytokines between women in preterm labor with ruptured membranes and those with intact membranes. There was also no difference found in the concentration of cytokines between women whose newborns had positive bacterial culture and those with negative culture. There was a positive correlation between the concentrations of IL-6, IL-8 and TNF-alpha. Serum levels of interleukin-6, interleukin-8 and tumor necrosis factor-alpha were not increased in preterm labor compared to normal control women. There is doubt regarding the usefulness of maternal serum measurement of these cytokines for the detection of early fetal infection in preterm labor, but this needs further evaluation.
Article
To compare tumor necrosis factor receptor 1 (TNFR1) protein expression in women with unexplained early spontaneous abortion (UESA) and normal pregnancy. In a prospective study, 62 women with UESA and 60 with normal pregnancy were studied. Decidual membrane TNFR1 was detected by flow cytometry and immunohistochemistry, and serum soluble TNFR1 were by ELISA. Statistical analyses of resulting data employed the student's t test, the Fisher's Exact, and the nonparametric Wilcoxon test The percentage of membrane tumor necrosis factor receptor 1 (mTNFR1) positive decidual cells was 16.42+/-7.1 for women with UESA and 12.47+/-5.3 for women with normal pregnancy (p<0.05). The number of mTNFR1 positive cells was more in decidual stromal and vessel endothelial cells in women with UESA, and serum soluble tumor necrosis factor receptor 1 (sTNFR1) concentration was significantly higher than in women with normal pregnancy (554.56+/-126.7 pg/ml vs. 175.3+/-52.4 pg/ml; p<0.001). The overexpression of TNFR1 may contribute to the development of ESA.
Article
Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. However, it remains less clear how cytokines are organized within a hierarchical regulatory network, and therefore which cytokines may be the best targets for clinical intervention a priori. Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis.
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