The Journal of Maternal-Fetal & Neonatal Medicine
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Pregnancy outcome in patients with ankylosing spondylitis Hakan Timur, Aytekin Tokmak, Gülenay G. Türkmen, Hasan Ali İnal, Dilek Uygur & Nuri Danışman To cite this article: Hakan Timur, Aytekin Tokmak, Gülenay G. Türkmen, Hasan Ali İnal, Dilek Uygur & Nuri Danışman (2015): Pregnancy outcome in patients with ankylosing spondylitis, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.3109/14767058.2015.1089432 To link to this article: http://dx.doi.org/10.3109/14767058.2015.1089432
Published online: 28 Sep 2015.
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http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2015 Taylor & Francis. DOI: 10.3109/14767058.2015.1089432
ORIGINAL ARTICLE
Pregnancy outcome in patients with ankylosing spondylitis Hakan Timur1, Aytekin Tokmak1, Gu¨lenay G. Tu¨rkmen2, Hasan Ali _Inal3, Dilek Uygur1, and Nuri Danı¸sman1 Department of Obstetrics and Gynecology, Zekai Tahir Burak Women’s Health Research and Education Hospital, Ankara, Turkey, 2Ankara Training and Research Hospital, Ankara, Turkey, and 3Department of Obstetrics and Gynecology, Konya Training and Reseach Hospital, Konya, Turkey
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Abstract
Keywords
Objective: The aim of this study was to evaluate pregnancy outcomes in women with Ankylosing Spondylitis (AS), and the course of disease during pregnancy was also assessed. Methods: This case–control study included 60 pregnant women who delivered in our clinic between March 2007 and 2015. Twenty of them diagnosed with AS formed the study group and 40 women were chosen as the control group. These patients were chosen and reviewed by their hospital records and were evaluated retrospectively in terms of their clinical characteristics, pregnancy complications and perinatal outcomes. The Ankylosing Spondylitis Disease Activity Score (ASDAS), a new composite index to assess disease activity in AS, was used in the assessment of the patients. Result: No adverse pregnancy outcome was noted in pregnant patients with AS. Mean age of AS patients was significantly higher than the controls (p ¼ 0.037). The proportion of female fetuses was higher in pregnancies with AS compared to pregnant patients with healthy controls (p ¼ 0.041). Fourteen (70%) of 20 patients displayed decrement in ASDAS during pregnancy. Course of AS was unaltered in 6 (30%) of 20 patients during pregnancy. Otherwise, the stage of the disease during pregnancy remained unchanged in 15 (75%) of cases as postpartum exacerbation was observed in 6 (30%). The reported symptoms of patients with AS during pregnancy were arthritis and uveitis. Conclusions: Women with AS have a favorable pregnancy outcome, and pregnancy does not substantially aggravate disease activity or severity in these patients.
Ankylosing spondylitis, pregnancy, pregnancy outcome
Introduction Ankylosing spondylitis (AS) is a chronic, systemic, inflammatory disease that primarily affects the sacroiliac joints and spine. It is one of the most common seronegative spondyloarthropathies, which have a strong genetic predisposition. Besides involvement of the axial skeleton, certain peripheral joints, tendons and non-articular structures may also be affected. The prevalence of AS ranges between 0.03% and 1.8% depending on the population studied [1]. The disease affects mostly young individuals in the third and fourth decade of their lives and may therefore have a major impact on their ability to work. In the past, AS was thought to be an overwhelmingly male disease [2], but recent studies revealed that male-to-female ratio is closer to 2.5:1 [3]. The etiology of the disease still remains unclear. However, approximately 90% of people with AS express the HLA-B27 genotype, meaning there is a strong genetic association [4]. A modulation of disease activity during pregnancy is observed in several autoimmune diseases. Unlike rheumatoid Address for correspondence: Hakan Timur, M.D., Zekai Tahir Burak Women’s Health Education and Research Hospital, Talatpa¸sa Bulvarı, Hamamo¨nu¨, Altındag˘/Ankara 06230, Turkey. Tel: +90 5054601719. Fax: +90 3123065917. E-mail: [email protected]
History Received 29 June 2015 Accepted 29 August 2015 Published online 25 September 2015
arthritis, most patients with AS enter pregnancy in state of active disease, and pregnancy does not have a significant beneficial effect on the disease activity of AS [5]. In addition, postpartum exacerbation of disease activity is observed in the vast majority of the patients with AS within 6 weeks to 6 months after delivery [6]. There are limited studies with relatively low sample sizes evaluating the effects of the disease on the fetal and neonatal outcomes in AS patients. Østensen et al. reported that pregnancy outcomes are not adversely affected by the disease in AS as well as rheumatoid arthritis [7]. Although some studies performed on the disease activity during pregnancy are present in the literature considering that AS is multi-systemic and occurs in women of reproductive ages, pregnancy and neonatal outcomes of the disease merit special attention. In this retrospective analysis, we investigated the relationship between AS and pregnancy outcomes.
Materials and methods This retrospective observational case–control study consisted of pregnant patients with AS who attended the perinatology clinic of Zekai Tahir Burak Research and Education Hospital, Ankara, Turkey between March 2007 and 2015. It is a referral hospital for high-risk pregnancies in Ankara and other parts of
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central Anatolia. The study was approved by the institutional review board of the hospital. In order to identify patients with AS and their respective controls, the hospital database was used. During the study period, 20 patients with AS were diagnosed according to the modified New York criteria [8]. The AS patients were referred to rheumatology clinics of other tertiary care centers to monitor disease activity and plan their treatment during pregnancy. Data on AS activity and use of medications during pregnancy were obtained for the most recent pregnancy of each patient only. The Ankylosing Spondylitis Disease Activity Score (ASDAS), a new composite index to assess disease activity in AS, was used in the assessment of the patients [9]. Patients with AS were questioned in this survey and disease activity was determined by ASDAS-CRP calculator. This survey includes questions related to axial and peripheral symptoms, patient’s global assessment and C-reactive protein (CRP). Disease activity was classified as follows: 51.3, inactive disease; 1.3 to 52.1, moderate disease; 2.1 to 3.5, high disease and 43.5, very high disease [10]. All patients were asked to complete the questionnaire for the third trimester of the most recent pregnancy and 6 months pre-/postpregnancy. The ASDAS-CRP score and disease activity were chosen as the outcome measure for prepregnancy, pregnancy and postpartum in AS. Two controls per case were selected from the following births that took place in the same unit of the current hospital. The following clinical and demographic data were obtained by reviewing the patients files and hospital database; age, body mass index, smoking status, educational level, obstetric history, medical treatment used during pregnancy, disease duration, maternal and fetal complication during pregnancy, and neonatal outcome. Statistical analysis Statistical Package for the Social Sciences version 17.0 (SPSS Inc., Chicago, IL) was used for statistical analysis. Kolmogorov–Smirnov was used to assess normal distribution of the univariate variables. Means ± standard deviations and median (minimum–maximum) for quantitative data and numbers and percents for qualitative data were computed. Independent-samples t test was used to compare unadjusted means between groups. Non-parametric variables between groups were compared through Mann–Whitney U test. Pearson chi-square and Fisher’s exact tests were used for categorical variables. Statistical significance was set at p50.05.
Results A total of 60 patients were included in this study. Mean age of diagnosis was 24.1 + 4.1 and duration of disease was 6.2 + 2.1 years. ASDAS–CRP decreased in 14 (70%) out of 20 patients from prepregnancy to late pregnancy while 15 patients showed increment in this score during postpartum period. On the other hand disease activity remained unchanged in 15 patients with AS during pregnancy, and 6 patients increased to an upper-class disease activity in the postpartum period. Most patients entered pregnancy in a stable state, so no changes were made in the treatment. While six patients did not use any medication during pregnancy, corticosteroids
J Matern Fetal Neonatal Med, Early Online: 1–5
were used by seven patients, salazopyrin by five, NSAI by four and colchicine by three of the patients (Table 1). Corticosteroid treatment instead of methotrexate was initiated in a patient who had a very high disease activity. Symptoms during pregnancy were uveitis in 2 patients and arthritis in 12 patients. Mean age of pregnant patients with AS was significantly higher than healthy controls. The proportion of female fetuses was also higher in pregnancies with AS. There was no statistically significant difference in the smoking status, rate of adverse pregnancy outcome, route of delivery, indications for C-section, birth weight of neonates, rates of admission to the Neonatal Intensive Care Unit, rates of administration of general anesthesia, mean duration of labor, levels of CRP, mean white blood cell counts and mean hemoglobin values between the study and the control group. Mean birth weight in the disease group was 3088.4 ± 480.0 and 3273 ± 585.8 g in the control group. Mean CRP level was 4.4 ± 4.1 in the disease and 3.7 ± 3.3 in the control group (Table 2). The only significant difference was the gender of the newborn (p ¼ 0.041).
Discussion Our results indicate that the majority of patients (70%) with AS were in a state of remission during pregnancy without an increase in the number or frequency of symptoms. We have also demonstrated there is no association of adverse pregnancy outcomes and AS. It is generally accepted that the course of AS is unaffected by pregnancy [11]. Lui et al. [12] evaluated the severity of back pain and morning stiffness pre, during and postpartum in patients with AS and controls. They included 19 women with AS and 33 controls in this retrospective study. A significant improvement in pains scores was reported in more than half of the patients with AS, especially in the first trimester. However, in both groups pain worsened in later stages of pregnancy, likely secondary to biomechanical loading. And postpartum pain scores in AS returned to prepartum levels. Zhou et al. [13] evaluated the interaction between pregnancy and AS in terms of pregnancy outcomes. In this retrospective study involving 12 patients, authors concluded that women with AS can be reassured that the pregnancy outcome is not significantly affected by the disease. Another retrospective, international study of reproductive performance in 939 women with AS, number of children was found on average 2.4 per woman, not different from the number of offspring in the healthy population [14]. It was also shown that the pregnancy and neonatal outcomes were not affected significantly by the disease. According to this study, perseverance of disease during pregnancy was shown to be more likely if patients entered pregnancy in a state of active disease, and improvement during pregnancy was related to a history of peripheral arthritis and a female fetus. Active disease at prepregnancy was found to be a predictor of disease exacerbation after pregnancy. Although pregnancy is associated with mitigation of disease in patients with rheumatoid arthritis, pregnant patients with AS may display worsening of symptoms such as increased pain scores, morning stiffness especially in the
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Table 1. Characteristics of patients with Ankylosing Spondylitis in pregnancy.
Age at diagnose (years) Duration of disease (years) ASDAS-CRP (prepregnancy–pregnancy) Decreased Unchanged Increased ASDAS-CRP (pregnancy–postpartum) Decreased Unchanged Increased Stage of disease (prepregnancy–pregnancy) Decreased Unchanged Increased Stage of disease(pregnancy–postpartum) Decreased Unchanged Increased Symptoms during pregnancy Uveitis Artritis Medication during pregnancy* NSAI Corticosteroid Cholchicine Salazopyrin Methotraxate Chloroquin None
Mean ± SD
Median (min–max)
24.1 + 4.1 6.2 + 2.1
23.5 (17–34) 6 (2–13)
n (%)
14 (70) 6 (30) 0 2 (10) 3 (15) 15 (75) 5 (25) 15 (75) 0 0 14 (70) 6 (30) 2 (10) 12 (60) 4 (20) 7 (35) 3 (15) 5 (25) 0 0 6 (30)
NSAI, non-steroid anti-inflammatory. *Some patients received combination therapy.
second trimester in comparison to gestational age-matched pregnancies with RA and healthy controls [7]. Fo¨rger et al. [15] showed that pregnant patients with AS had the biggest decline in health related quality of life when compared to pregnant patients with other rheumatic diseases. Despite the prospective nature of both studies, the small number of pregnant patients included was their major limitation (9 and 10 patients, respectively). Unlike these studies, we observed a significant reduction in ASDAS-CRP levels in pregnant patients with AS during pregnancy when compared to the previous sixth month of pregnancy. In comparison to the prepregnancy state the disease followed a variable course during pregnancy. Pain intensity was higher in pregnant patients with AS in the first and second trimester when compared to the third trimester. Patients with AS showed improvement in pain score and morning stiffness in the third trimester. Pregnant patients with AS demonstrated an increase in anti-inflammatory cytokines including soluble tumor necrosis factor receptor and interleukin receptor antagonist as the pregnancy proceeded from the second into the third trimester and a decrease in disease activity was observed during the corresponding time period [16]. T regulatory cells have a suppressive role on immune function, and their number increases in healthy pregnant controls as well as in patients with AS [17]. However, defective functioning rather than the number of regulatory T cells may be responsible for inadequate immunomodulation during pregnancy in patients with AS [18]. Our results showed no statistically significant difference in pregnancy and neonatal outcomes between the two groups,
consistent with results obtained from other studies [7,16]. Interestingly, the proportion of female fetuses was higher in pregnancies with AS compared to pregnant patients with healthy controls. In our study, we observed lower disease activity during pregnancy that may be due to the higher number of female fetuses. The female fetuses may have induced maternal immune tolerance. Mean age of pregnant patients with AS was also significantly higher than healthy controls. It is known that patients with chronic diseases of the spine represent specific challenges to the anesthesiologist [19]. When we looked at the anesthesia types performed in patients undergoing C-section, we observed that general anesthesia was administered in most of those patients, despite the presence of difficult airways. The symptoms of AS remain unchanged in 80% of the cases, during pregnancy. However, a worsening of symptoms is seen in 60–90% of patients up to 6 months after labor [7]. Therefore, although patients with AS may enter remission during pregnancy, the first 6 months postpartum is accompanied by exacerbation of the disease [16]. Even though none of the study subjects experienced aggravation of the disease during pregnancy, six did so postpartum. In our study, the stage of the disease during pregnancy remained unchanged in 75% of cases as postpartum exacerbation was observed in 30%. The patients with active AS who plans a pregnancy or is already pregnant require therapy compatible with pregnancy. This situation limits the choice of disease modifying antirheumatic drugs considerably. For example, methotrexate should be replaced by a drug compatible with pregnancy.
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Table 2. Pregnancy outcomes in patients with ankylosing spondylitis and healthy controls. Age (years) Gravida Parity Live children Abortion Height (cm) Weight (kg) BMI (kg/m2) Smoker Gestational week 537 37–41 441 Educational level Primary High University Pregnancy complications Preterm delivery Twin pregnancy IUGR Abruptio Plasenta C-section Primary cesarean C-section indications Repeat cesarean Fetal distress Malpresentation CPD General anesthesia Male gender NICU Birth weight (g) 52500 2500–4000 44000 Labor duration (h) Hospital stay (days) C-RP (mg/dL) Hemaglobine (103 mL1) White blood cell (103 mL1) Thrombocyte (103 mL1)
30.2 ± 5.1 2 ± 0.8 0.8 ± 0.6 0.7 ± 0.6 0.2 ± 0.4 164.6 + 6.1 71.7 ± 10.8 26.5 ± 4.1 4 (20)
27.0 ± 5.3 2.1 ± 1.1 0.9 ± 1.0 0.9 ± 1.0 0.2 ± 0.4 163.2±4.6 74.2 ± 10.3 27.9 ± 4.2 6 (15)
4 (20) 16 (80) 0
3 (7.5) 35 (87.5) 2 (5)
14 (70) 5 (25) 1 (5)
24 (60) 14 (35) 2 (5)
3 (15) 1 (5) 0 0 11 (55) 7 (35)
3 (7.5) 0 2 (5) 1 (2.5) 22 (55) 12 (30)
0.037 0.551 0.621 0.718 1.000 0.306 0.386 0.211 0.718 0.101
0.855
4(36.3) 3 (27.3) 1 (9.1) 3 (27.3) 5 (45.5) 4 (19) 4 (19) 3088.4 ± 480.0 5 (23.8) 16 (76.2) 0 7.8 ± 4.6 2.2 ± 0.5 3.28 (0.65–17.59) 11.7 ± 1.7 12.9 ± 4.3 232 ± 87
10 (45.5) 7 (31.8) 1 (4.5) 4 (18.2) 4 (10) 18 (45) 5 (12.5) 3273 ± 585.8 3 (7.5) 33 (82.5) 4 (10) 8.6 ± 3.9 2.1 ± 1.0 3.11 (0.24–14.17) 12.2 ± 1.4 12.3 ± 3.1 202 ± 61
0.390 0.333 0.548 1.000 1.000 0.696 0.719 1.000 1.000 0.661 0.121 0.041 0.342 0.237 0.150 0.651 0.381 0.508 0.164 0.572 0.127
BMI, body mass index; IUGR, intrauterine growth restriction; CPD, cephalopelvic disproportion; NICU, neonatal intensive care unit; C-RP; C, reactive protein. A p values50.05 are considered as statistically significant. p values 50.05 are represented in boldface.
There are several reasons for drug therapy during pregnancy and postpartum period. One of them is to prevent a flare occurring during or after pregnancy that would be possibly harmful for both mother and fetus. The aim of drug therapy is to keep the patient at a low disease activity or in remission. The persistent active disease usually requires symptomatic treatment [7]. In one of our patients, methotrexate was replaced with corticosteroids. Patients with AS frequently have active arthritis at different stages of pregnancy. Corticosteroids with the advantage of a very fast action are suitable treatment of arthritis in pregnancy. Local injections of steroids into a limited number of actively inflamed joints can be given to AS patients [20]. Patients with AS particularly benefit from nonsteroidal anti-inflammatory drugs (NSAID). However, these treatments need to be discontinued during the last weeks of pregnancy to prevent the risk of patent ductus arteriosus. In addition, folic acid supplementation during the early stages of pregnancy should be considered in the prophylaxis of neural tube defects, predominantly for patients who have
received therapy with methotrexate or sulfasalazine before pregnancy [21]. Pregnant patients with AS need more intensive prenatal care than healthy controls. The schedule for follow-up visits depends on disease activity, and maternal and fetal risk factors present at conception. An aggravation of disease activity occurs in a majority of patients with AS in the first 6 months after labor [22]. Therefore follow up visits should be carried on during postpartum period. Postpartum exacerbation of disease activity coincides with breastfeeding period. The available literature on therapy with antirheumatic drugs during lactation is limited, and many women feel obliged to choose between breastfeeding and to control the disease [23]. There are several studies carried out on the autoimmune disease and pregnancy outcomes, but those associated with AS are limited [24]. The strength of this study includes a relatively large sample size. The weakness of our study is its retrospective nature. We were also unable to assess patients according to their trimester. One of the limitations of this study is that to best understand the effect of pregnancy on AS,
DOI: 10.3109/14767058.2015.1089432
a study would need to be conducted comparing reproductive age women who became pregnant versus those who did not, in terms of alterations in disease activity either during pregnancy or postpartum. In conclusion, adverse pregnancy and neonatal outcomes are not associated with AS, and patients may enter remission during pregnancy without aggravation of disease symptoms. Furthermore, no increase in medication appears to be required during pregnancy. We think that pregnancy outcomes of patients with AS are not different from healthy patients through close antenatal care visits.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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References 1. Exarchou S, Lindstro¨m U, Askling J, et al. The prevalence of clinically diagnosed ankylosing spondylitis and its clinical manifestations: a nationwide register study. Arthritis Res Ther 2015;17: 118. 2. Hart FD, Bell AC, Organe GS. Pregnancy in ankylosing spondylitis: a report of 2 cases. Ann Rheum Dis 1951;10:54–60. 3. Bodur H, Ataman S, Akbulut L, et al. Characteristics and medical management of patients with rheumatoid arthritis and ankylosing spondylitis. Clin Rheumatol 2008;27:1119–25. 4. Schlosstein L, Terasaki PI, Bluestone R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 1973;288:704–6. 5. Correia JA. Coping with rheumatoid arthritis or ankylosing spondylitis during pregnancy. Med Int 2009;16:180–4. 6. Lee W, Reveille JD, Weisman MH. Women with Ankylosing spondylitis: a review. Arthritis Rheum 2008;59:449–54. 7. Østensen M, Fuhrer L, Mathieu R, et al. A prospective study of pregnant patients with rheumatoid arthritis and ankylosing spondylitis using validated clinical instruments. Ann Rheum Dis 2004; 63:1212–7. 8. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361–8. 9. Lukas C, Landewe R, Sieper J, et al. Development of an ASASendorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis 2009;68:18–24.
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10. Machado P, Landewe´ R, Lie E, et al. Assessment of SpondyloArthritis International Society. Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis 2011;70:47–53. 11. Gromnica-Ihle E, Ostensen M. Pregnancy in patients with rheumatoid arthritis and inflammatory spondylarthropathies. Z Rheumatol 2006;65:209–12. 214–216. 12. Lui NL, Haroon N, Carty A, et al. Effect of pregnancy on ankylosing spondylitis: a case–control study. J Rheumatol 2011;38: 2442–4. 13. Zhou Q, Bian XM, Liu JT. Management of pregnancy with ankylosing spondylitis. Chin Med Sci J 2012;27:46–9. 14. Ostensen M, Ostensen H. Ankylosing spondylitis – the female aspect. . J Rheumatol 1998;25:120–4. 15. Fo¨rger F, Østensen M, Schumacher A, Villiger PM. Impact of pregnancy on health related quality of life evaluated prospectively in pregnant women with rheumatic diseases by the SF-36 health survey. Ann Rheum Dis 2005;64:1494–9. 16. Østensen M, Fo¨rger F, Nelson JL, et al. Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum. Ann Rheum Dis 2005;64:839–44. 17. Fo¨rger F, Villiger P, Østensen M. Pregnancy in patients with ankylosing spondylitis: do regulatory T cells play a role? Arthritis Rheum 2009;61:279–83. 18. Somerset DA, Zheng Y, Kilby MD, et al. Normal human pregnancy is associated with an elevation in the immune suppressive CD25 + CD4 + regulatory T-cell subset. Immunology 2004;112: 38–43. 19. Oliveira CR. [Ankylosing spondylitis and anesthesia]. Rev Bras Anestesiol 2007;57:214–22. 20. Sammaritano LR, Bermas BL, eds. Contraception and pregnancy in patients with rheumatic disease. Part II: Pregnancy in specific rheumatic diseases. New York: Springer Science + Business Media; 2014:151–2. 21. Chandler AL, Hobbs CA, Mosley BS, National Birth Defects Prevention Study, et al. Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity. Birth Defects Res Part Clin Mol Teratol 2012;94: 864–74. 22. Østensen M, Villiger PM, Fo¨rger F. Interaction of pregnancy and autoimmune rheumatic disease. Autoimmun Rev 2012;11: 437–46. 23. Østensen M, Motta M. Therapy insight: the use of antirheumatic drugs during nursing. Nat Clin Pract Rheumatol 2007;3:400–6. 24. Vengetesh PM, Hebbar S, Rai L. Autoimmune diseases in pregnancy: maternal and fetal outcomes. Int J Reprod Contracept Obstet Gynecol 2015;4:9–14.
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20
Pregnancy outcome in patients with ankylosing spondylitis Hakan Timur, Aytekin Tokmak, Gülenay G. Türkmen, Hasan Ali İnal, Dilek Uygur & Nuri Danışman To cite this article: Hakan Timur, Aytekin Tokmak, Gülenay G. Türkmen, Hasan Ali İnal, Dilek Uygur & Nuri Danışman (2015): Pregnancy outcome in patients with ankylosing spondylitis, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.3109/14767058.2015.1089432 To link to this article: http://dx.doi.org/10.3109/14767058.2015.1089432
Published online: 28 Sep 2015.
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Article views: 1
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20 Download by: [University of Otago]
Date: 03 October 2015, At: 22:29
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2015 Taylor & Francis. DOI: 10.3109/14767058.2015.1089432
ORIGINAL ARTICLE
Pregnancy outcome in patients with ankylosing spondylitis Hakan Timur1, Aytekin Tokmak1, Gu¨lenay G. Tu¨rkmen2, Hasan Ali _Inal3, Dilek Uygur1, and Nuri Danı¸sman1 Department of Obstetrics and Gynecology, Zekai Tahir Burak Women’s Health Research and Education Hospital, Ankara, Turkey, 2Ankara Training and Research Hospital, Ankara, Turkey, and 3Department of Obstetrics and Gynecology, Konya Training and Reseach Hospital, Konya, Turkey
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Abstract
Keywords
Objective: The aim of this study was to evaluate pregnancy outcomes in women with Ankylosing Spondylitis (AS), and the course of disease during pregnancy was also assessed. Methods: This case–control study included 60 pregnant women who delivered in our clinic between March 2007 and 2015. Twenty of them diagnosed with AS formed the study group and 40 women were chosen as the control group. These patients were chosen and reviewed by their hospital records and were evaluated retrospectively in terms of their clinical characteristics, pregnancy complications and perinatal outcomes. The Ankylosing Spondylitis Disease Activity Score (ASDAS), a new composite index to assess disease activity in AS, was used in the assessment of the patients. Result: No adverse pregnancy outcome was noted in pregnant patients with AS. Mean age of AS patients was significantly higher than the controls (p ¼ 0.037). The proportion of female fetuses was higher in pregnancies with AS compared to pregnant patients with healthy controls (p ¼ 0.041). Fourteen (70%) of 20 patients displayed decrement in ASDAS during pregnancy. Course of AS was unaltered in 6 (30%) of 20 patients during pregnancy. Otherwise, the stage of the disease during pregnancy remained unchanged in 15 (75%) of cases as postpartum exacerbation was observed in 6 (30%). The reported symptoms of patients with AS during pregnancy were arthritis and uveitis. Conclusions: Women with AS have a favorable pregnancy outcome, and pregnancy does not substantially aggravate disease activity or severity in these patients.
Ankylosing spondylitis, pregnancy, pregnancy outcome
Introduction Ankylosing spondylitis (AS) is a chronic, systemic, inflammatory disease that primarily affects the sacroiliac joints and spine. It is one of the most common seronegative spondyloarthropathies, which have a strong genetic predisposition. Besides involvement of the axial skeleton, certain peripheral joints, tendons and non-articular structures may also be affected. The prevalence of AS ranges between 0.03% and 1.8% depending on the population studied [1]. The disease affects mostly young individuals in the third and fourth decade of their lives and may therefore have a major impact on their ability to work. In the past, AS was thought to be an overwhelmingly male disease [2], but recent studies revealed that male-to-female ratio is closer to 2.5:1 [3]. The etiology of the disease still remains unclear. However, approximately 90% of people with AS express the HLA-B27 genotype, meaning there is a strong genetic association [4]. A modulation of disease activity during pregnancy is observed in several autoimmune diseases. Unlike rheumatoid Address for correspondence: Hakan Timur, M.D., Zekai Tahir Burak Women’s Health Education and Research Hospital, Talatpa¸sa Bulvarı, Hamamo¨nu¨, Altındag˘/Ankara 06230, Turkey. Tel: +90 5054601719. Fax: +90 3123065917. E-mail: [email protected]
History Received 29 June 2015 Accepted 29 August 2015 Published online 25 September 2015
arthritis, most patients with AS enter pregnancy in state of active disease, and pregnancy does not have a significant beneficial effect on the disease activity of AS [5]. In addition, postpartum exacerbation of disease activity is observed in the vast majority of the patients with AS within 6 weeks to 6 months after delivery [6]. There are limited studies with relatively low sample sizes evaluating the effects of the disease on the fetal and neonatal outcomes in AS patients. Østensen et al. reported that pregnancy outcomes are not adversely affected by the disease in AS as well as rheumatoid arthritis [7]. Although some studies performed on the disease activity during pregnancy are present in the literature considering that AS is multi-systemic and occurs in women of reproductive ages, pregnancy and neonatal outcomes of the disease merit special attention. In this retrospective analysis, we investigated the relationship between AS and pregnancy outcomes.
Materials and methods This retrospective observational case–control study consisted of pregnant patients with AS who attended the perinatology clinic of Zekai Tahir Burak Research and Education Hospital, Ankara, Turkey between March 2007 and 2015. It is a referral hospital for high-risk pregnancies in Ankara and other parts of
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central Anatolia. The study was approved by the institutional review board of the hospital. In order to identify patients with AS and their respective controls, the hospital database was used. During the study period, 20 patients with AS were diagnosed according to the modified New York criteria [8]. The AS patients were referred to rheumatology clinics of other tertiary care centers to monitor disease activity and plan their treatment during pregnancy. Data on AS activity and use of medications during pregnancy were obtained for the most recent pregnancy of each patient only. The Ankylosing Spondylitis Disease Activity Score (ASDAS), a new composite index to assess disease activity in AS, was used in the assessment of the patients [9]. Patients with AS were questioned in this survey and disease activity was determined by ASDAS-CRP calculator. This survey includes questions related to axial and peripheral symptoms, patient’s global assessment and C-reactive protein (CRP). Disease activity was classified as follows: 51.3, inactive disease; 1.3 to 52.1, moderate disease; 2.1 to 3.5, high disease and 43.5, very high disease [10]. All patients were asked to complete the questionnaire for the third trimester of the most recent pregnancy and 6 months pre-/postpregnancy. The ASDAS-CRP score and disease activity were chosen as the outcome measure for prepregnancy, pregnancy and postpartum in AS. Two controls per case were selected from the following births that took place in the same unit of the current hospital. The following clinical and demographic data were obtained by reviewing the patients files and hospital database; age, body mass index, smoking status, educational level, obstetric history, medical treatment used during pregnancy, disease duration, maternal and fetal complication during pregnancy, and neonatal outcome. Statistical analysis Statistical Package for the Social Sciences version 17.0 (SPSS Inc., Chicago, IL) was used for statistical analysis. Kolmogorov–Smirnov was used to assess normal distribution of the univariate variables. Means ± standard deviations and median (minimum–maximum) for quantitative data and numbers and percents for qualitative data were computed. Independent-samples t test was used to compare unadjusted means between groups. Non-parametric variables between groups were compared through Mann–Whitney U test. Pearson chi-square and Fisher’s exact tests were used for categorical variables. Statistical significance was set at p50.05.
Results A total of 60 patients were included in this study. Mean age of diagnosis was 24.1 + 4.1 and duration of disease was 6.2 + 2.1 years. ASDAS–CRP decreased in 14 (70%) out of 20 patients from prepregnancy to late pregnancy while 15 patients showed increment in this score during postpartum period. On the other hand disease activity remained unchanged in 15 patients with AS during pregnancy, and 6 patients increased to an upper-class disease activity in the postpartum period. Most patients entered pregnancy in a stable state, so no changes were made in the treatment. While six patients did not use any medication during pregnancy, corticosteroids
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were used by seven patients, salazopyrin by five, NSAI by four and colchicine by three of the patients (Table 1). Corticosteroid treatment instead of methotrexate was initiated in a patient who had a very high disease activity. Symptoms during pregnancy were uveitis in 2 patients and arthritis in 12 patients. Mean age of pregnant patients with AS was significantly higher than healthy controls. The proportion of female fetuses was also higher in pregnancies with AS. There was no statistically significant difference in the smoking status, rate of adverse pregnancy outcome, route of delivery, indications for C-section, birth weight of neonates, rates of admission to the Neonatal Intensive Care Unit, rates of administration of general anesthesia, mean duration of labor, levels of CRP, mean white blood cell counts and mean hemoglobin values between the study and the control group. Mean birth weight in the disease group was 3088.4 ± 480.0 and 3273 ± 585.8 g in the control group. Mean CRP level was 4.4 ± 4.1 in the disease and 3.7 ± 3.3 in the control group (Table 2). The only significant difference was the gender of the newborn (p ¼ 0.041).
Discussion Our results indicate that the majority of patients (70%) with AS were in a state of remission during pregnancy without an increase in the number or frequency of symptoms. We have also demonstrated there is no association of adverse pregnancy outcomes and AS. It is generally accepted that the course of AS is unaffected by pregnancy [11]. Lui et al. [12] evaluated the severity of back pain and morning stiffness pre, during and postpartum in patients with AS and controls. They included 19 women with AS and 33 controls in this retrospective study. A significant improvement in pains scores was reported in more than half of the patients with AS, especially in the first trimester. However, in both groups pain worsened in later stages of pregnancy, likely secondary to biomechanical loading. And postpartum pain scores in AS returned to prepartum levels. Zhou et al. [13] evaluated the interaction between pregnancy and AS in terms of pregnancy outcomes. In this retrospective study involving 12 patients, authors concluded that women with AS can be reassured that the pregnancy outcome is not significantly affected by the disease. Another retrospective, international study of reproductive performance in 939 women with AS, number of children was found on average 2.4 per woman, not different from the number of offspring in the healthy population [14]. It was also shown that the pregnancy and neonatal outcomes were not affected significantly by the disease. According to this study, perseverance of disease during pregnancy was shown to be more likely if patients entered pregnancy in a state of active disease, and improvement during pregnancy was related to a history of peripheral arthritis and a female fetus. Active disease at prepregnancy was found to be a predictor of disease exacerbation after pregnancy. Although pregnancy is associated with mitigation of disease in patients with rheumatoid arthritis, pregnant patients with AS may display worsening of symptoms such as increased pain scores, morning stiffness especially in the
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Table 1. Characteristics of patients with Ankylosing Spondylitis in pregnancy.
Age at diagnose (years) Duration of disease (years) ASDAS-CRP (prepregnancy–pregnancy) Decreased Unchanged Increased ASDAS-CRP (pregnancy–postpartum) Decreased Unchanged Increased Stage of disease (prepregnancy–pregnancy) Decreased Unchanged Increased Stage of disease(pregnancy–postpartum) Decreased Unchanged Increased Symptoms during pregnancy Uveitis Artritis Medication during pregnancy* NSAI Corticosteroid Cholchicine Salazopyrin Methotraxate Chloroquin None
Mean ± SD
Median (min–max)
24.1 + 4.1 6.2 + 2.1
23.5 (17–34) 6 (2–13)
n (%)
14 (70) 6 (30) 0 2 (10) 3 (15) 15 (75) 5 (25) 15 (75) 0 0 14 (70) 6 (30) 2 (10) 12 (60) 4 (20) 7 (35) 3 (15) 5 (25) 0 0 6 (30)
NSAI, non-steroid anti-inflammatory. *Some patients received combination therapy.
second trimester in comparison to gestational age-matched pregnancies with RA and healthy controls [7]. Fo¨rger et al. [15] showed that pregnant patients with AS had the biggest decline in health related quality of life when compared to pregnant patients with other rheumatic diseases. Despite the prospective nature of both studies, the small number of pregnant patients included was their major limitation (9 and 10 patients, respectively). Unlike these studies, we observed a significant reduction in ASDAS-CRP levels in pregnant patients with AS during pregnancy when compared to the previous sixth month of pregnancy. In comparison to the prepregnancy state the disease followed a variable course during pregnancy. Pain intensity was higher in pregnant patients with AS in the first and second trimester when compared to the third trimester. Patients with AS showed improvement in pain score and morning stiffness in the third trimester. Pregnant patients with AS demonstrated an increase in anti-inflammatory cytokines including soluble tumor necrosis factor receptor and interleukin receptor antagonist as the pregnancy proceeded from the second into the third trimester and a decrease in disease activity was observed during the corresponding time period [16]. T regulatory cells have a suppressive role on immune function, and their number increases in healthy pregnant controls as well as in patients with AS [17]. However, defective functioning rather than the number of regulatory T cells may be responsible for inadequate immunomodulation during pregnancy in patients with AS [18]. Our results showed no statistically significant difference in pregnancy and neonatal outcomes between the two groups,
consistent with results obtained from other studies [7,16]. Interestingly, the proportion of female fetuses was higher in pregnancies with AS compared to pregnant patients with healthy controls. In our study, we observed lower disease activity during pregnancy that may be due to the higher number of female fetuses. The female fetuses may have induced maternal immune tolerance. Mean age of pregnant patients with AS was also significantly higher than healthy controls. It is known that patients with chronic diseases of the spine represent specific challenges to the anesthesiologist [19]. When we looked at the anesthesia types performed in patients undergoing C-section, we observed that general anesthesia was administered in most of those patients, despite the presence of difficult airways. The symptoms of AS remain unchanged in 80% of the cases, during pregnancy. However, a worsening of symptoms is seen in 60–90% of patients up to 6 months after labor [7]. Therefore, although patients with AS may enter remission during pregnancy, the first 6 months postpartum is accompanied by exacerbation of the disease [16]. Even though none of the study subjects experienced aggravation of the disease during pregnancy, six did so postpartum. In our study, the stage of the disease during pregnancy remained unchanged in 75% of cases as postpartum exacerbation was observed in 30%. The patients with active AS who plans a pregnancy or is already pregnant require therapy compatible with pregnancy. This situation limits the choice of disease modifying antirheumatic drugs considerably. For example, methotrexate should be replaced by a drug compatible with pregnancy.
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Table 2. Pregnancy outcomes in patients with ankylosing spondylitis and healthy controls. Age (years) Gravida Parity Live children Abortion Height (cm) Weight (kg) BMI (kg/m2) Smoker Gestational week 537 37–41 441 Educational level Primary High University Pregnancy complications Preterm delivery Twin pregnancy IUGR Abruptio Plasenta C-section Primary cesarean C-section indications Repeat cesarean Fetal distress Malpresentation CPD General anesthesia Male gender NICU Birth weight (g) 52500 2500–4000 44000 Labor duration (h) Hospital stay (days) C-RP (mg/dL) Hemaglobine (103 mL1) White blood cell (103 mL1) Thrombocyte (103 mL1)
30.2 ± 5.1 2 ± 0.8 0.8 ± 0.6 0.7 ± 0.6 0.2 ± 0.4 164.6 + 6.1 71.7 ± 10.8 26.5 ± 4.1 4 (20)
27.0 ± 5.3 2.1 ± 1.1 0.9 ± 1.0 0.9 ± 1.0 0.2 ± 0.4 163.2±4.6 74.2 ± 10.3 27.9 ± 4.2 6 (15)
4 (20) 16 (80) 0
3 (7.5) 35 (87.5) 2 (5)
14 (70) 5 (25) 1 (5)
24 (60) 14 (35) 2 (5)
3 (15) 1 (5) 0 0 11 (55) 7 (35)
3 (7.5) 0 2 (5) 1 (2.5) 22 (55) 12 (30)
0.037 0.551 0.621 0.718 1.000 0.306 0.386 0.211 0.718 0.101
0.855
4(36.3) 3 (27.3) 1 (9.1) 3 (27.3) 5 (45.5) 4 (19) 4 (19) 3088.4 ± 480.0 5 (23.8) 16 (76.2) 0 7.8 ± 4.6 2.2 ± 0.5 3.28 (0.65–17.59) 11.7 ± 1.7 12.9 ± 4.3 232 ± 87
10 (45.5) 7 (31.8) 1 (4.5) 4 (18.2) 4 (10) 18 (45) 5 (12.5) 3273 ± 585.8 3 (7.5) 33 (82.5) 4 (10) 8.6 ± 3.9 2.1 ± 1.0 3.11 (0.24–14.17) 12.2 ± 1.4 12.3 ± 3.1 202 ± 61
0.390 0.333 0.548 1.000 1.000 0.696 0.719 1.000 1.000 0.661 0.121 0.041 0.342 0.237 0.150 0.651 0.381 0.508 0.164 0.572 0.127
BMI, body mass index; IUGR, intrauterine growth restriction; CPD, cephalopelvic disproportion; NICU, neonatal intensive care unit; C-RP; C, reactive protein. A p values50.05 are considered as statistically significant. p values 50.05 are represented in boldface.
There are several reasons for drug therapy during pregnancy and postpartum period. One of them is to prevent a flare occurring during or after pregnancy that would be possibly harmful for both mother and fetus. The aim of drug therapy is to keep the patient at a low disease activity or in remission. The persistent active disease usually requires symptomatic treatment [7]. In one of our patients, methotrexate was replaced with corticosteroids. Patients with AS frequently have active arthritis at different stages of pregnancy. Corticosteroids with the advantage of a very fast action are suitable treatment of arthritis in pregnancy. Local injections of steroids into a limited number of actively inflamed joints can be given to AS patients [20]. Patients with AS particularly benefit from nonsteroidal anti-inflammatory drugs (NSAID). However, these treatments need to be discontinued during the last weeks of pregnancy to prevent the risk of patent ductus arteriosus. In addition, folic acid supplementation during the early stages of pregnancy should be considered in the prophylaxis of neural tube defects, predominantly for patients who have
received therapy with methotrexate or sulfasalazine before pregnancy [21]. Pregnant patients with AS need more intensive prenatal care than healthy controls. The schedule for follow-up visits depends on disease activity, and maternal and fetal risk factors present at conception. An aggravation of disease activity occurs in a majority of patients with AS in the first 6 months after labor [22]. Therefore follow up visits should be carried on during postpartum period. Postpartum exacerbation of disease activity coincides with breastfeeding period. The available literature on therapy with antirheumatic drugs during lactation is limited, and many women feel obliged to choose between breastfeeding and to control the disease [23]. There are several studies carried out on the autoimmune disease and pregnancy outcomes, but those associated with AS are limited [24]. The strength of this study includes a relatively large sample size. The weakness of our study is its retrospective nature. We were also unable to assess patients according to their trimester. One of the limitations of this study is that to best understand the effect of pregnancy on AS,
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a study would need to be conducted comparing reproductive age women who became pregnant versus those who did not, in terms of alterations in disease activity either during pregnancy or postpartum. In conclusion, adverse pregnancy and neonatal outcomes are not associated with AS, and patients may enter remission during pregnancy without aggravation of disease symptoms. Furthermore, no increase in medication appears to be required during pregnancy. We think that pregnancy outcomes of patients with AS are not different from healthy patients through close antenatal care visits.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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