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Human Antibodies -1 (2019) 1–7 1

DOI 10.3233/HAB-180359
IOS Press

Impact of extractable nuclear antigen,

anti-double stranded DNA, antiphospholipid
antibody, and anticardiolipin antibody
positivity on obstetrical complications and
pregnancy outcomes

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Atakan Tanacana,∗ , M. Sinan Beksaca , Gokcen Orgula , Sinem Durua , Burcin Senerb and

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Ergun Karaagaoğluc
a
Division of Perinatology, Department of Obstetrics and Gynecology, Hacettepe University, Ankara, Turkey

er
b
Department of Clinical Biochemistry, Hacettepe University, Ankara, Turkey
c
Department of Biostatistics, Hacettepe University, Ankara, Turkey
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Abstract.
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BACKGROUND: Extractable nuclear antigen (ENA) and anti-double stranded DNA (anti-dsDNA) positivity and related dis-
eases like systemic lupus erythematosus, Sjögren syndrome, and other autoimmune diseases are known to be associated with
obstetrical complications and poor perinatal outcomes.
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OBJECTIVE: To demonstrate the importance of ENA, anti-dsDNA, antiphospholipid (APL), and anticardiolipin (ACL) anti-
body positivity on pregnancy outcomes.
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METHODS: Ninety one pregnant women with known ENA, anti-dsDNA, APL IgG and IgM, and ACL IgG and IgM antibody
positivity were retrospectively compared with 91 randomly selected pregnant woman in terms of obstetrical complications and
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pregnancy outcomes. Beksac Obstetrics Index-pregnancy (BOIp), calculated as (number of children + (π/10))/gravidity in the
current pregnancy, was used to compare the risk level between groups.
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RESULTS: Significant differences were found in the median maternal age, gravidity, number of previous miscarriages, and
BOIp between the groups (p = 0.04, p < 0.001, p < 0.001, and p < 0.001, respectively). Significant differences were also found
between the study and control groups in the median gestational age at birth, birth weight, and APGAR1 score (p < 0.001 for all).
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Similarly, significant differences were found between groups in the rates of intra-uterine growth restriction, oligohydramnios,
and gestational hypertension (p < 0.001, p = 0.05, and p = 0.05, respectively). There were 3 (3.3%) stillbirths in the study
group and none in the control group (p = 0.123).
CONCLUSION: We evaluated the impact of anti-dsDNA, ENA, APL, and ACL antibody positivity, which may cause immuno-
logic inflammation at placenta and thereby affect pregnancy outcomes.

Keywords: Pregnancy, extractable nuclear antigen, anti-double stranded DNA, antiphospholipid antibody, anticardiolipin anti-
body, perinatal morbidity and mortality, placental inflammation

1. Introduction 1

Extractable nuclear antigen (ENA) and anti-double 2

∗ Corresponding stranded DNA (anti-dsDNA) positivity and related 3

author: Atakan Tanacan, Hacettepe University,
Sıhhiye, Ankara, Turkey. Tel.: +90 532 353 0892; Fax: +90 312 305 diseases like systemic lupus erythematosus (SLE), 4

1998; E-mail: atakantanacan@yahoo.com. Sjögren syndrome, and other autoimmune connec- 5

ISSN 1093-2607/19/$35.00 c 2019 – IOS Press and the authors. All rights reserved
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2 A. Tanacan et al. / Impact of ENA, anti-dsDNA, APL antibody, and ACL antibody positivity on obstetrical complications

6 tive tissue diseases (CTDs) are known to be associ- who had miscarried or delivered infants before the 23rd 54

7 ated with obstetrical complications and poor perinatal gestational week were excluded due to lack of ade- 55

8 outcomes [16]. Further, positivity to antiphospholipid quate information. 56

9 (APL) and anticardiolipin (ACL) antibodies (with and The study group patients were registered to a spe- 57

10 without syndromic findings such as antiphospholipid cial antenatal care program. Necessary laboratory tests 58

11 syndrome (APS)) most probably causes placental in- such as complete blood count; clinical urine test; and 59

12 flammation and is associated with poor perinatal out- tests for blood sugar, liver function, C-reactive protein, 60

13 comes as it leads to vascular/thrombotic problems and complement components 3 and 4, activated protein- 61

14 obstetrical complications [9,26]. C resistance, anti-thrombin III activity, protein-S ac- 62

15 ENA, anti-dsDNA, ACL, and APL antibodies are tivity, lupus anticoagulant, and von Willebrand factor 63

16 widely used to initially detect autoimmune prob- antigen were also conducted during this program. Pa- 64

17 lems [5,15,29]. Subsequently, various complex anti- tients with clinical symptoms were all treated in col- 65

18 bodies are used to identify and describe the exact au- laboration with the rheumatology department (hydrox- 66

19 toimmune disorders [15,29]. Obstetricians aim to de- ychloroquine and patient-specific treatment were pro- 67

20 tect “autoimmune events” and prevent “immunologi- vided as necessary). 68

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21 cal inflammation of the placenta” (maternal-fetal in- The patients were started on LMWH (enoxaparin; 69

22 terface; mainly cellular structures of intervillous space 2000 anti-Xa IU/0.2 ml), oral prednisone (4 mg methyl- 70

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23 and endothelial tissues of spiral veins) in order to re- prednisolone), and aspirin (100 mg acetylsalicylic 71

duce perinatal morbidity and mortality [2,3,19,20]. It acid) as early as possible after they were found to be

er
24 72

25 has also been reported that low-molecular weight hep- pregnant. Pregnancy follow-up involved serial ultra-
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26 arin (LMWH), low-dose salicylic acid, and low-dose sonography, aneuploidy screening (combined or triple 74

27 corticosteroids can be used to successfully treat preg- test), fetal anatomy scanning at the 20–24th gestational 75

nancies complicated by autoimmune disorders or/and weeks, oral glucose challenge test, and weekly non-
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28 76

29 chronic inflammatory diseases along with thrombotic stress tests (after the 28th gestational week). All pa- 77

30 events and inflammatory events [2,3,19,20]. tients gave birth at Hacettepe University Hospital be- 78
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31 In the present study, we examined the association tween January 2003 and October 2017. The necessary 79

32 between positivity to these four autoantibodies – ENA, data were collected from the Perinatology Database 80
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33 anti-dsDNA, ACL, and APL – and poor perinatal out- and Hacettepe University electronic registry system. 81

34 come in pregnant women. We also studied the effects Obstetric and perinatal complications were analyzed 82
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35 of LMWH, low-dose salicylic acid, and low-dose cor- in the study group. Preterm delivery was defined as 83

36 ticosteroids on pregnancy outcomes in these cases. spontaneous onset of labor before the 37th gestational 84
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week. Fetuses were diagnosed to have intrauterine 85

growth restriction (IUGR) when their birthweight was 86

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37 2. Materials and methods below the 10th percentile. Oligohydramnios was con- 87

sidered when the sonographic amniotic fluid index was 88

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38 This retrospective study included 91 randomly se- 6 5 mm. Gestational diabetes mellitus (GDM) was 89

39 lected normal deliveries (control group) and 91 de- defined as the onset or first recognition of abnormal 90

40 liveries with known maternal positivity to ENA, anti- glucose tolerance during pregnancy, and gestational 91

41 dsDNA, APL IgG and IgM, and ACL IgG and IgM, hypertension (GHT) was defined as the development 92

42 with or without active maternal disease (study group). of new hypertension in a pregnant woman after 20 93

43 Thirty-nine patients from the latter group (42.8%) were weeks gestation without the presence of protein in the 94

44 nulliparous, while the remaining 52 (57.2%) were mul- urine or other signs of preeclampsia (blood pressure > 95

45 tiparous. All study group patients had tested positive 140/90 mm Hg). In the present study, the Beksac Ob- 96

46 for antinuclear antibody before positivity to more spe- stetrics Index-pregnancy (BOIp), calculated as (num- 97

47 cific autoantibodies was detected. The study group ber of children + (π/10))/gravidity in the current preg- 98

48 were also screened for other autoimmune antibodies nancy, was used to demonstrate the risk levels in the 99

49 (anti-parietal antibody, anti-smooth muscle antibody, control and study groups [3,4]. 100

50 and anti-mitochondrial antibody), hereditary throm- Autoantibody-positive patients were divided into 101

51 bophilia, methylenetetrahydrofolate reductase poly- two subgroups: (1) those that tested positive for only 102

52 morphisms, chronic inflammatory diseases, coagula- one and (2) those that tested positive for two or 103

53 tion disorders, anemia, and infectious diseases. Women more antibodies. Maternal age, gravidity, parity, num- 104
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A. Tanacan et al. / Impact of ENA, anti-dsDNA, APL antibody, and ACL antibody positivity on obstetrical complications 3

105 ber of previous miscarriages, gestational age at birth,

106 birthweight, APGAR scores, preterm delivery, IUGR,
107 oligohydramnios, GDM, GHT, and stillbirth rates were
108 compared between these subgroups.
109 Statistical analyses were performed using Statistical
110 Package for the Social Sciences (SPSS, version 23).
111 Data were presented as number, percentage, mean ±
112 standard deviation, or median and inter-quartile range
113 according to the distribution. Groups were compared
114 using the Student t-test, Mann-Whitney U test, or chi-
115 square test, as appropriate. p values < 0.05 were con-
116 sidered statistically significant. The study protocol has
117 been approved by the institutional ethics committee of
118 Hacettepe University (GO 18/326).

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119 3. Results

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The demographic characteristics and clinical fea-

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120

121 tures were compared between all study patients (n = Fig. 1. Linear graph of the BOIp values for the study and control
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122 91) and the randomly selected controls (antenatal care groups.
123 patients who delivered at our hospital) (n = 91). The
median maternal age of the study and control groups
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124 for the study and control groups. Finally, the median 153

125 were 31 (21–42 years) and 29 years (19–44 years), APGAR1 scores of the study and control groups were 154

respectively. The median gravidity, parity, number of 9 (0–10) and 10 (5–10), respectively. Statistically sig-
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126 155

127 previous miscarriages, and number of living children nificant differences were found between the groups in 156

128 were 3 (1–7), 1 (0–3), 1 (0–5), and 0 (0–2), respec- the median gestational age at birth, birth weight, and 157
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129 tively, for the study group and 2 (1–9), 2 (0–6), 0 (0– APGAR1 scores (p < 0.001 for all). The rates of 158

130 3), and 1 (0–6), respectively, for the control group. The some gestational risk factors and obstetrical compli- 159
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131 median BOIp scores of the study and control groups cations such as preterm delivery, IUGR, oligohydram- 160

132 were 0.14 (0.04–0.31) and 0.20 (0.08–0.41), respec- nios, GDM, and GHT were also compared between the 161
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133 tively. The median maternal age, gravidity, number of groups. The rates of preterm delivery, IUGR, oligohy- 162

134 previous miscarriages, and BOIp differed significantly dramnios, GDM, and GHT were 8.8% (8/91), 17.6% 163
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135 between groups (p = 0.04, p < 0.001, p < 0.001, (16/91), 6.6% (6/91), 8.8% (8/91), and 6.6% (6/91), 164

136 and p < 0.001, respectively). However, no signifi- respectively, for the study group and 8.8% (8/91), 1% 165
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137 cant changes were found in median parity and num- (1/91), 1% (1/91), 7.7% (7/91), and 1% (1/91), respec- 166

138 ber of living children between groups (p = 0.80 and tively, for the control group. Statistically significant 167

139 p = 0.15, respectively). Table 1 median, minimum, differences were found between groups in the rates of 168

140 and maximum values of maternal age, gravidity, par- IUGR, oligohydramnios, and GHT (p < 0.001, p = 169

141 ity, number of miscarriages, number of living chil- 0.06, and p = 0.05, respectively). However, none were 170

142 dren, BOIp, obstetric outcomes and rates of some ges- found in preterm delivery and GDM between the study 171

143 tational risk factors and obstetric complications for the and control groups (p = 0.6 and p = 0.8, respec- 172

144 study and control groups along with p-values for com- tively). Additionally, there were 3 (3.3%) stillbirths in 173

145 parisons between the study and control groups. Fig- the study group but none in the control group (p = 174

146 ure 1 shows a linear graph of the BOIp values for both 0.123). 175

147 groups. In the study group, 65 women tested positive for one 176

148 The median value of gestational age at birth for autoantibody (71.4%), while the remaining 26 women 177

149 the study and control groups was 37 (27–39 weeks) tested positive for two or more (two in 22 [24.1%], 178

150 and 38 weeks (32–41 weeks), respectively. Further, three in 1 [1.1%], and four in 3 women [3.4%]). Ta- 179

151 the median birth weight of the newborns was 2860 ble 2 shows the maternal demographic characteristics 180

152 (800–3880 g) and 3270 (2010–4200 g), respectively, and neonatal outcomes for these subgroups. No statis- 181
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4 A. Tanacan et al. / Impact of ENA, anti-dsDNA, APL antibody, and ACL antibody positivity on obstetrical complications

Table 1
Median, minimum, and maximum values of maternal age, gravidity, parity, number of miscarriages, number of living children, BOIp, obstet-
ric outcomes and rates of some gestational risk factors and obstetric complications for the study and control groups along with p-values for
comparisons between the study and control groups
Variables Autoantibody positive group (n = 91) Control group (n = 91) p-value
Maternal age (years) 31 (21–42) 29 (19–44) 0.04
Gravidity 3 (1–7) 2 (1–9) < 0.001
Parity 1 (0–3) 2 (0–6) 0.80
Number of previous miscarriages 1 (–5) 0 (0–3) < 0.001
Number of living children 0 (0–2) 1 (0–6) 0.15
BOIp 0.14 (0.04–0.31) 0.20 (0.08–0.41) < 0.001
Gestational age at birth (weeks) 37 (27–39) 38 (32–41) < 0.001
Birth weight (g) 2860 (800–3880) 3270 (2010–4200) < 0.001
1st minute APGAR score 9 (0–10) 10 (5–10) < 0.001
Preterm delivery rate 8.8% (8/91) 8.8% (8/91) 0.6
IUGR rate 17.6% (16/91) 1% (1/91) < 0.001
Oligohydramnios rate 6.6% (6/91) 1% (1/91) 0.06
GDM rate 8.8% (8/91) 7.7% (7/91) 0.8
GHT rate 6.6% (6/91) 1% (1/91) 0.05

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Stillbirth rate 3.3% (3/91) 0% (0/91) 0.123

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Table 2
Maternal demographics and neonatal outcomes in the subgroups that tested positive for only one antibody and two or more antibodies

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Positivity for one autoantibody n = 65 Positivity for two or more autoantibodies n = 26 p-value
Maternal age (years) 30.9 ± 4.730
fv 30.1 ± 5.694 0.487
Gravidity 2.9 ± 1.546 2.9 ± 1.592 0.625
Parity 0.8 ± 0.864 0.7 ± 0.788 0.401
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Number of previous miscarriages 0.9 ± 1.166 1 ± 1.356 0.752

Gestational age (weeks) 36.4 ± 1.768 36 ± 1.949 0.345
Birth weight (g) 2837 ± 502.550 2693 ± 627.604 0.524
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APGAR 1st minute 8.8 ± 2.162 8.9 ± 1.113 0.226

APGAR 5th minute 9.4 ± 2.142 9.5 ± 1.503 0.851
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182 tically significant differences were found between the are necessary for normal fetal growth [17]. Various im- 202

subgroups in terms of maternal age, gravidity, parity, munological, metabolic, infectious, and epigenetic fac-
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183 203

184 number of miscarriages, gestational age at birth, birth- tors can affect the cellular components of the inter- 204
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185 weight, and APGAR scores. No significant difference villous space (syncytiotrophoblasts, endovascular tro- 205

186 was found between subgroups in terms of various ob- phoblasts covering the tip of the spiral arteries, su- 206

stetrical complications (Table 3). Although the rates of perficial and glandular epithelial cells of the decidua,
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187 207

188 preterm delivery, IUGR, oligohydramnios, and GHT endothelial cells of the spiral veins, etc.) and may 208

were higher in the two or more autoantibody-positive cause obstetrical complications [2,3,19,20]. Entry of
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189 209

190 group, although these findings were not significant. cell debris in maternal circulation triggers inflamma- 210

191 GDM was detected in 7 of the 65 women who tested tory processes (and stimulates the maternal innate and 211

192 positive for one antibody (10.8%), and there were three humeral immune systems), which are most probably 212

193 stillbirths in this group. However, this finding was also the main reasons for impaired fetal perfusion and in- 213

194 not significant compared to those obtained for the other trauterine hypoxia [1,7]. Syncytiotrophoblasts and en- 214

195 group. dovascular trophoblasts with paternal tissue character- 215

istics are important triggers for the maternal immune 216

system [10,11]. 217

196 4. Discussion Immunological inflammation in the intervillous 218

space structures due to autoimmune antibodies with or 219

197 The placenta plays a key role in the gestational bi- without related diseases/syndromes such as SLE, Sjö- 220

198 ological processes, and balanced maternal-fetal inter- gren’s syndrome, APS, Hashimoto’s thyroiditis, scle- 221

199 action is necessary to have a normal pregnancy [22]. roderma, type-1 diabetes mellitus, rheumatoid arthri- 222

200 Thus, a stable ambience in the intervillous space tis, psoriasis, Addison’s disease, multiple sclerosis, in- 223

201 (maternal-fetal interface) and sufficient fetal perfusion flammatory bowel disease, Graves’ disease, myasthe- 224
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A. Tanacan et al. / Impact of ENA, anti-dsDNA, APL antibody, and ACL antibody positivity on obstetrical complications 5

Table 3
Gestational risk factors and obstetrical complications
Positivity for one autoantibody (n = 65) Positivity for two or more autoantibodies (n = 26) p-value
n % n %
Preterm delivery 5 7.7 3 11.5 0.684
IUGR 10 15.4 6 23.1 0.379
Oligohydramnios 3 4.6 3 11.5 0.348
GDM 7 10.8 1 3.8 0.431
GHT 4 6.2 2 7.7 1.00
Stillbirth 3 4.6 0 0 0.260

225 nia gravis, vasculitis, celiac disease, and Behçet’s dis- APS is an another immunopathological condition 266

226 ease is associated with vascular/thrombotic disorders that most probably causes placental inflammation and 267

227 and obstetrical complications [2,3,19,20]. Autoanti- is associated with poor perinatal outcomes, vascu- 268

228 bodies and/or disease-related inflammatory cytokines lar/thrombotic problems, and maternal complica- 269

229 and cell debris (e.g., lysosomal enzymes) are most tions [9,26]. APL screen IgG is an ELISA-based 270

screening test for the quantitative determination of

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230 probably responsible for destruction of the cellular 271

231 components of the intervillous space and the endothe- IgG antibodies against cardiolipin, phosphatidyl ser- 272

lial tissues of the vascular structures of the placenta ine, phosphatidyl inositol, phosphatidic acid, and co- 273

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232

233 (mainly, the spiral veins that supply blood to the inter- factor beta-2-glycoprotein I in human serum or plasma. 274

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234 villous space) [12,16]. This test is for the serological detection of primary 275

235 In the present study, we retrospectively evaluated and secondary APS [25,27]. On the other hand, anti- 276
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236 pregnant women who had tested autoimmune antibody phospholipid IgM antibodies against the same antigens 277

237 positive prior to becoming pregnant and who delivered also serve the same function [24,25]. Similarly, IgG 278
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238 at our hospital. We selected anti-dsDNA, ENA, APL, and IgM ACL antibodies are also used to diagnose or 279

239 and ACL antibody-positive patients, which are widely screen for APS and vascular thrombosis [24,27]. 280
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240 used autoimmune markers of injury to endothelial cells In addition to its antithrombotic effects, LMWH 281

241 of the vascular structures of the placenta and obstet- also has anti-inflammatory effects and has success- 282

fully been used to manage high-risk pregnancies and 283

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242 rical complications [14,18]. We focused on autoanti-

autoimmune disorders [2,3,19,20]. Low-dose corticos- 284
243 bodies rather than specific autoimmune diseases, since
teroids are also used for immune disorders during preg- 285
these are better markers to demonstrate the association
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244
nancy in order to prevent obstetrical complications 286
245 between immune system problems and pregnancy out-
and improve pregnancy outcomes [2,3,19,20]. Sali-
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287
246 comes.
cylic acid is another therapeutic agent used in preg- 288
247 Anti-dsDNA antibody is the most commonly used
nancies to improve the outcomes, especially in women 289
antibody for the diagnosis of SLE [13,23]. SLE is a
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248
with autoimmune disorders [2,3,19,20]. 290
249 disease affecting multiple organs with circulating au- In this series, we evaluated the effect of LMWH and 291
toantibodies of complex specificities [6,30]. In con-
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250
low-dose corticosteroids and salicylic acid on pregnant 292
251 trast, tests for ENA antibodies establish a diagnosis of women with anti-dsDNA, ENA, APL, and ACL anti- 293
252 autoimmune CTDs in patients with indicative clinical body positivity with or without active disease. All pa- 294
253 features [8,28]. Both these antibodies are disease spe- tients were enrolled in a special follow-up program 295
254 cific and directed against nuclear or cytoplasmic anti- prior to becoming pregnant, and we started them on 296
255 gens. LMWH (enoxaparin; 2000 anti-Xa IU/0.2 ml), oral 297
256 ENA and anti-dsDNA positivity and the related ma- prednisone (4 mg methylprednisolone), and aspirin 298
257 ternal diseases (SLE, Sjögren’s syndrome, and other (100 mg acetylsalicylic acid) as early as possible af- 299
258 CTDs) are known to be associated with obstetrical ter they became pregnant. Although the study group 300

259 complications and poor perinatal outcomes [16,21]. was under treatment, statistically significant differ- 301

260 However, the generally reported sensitivities and speci- ences were found between this group and the con- 302

261 ficities for the diseases associated with ENA and anti- trol group in terms of the median gestational age at 303

262 dsDNA antibodies are based on a large body of litera- birth, birth weight, and APGAR1 scores (p < 0.001 304

263 ture that is difficult to interpret because the studies are for all). We also found statistically significant differ- 305

264 heterogeneous in terms of design, subject population, ences between the groups in the rates of IUGR, oligo- 306

265 and the methodology [8,28]. hydramnios, and GHT (p < 0.001, p = 0.05, and p = 307
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6 A. Tanacan et al. / Impact of ENA, anti-dsDNA, APL antibody, and ACL antibody positivity on obstetrical complications

308 0.05, respectively). Additionally, there were 3 (3.3%) [6] E. Borella, A. Lojacono, M. Gatto, L. Andreoli, M. Taglietti, 354

309 stillbirths in the study group but none in the control L. Iaccarino, E. Casiglia, L. Punzi, A. Tincani and A. Do- 355
ria, Predictors of maternal and fetal complications in SLE pa- 356
310 group (p < 0.001). Comparison of the obstetrical his- tients: a prospective study, Immunologic Research 60 (2014), 357
311 tories between groups showed statistically significant 170–176. 358

312 differences between the groups in terms of the median [7] J.R. Challis, C.J. Lockwood, L. Myatt, J.E. Norman, J.F. 359

313 maternal age, gravidity, number of miscarriages, and Strauss, III. and F. Petraglia, Inflammation and pregnancy, Re- 360
productive Sciences 16 (2009), 206–215. 361
314 BOIp values (p = 0.04, p < 0.001, p < 0.001, and [8] J. Damoiseaux and J.C. Tervaert, From ANA to ENA: how to 362
315 p < 0.001, respectively). The main limitation of our proceed? Autoimmunity Reviews 5 (2006), 10–17. 363

316 study is the lack of reliable information about the rate [9] M. Deguchi, H. Yamada, M. Sugiura-Ogasawara, M. 364
Morikawa, D. Fujita, A. Miki, S. Makino and A. Murashima, 365
317 of early pregnancy losses in the study population of Factors associated with adverse pregnancy outcomes in 366
318 which the study group was a subset. women with antiphospholipid syndrome: A multicenter study, 367
319 In conclusion, we found that anti-dsDNA, ENA, Journal of Reproductive Immunology 122 (2017), 21–27. 368

320 APL, and ACL antibody positivity had unfavorable ef- [10] C. Gerard, 10 workshops on Immunology of preeclampsia, 369
Journal of Reproductive Immunology 123 (2017), 94–99. 370
321 fects on pregnancy outcomes, despite treatment with [11] B. Huppertz, G. Weiss and G. Moser, Trophoblast invasion 371
322 LMWH and low-dose corticosteroids and salicylic and oxygenation of the placenta: measurements versus pre- 372

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323 acid. sumptions, Journal of Reproductive Immunology 101 (2014), 373
74–79. 374
[12] J.V. Ilekis, E. Tsilou, S. Fisher, V.M. Abrahams, M.J. Soares,

si
375
J.C. Cross, S. Zamudio, N.P. Illsley, L. Myatt and C. Colvis, 376
Acknowledgments

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324 Placental origins of adverse pregnancy outcomes: potential 377
molecular targets: an Executive Workshop Summary of the 378
Eunice Kennedy Shriver National Institute of Child Health
fv 379
325 Special thanks to all the perinatology division staff and Human Development, American Journal of Obstetrics & 380
326 who work with devotion for the treatment of high-risk Gynecology 215 (2016), S1–S46. 381
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327 pregnancy patients. [13] D. Isenberg, J. Manson, M. Ehrenstein and A. Rahman, Fifty 382
years of anti-ds DNA antibodies: are we approaching jour- 383
ney’s end, (2007). 384
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[14] M.Y. Kim, M.M. Guerra, E. Kaplowitz, C.A. Laskin, M. Petri, 385

328 Conflict of interest D.W. Branch, M.D. Lockshin, L.R. Sammaritano, J.T. Merrill 386
and T.F. Porter, Complement activation predicts adverse preg- 387
ed

nancy outcome in patients with systemic lupus erythematosus 388

329 All authors state that they have no conflict of interest and/or antiphospholipid antibodies, Annals of the Rheumatic 389

330 in this study. Diseases (2018), annrheumdis-2017-212224. 390

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[15] W.-T. Ma, C. Chang, M.E. Gershwin and Z.-X. Lian, Devel- 391
opment of autoantibodies precedes clinical manifestations of 392
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autoimmune diseases: a comprehensive review, Journal of Au- 393

331 References toimmunity 83 (2017), 95–112. 394
[16] F. Mecacci, A. Pieralli, B. Bianchi and M.J. Paidas, The im- 395
co

332 [1] V. Abrahams, Novel mechanisms of placental inflammation pact of autoimmune disorders and adverse pregnancy out- 396

333 in obstetric antiphospholipid syndrome, Placenta 57 (2017), come, in: Semin Perinatol, Elsevier, 2007, pp. 223–226. 397
[17] A. Moffett and F. Colucci, Uterine NK cells: active regulators
un

398
334 243.
335 [2] K. Beksac, G. Orgul, G.S. Can, A. Oktem, T. Kav and M.S. at the maternal-fetal interface, The Journal of Clinical Inves- 399

336 Beksac, Management of inflammatory bowel disease and tigation 124 (2014), 1872–1879. 400

337 pregnancy using prophylactic low dose low molecular weight [18] S. Mumusoglu, M.S. Beksac, A. Ekiz, P. Ozdemir and G. 401

338 heparin and corticosteroids, Journal of Clinical & Diagnostic Hascelik, Does the presence of autoantibodies without au- 402

339 Research 11 (2017). toimmune diseases and hereditary thrombophilia have an ef- 403

340 [3] K. Beksaç, G. Örgül, M. Çağan, E. Karaağaoğlu, S. Ar- fect on recurrent pregnancy loss, The Journal of Maternal- 404

341 slan and M.S. Beksaç, Retrospective evaluation of pregnant Fetal & Neonatal Medicine 29 (2016), 2352–2357. 405

342 women with celiac disease, Journal of the Turkish German [19] G. Orgul, F. Aktoz and M.S. Beksac, Behcet’s disease and 406

343 Gynecological Association 18 (2017), 56. pregnancy: what to expect? Journal of Obstetrics and Gynae- 407

344 [4] M.S. Beksaç, E. Aydın, M. Tuğral and E. Karaağaoğlu, An cology (2017), 1–4. 408

345 obstetrics index for the assessment of risk levels of “high risk [20] G. Orgul, E.U. Ozkan, H.T. Celik and M.S. Beksac, Autoim- 409

346 pregnancy” groups, Gynecology Obstetrics & Reproductive mune hepatitis and pregnancy: report of two cases with dif- 410

347 Medicine 21 (2016). ferent maternal outcomes, Clinical and Experimental Hepa- 411

348 [5] N. Bizzaro, A. Antico, S. Platzgummer, E. Tonutti, D. Bas- tology 3 (2017), 212. 412

349 setti, F. Pesente, R. Tozzoli, M. Tampoia, D. Villalta and [21] E. Peart and M.E. Clowse, Systemic lupus erythematosus and 413

350 S.G.o.A.D.o.t.I.S.o.L. Medicine, Automated antinuclear im- pregnancy outcomes: an update and review of the literature, 414

351 munofluorescence antibody screening: A comparative study Current Opinion in Rheumatology 26 (2014), 118–123. 415

352 of six computer-aided diagnostic systems, Autoimmunity Re- [22] M. PrabhuDas, E. Bonney, K. Caron, S. Dey, A. Erlebacher, 416

353 views 13 (2014), 292–298. A. Fazleabas, S. Fisher, T. Golos, M. Matzuk and J.M. Mc- 417
 Galley Proof 1/03/2019; 14:50 File: hab–1-hab180359.tex; BOKCTP/ljl p. 7

A. Tanacan et al. / Impact of ENA, anti-dsDNA, APL antibody, and ACL antibody positivity on obstetrical complications 7

418 Cune, Immune mechanisms at the maternal-fetal interface: [27] S. Sciascia, B. Hunt, E. Talavera-Garcia, G. Lliso, M. 441
419 perspectives and challenges, Nature Immunology 16 (2015), Khamashta and M. Cuadrado, The impact of hydroxychloro- 442
420 328. quine treatment on pregnancy outcome in women with an- 443
421 [23] O. Rekvig, Anti-dsDNA antibodies as a classification crite- tiphospholipid antibodies, American Journal of Obstetrics & 444
422 rion and a diagnostic marker for systemic lupus erythemato- Gynecology 214 (2016), 273. e271–273. e278. 445
423 sus: critical remarks, Clinical & Experimental Immunology [28] C. Tani, L. Carli, S. Vagnani, R. Talarico, C. Baldini, M. 446
424 179 (2015), 5–10. Mosca and S. Bombardieri, The diagnosis and classification 447
425 [24] Q. Reynaud, J.-C. Lega, P. Mismetti, C. Chapelle, D. Wahl, of mixed connective tissue disease, Journal of Autoimmunity 448
426 P. Cathébras and S. Laporte, Risk of venous and arterial 48 (2014), 46–49. 449
427 thrombosis according to type of antiphospholipid antibodies [29] M. Van Blerk, X. Bossuyt, R. Humbel, A. Mewis, G. Ser- 450
428 in adults without systemic lupus erythematosus: a systematic vais, J.-P. Tomasi, C. Van Campenhout, L. Van Hoovels, M. 451
429 review and meta-analysis, Autoimmunity Reviews 13 (2014), Vercammen and J. Damoiseaux, Belgian recommendations on 452
430 595–608. ANA, anti-dsDNA and anti-ENA antibody testing, Acta Clin- 453
431 [25] G. Saccone, V. Berghella, G.M. Maruotti, T. Ghi, G. Rizzo, ica Belgica 69 (2014), 83–86. 454
432 G. Simonazzi, N. Rizzo, F. Facchinetti, A. Dall’Asta and S. [30] G. Yaniv, G. Twig, D.B.-A. Shor, A. Furer, Y. Sherer, O. 455
433 Visentin, Antiphospholipid antibody profile based obstetric Mozes, O. Komisar, E. Slonimsky, E. Klang and E. Lotan, A 456
434 outcomes of primary antiphospholipid syndrome: the PREG- volcanic explosion of autoantibodies in systemic lupus ery- 457
435 NANTS study, American Journal of Obstetrics & Gynecology thematosus: a diversity of 180 different antibodies found in 458
436 216 (2017), 525. e521-525. e512. SLE patients, Autoimmunity Reviews 14 (2015), 75–79. 459

on
437 [26] L.J. Scheres, M.C. Marijnen and S. Middeldorp, Aspirin
438 or heparin or both for improving pregnancy outcomes in
women with persistent antiphospholipid antibodies and recur-

si
439
440 rent pregnancy loss, The Cochrane Library (2017).

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