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Factors associated with adverse pregnancy outcomes in women with antiphospholipid syndrome: A multicenter study
Accepted Manuscript Title: Factors associated with adverse pregnancy outcomes in women with antiphospholipid syndrome: A multicenter study Authors: Masashi Deguchi, Hideto Yamada, Mayumi Sugiura-Ogasawara, Mamoru Morikawa, Daisuke Fujita, Akinori Miki, Shintaro Makino, Atsuko Murashima PII: DOI: Reference:
S0165-0378(17)30093-1 http://dx.doi.org/doi:10.1016/j.jri.2017.08.001 JRI 2485
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Journal
Received date: Revised date: Accepted date:
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of
Reproductive
Immunology
Please cite this article as: Deguchi, Masashi, Yamada, Hideto, Sugiura-Ogasawara, Mayumi, Morikawa, Mamoru, Fujita, Daisuke, Miki, Akinori, Makino, Shintaro, Murashima, Atsuko, Factors associated with adverse pregnancy outcomes in women with antiphospholipid syndrome: A multicenter study.Journal of Reproductive Immunology http://dx.doi.org/10.1016/j.jri.2017.08.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Journal of Reproductive Immunology Factors associated with adverse pregnancy outcomes in women with antiphospholipid syndrome: A multicenter study
Masashi Deguchi1, Hideto Yamada1, Mayumi Sugiura-Ogasawara2, Mamoru Morikawa3, Daisuke Fujita4, Akinori Miki5, Shintaro Makino6, Atsuko Murashima7
1 Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, JAPAN. 2 Department of Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. 3 Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-0818, Japan. 4 Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569- 8686, Japan. 5 Department of Obstetrics and Gynecology, Kitasato University Medical Center, 6-100 Arai, Kitamoto City, Saitama 364-8501, Japan. 6 Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan. 7 Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
2 Corresponding author: Professor Hideto Yamada, MD, PhD Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho Chuo-ku, Kobe 650-0017, Japan Tel: +81-78-382-6000; fax: +81-78-382-6019 E-mail: [email protected]
Highlights
LDA+UFH therapy decreased the risk of pregnancy loss in APS women
A history of pregnancy loss despite LDA+UFH increased the risk of pregnancy loss
LDA therapy prior to pregnancy decreased the risk of premature delivery
Positive tests for two or more aPLs related to premature delivery and thrombocytopenia
Low complements increased the risk of hypertenive disorder of pregnancy
Abstract The aim of this study was to understand the clinical features of antiphospholipid syndrome (APS)-complicated pregnancies and evaluate risk factors for the adverse pregnancy outcomes. This multicenter study evaluated live-birth rates according to therapy modality for APS and risk factors of pregnancy loss in 81 pregnancies. Risk factors for pregnancy complications, including premature delivery before 34 gestational weeks, hypertensive disorders of pregnancy, thrombocytopenia, and light-for-date neonate, were evaluated in 51 women who received low dose aspirin (LDA) plus unfractionated heparin (UFH) and delivered after 24 GW. The live-birth rate in APS pregnancies with LDA+UFH therapy was
3 92.6%. A multiple logistic regression analysis demonstrated that LDA+UFH therapy decreased the risk of pregnancy loss (OR 0.13, 95%CI 0.03-0.62), and that a history of pregnancy loss despite LDA+UFH therapy increased the risk of pregnancy loss (OR 8.74, 95%CI 1.69-45.2). LDA therapy prior to pregnancy decreased the risk of premature delivery (OR 0.14, 95%CI 0.03-0.69). Positive tests for two or more anti-phospholipid antibodies increased the risks of premature delivery (OR 9.61, 95%CI 1.78-51.8) and thrombocytopenia (OR 4.90, 95%CI 1.11~21.7). Laboratory findings of low complements increased the risk of hypertensive disorders of pregnancy (OR 12.1, 95%CI 1.61-91.0). Standard therapy yielded high live-birth rates. Positive tests for two or more anti-phospholipid antibodies and low complements were associated with adverse pregnancy outcomes. These results have important implications for clinicians.
Key words: antiphospholipid syndrome, pregnancy, pregnancy complications, risk factor, therapy modality
1. Introduction Antiphospholipid syndrome (APS) causes pregnancy complications (Hughes, 1993) and vascular thrombosis (Roubey et al., 1997) in patients who test positive for antiphospholipid antibody (aPL). A wide variety of pregnancy complications in APS, including recurrent early miscarriages, late pregnancy loss, hypertensive disorders of pregnancy (HDP), pre-eclampsia, placental insufficiency, fetal growth restriction, and premature delivery are recognized. Recently, antiphospholipid score, a quantitative marker representing the aPL profile, has been determined to predict thrombotic events in patients with APS (Oku et al., 2014; Otomo
4 et al., 2012). On the other hand, in terms of pregnancy complications, a positive test for lupus anticoagulant (LA) rather than anti-cardiolipin (aCL) or anti-ß2 glycoprotein I (aß2GPI) antibody has been found to be a risk factor for adverse pregnancy outcomes (Lockshin et al., 2012; Sailer et al., 2006). Other investigators have found that a positive test for aß2GPI, triple positive tests for aCL/aß2GPI/LA, a high value of aPL antibody, secondary APS, and thrombotic history are associated with adverse pregnancy outcomes (Ruffatti et al., 2011; Simchen et al., 2011). Therefore, some controversy remains about risk factors for adverse pregnancy outcomes in women with APS. This multicenter study aimed to understand the clinical features of APS-complicated pregnancies, and evaluate whether any clinical factors were associated with adverse pregnancy outcome.
2. Patients and Methods This study was approved by the institutional review boards of seven hospitals with perinatal centers in Japan, including Kobe University, Osaka Medical College, Nagoya City University, Hokkaido University, Saitama Medical University, Juntendo University, and the National Center for Child Health and Development. Clinical data were retrospectively collected from medical records of pregnant women with APS who received perinatal management and medication between November 2008 and October 2013. This study enrolled pregnancies from women who were diagnosed as having APS according to the clinical and laboratory criteria of the updated Sydney classification criteria (Miyakis et al., 2006). The clinical criteria used in the present study included vascular thrombosis and obstetrical manifestations of the following: premature delivery of a
5 morphologically normal neonate before 34 gestational weeks (GW) due to eclampsia, severe preeclampsia or placental insufficiency, unexplained miscarriage without fetal abnormality at 10 GW or later, and three or more recurrent early miscarriages. The laboratory criteria used in the present study included repeated positive tests for LA, IgG/IgM aCL, and IgG ß2 glycoprotein I-dependent anti-aCL (aCLß2GPI). A dilute Russell's viper venom time-based test (Gradipore LA Screen and LA Confirm, Gradipore Ltd., Australia) was used for LA measurements. Screen clotting times/ Confirm clotting time ratio of 1.3 (99%ile) was defined as the cut off value of LA. IgG/IgM aCL was measured using specific enzyme-linked immunosorbent assay for cardiolipin (MESACUP cardiolipin test IgG/IgM, MBL Co Ltd., Japan), based on the methods described by Harris et al. (Harris et al., 1987); 19.2 unit/ml of IgG (99%ile) and 23.4 unit/ml of IgM (99%ile) were defined as cut off values. IgG aCLß2GPI was measured using specific enzyme immunoassay for ß2GPI (Yamasa kit, Yamasa Co., Japan); 3.5 unit/ml (+6SD) was defined as the cut off value. In the present study, data for IgG aCLß2GPI were used as the measurement of aß2GPI or IgM aCLß2GPI is not commercially available in Japan. Clinical and laboratory data including maternal age, primary/secondary APS, histories of thrombosis and pregnancy, therapy modality for APS, positive testes of LA, IgG/IgM aCL, IgG aCLß2GPI, antinuclear antigen, activated partial thromboplastin time (aPTT) prolongation, and low complements (C3, C4, or CH50), and therapy modality were collected. Information about chromosome karyotype of the conceptus in cases of pregnancy loss was also obtained. Live-birth rates according to therapy modality for APS and risk factors for pregnancy loss were evaluated for all enrolled pregnancies. Risk factors for pregnancy
complications
including
premature
delivery
before
34
GW,
HDP,
6 thrombocytopenia during pregnancy, and light-for-date (LFD) neonate were evaluated for women who received standard APS therapy of low-dose aspirin (LDA) plus unfractionated heparin (UFH), and delivered after 24 GW. The present study focused on the preterm birth before 34 GW, because the updated Sydney classification criteria adopt the preterm birth before 34 GW as one of the clinical criteria. HDP was defined as an in-hospital systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, based on the average of at least apart two measurements, using the same arm. LFD was defined as a birthweight less than 10 percentile. Fisher’s exact and Mann-Whitney tests were used for comparison. Univariate and multivariate logistic regression analyses were performed to identify independent factors yielding odds ratios (OR) and 95% confidence intervals (CI). Covariates with a significant univariate test (p <0.05) were selected as candidates for multivariate analysis. The number of variables in the final model of multivariable analyses was restricted to two covariates based on the case number, to avoid overfitting in multivariable logistic regression analyses. When the sample number of one of four comparative arms was zero in the univariate analysis, Fisher’s exact test was applied to calculate p-values and OR; these covariates were not selected further for multivariable analyses. Statistical analyses were performed using GraphPad Prism version 6 and R statistics version 3; p-values <0.05 were considered significant.
3. Results In total, 81 pregnancies from 69 women with APS were enrolled in the present study: 24 pregnancies from Kobe University Hospital; 15 from Nagoya City University
7 Hospital, 14 from Hokkaido University Hospital, 13 from Osaka Medical College Hospital, 10 from National Center for Child Health and Development, three from Saitama Medical University Hospital, and three from Juntendo University Hospital. Maternal age (mean ± SD) at pregnancy was 34.1 ± 4.0 years. They had a history of median three (range 0-7) gravida, 0 (0-2) para, and two (0-7) pregnancy losses. Twenty-four women had a history of thrombosis. The 81 pregnancies consisted of 45 pregnancies from women with primary APS and 36 from women with secondary APS. Secondary APS included 35 women with systemic lupus erythematosus (SLE) and one with autoimmune hepatitis. None had hypertensive disorder or antihypertensive medications at the time of pregnancy diagnosis.
3.1 Pregnancy outcomes and therapy modality Table 1 shows live-birth rates according to therapy modality in 81 APS complicated pregnancies. According to therapy modality for APS, the 81 pregnancies were divided into six groups as the following: none (n=3), LDA alone (n=7), UFH alone (n=4), LDA plus danaparoid (LDA+danaparoid, n=1), LDA plus UFH (LDA+UFH, n=54), and LDA plus UFH plus high dose intravenous immunoglobulin (HIVIg) before 17 GW (LDA+UFH+HIVIg, n=12). Doses of 81 or 100 mg/day of LDA, median 10000 (range 5000-24000) IU/day of UFH, and 2500 IU/day of danaparoid were administered. HIVIg (20 g/day, 5 consecutive days, total 100 g) was performed at median 6 (5-16) GW. Forty-three women received median 10 (5-50) mg/day of prednisolone (PSL), and one received pulse methyl-PSL (500 mg/day, 3 days) additionally due to a flare of SLE. Three of four women who received UFH only had
8 suspected aspirin allergy. Seven women who received LDA only did not consent to continuous UFH therapy. A total 67 of 81 pregnancies ended in live births, yielding the live-birth rate of 82.7%. The live-birth rate (92.6%) in pregnancies with LDA+UFH therapy did not statically differ from 71.4% with LDA alone (p=0.14), 75.0% with UFH alone (p=0.31), or 75.0% with LDA+UFH+HIVIg (p=0.11) (Tab. 1). Eight pregnant women who had experienced pregnancy loss despite LDA+UFH therapy received LDA+UFH+HIVIg therapy in the index pregnancy, yielding the live-birth rate of 62.5% (5/8). Gestational weeks at delivery in the 67 live births were compared as shown in Figure 1. The gestational week at delivery in pregnancies with LDA+UFH (median 36, range 24-41 GW) or pregnancies with LDA+UFH+HIVIg therapy (34, 26-39 GW) was significantly (p<0.05) shorter than that with LDA alone (40, 36-41 GW). Fourteen pregnancies ended in pregnancy losses: four spontaneous miscarriages before 10 GW at median 7 (range 6-9) GW, eight spontaneous miscarriages at median 21 (10-22) GW, and two stillbirths at 26 and 27 GW. Eleven of the 14 conceptuses of pregnancy losses carried normal chromosome karyotypes; two carried abnormal karyotypes; and one was unknown. 3.2 Risk factors for pregnancy loss To identify risk factors associated with pregnancy loss in women with APS, a stepwise logistic regression analysis was performed for 67 pregnancies ending in live births and 14 pregnancies ending in miscarriages/stillbirths. Maternal age at pregnancy, primary/secondary APS, therapy modality, positive testes for aPL, antinuclear antigen, aPTT prolongation, and low complements were assessed. Univariate logistic regression analyses
9 identified, a history of pregnancy loss despite LDA+UFH therapy (OR 8.59, 95%CI 1.69-43.8, p<0.05) and LDA+UFH therapy (OR 0.14, 95%CI 0.03-0.57, p<0.01) as factors associated with pregnancy loss in the index pregnancy (Table 2). Multiple logistic regression analysis demonstrated that LDA+UFH therapy (OR 0.13, 95%CI 0.03-0.62, p<0.05) was an independent factor that decreased risks of pregnancy loss, and that a history of pregnancy loss despite LDA+UFH therapy was an independent factor that increased risks of pregnancy loss (OR 8.74, 95%CI 1.69-45.2, p<0.01). 3.3 Risk factors for pregnancy complications in women with LDA+UFH therapy Risk factors for pregnancy complications, including premature delivery before 34 GW, HDP, thrombocytopenia, and LFD neonate were evaluated for 51 pregnant women who received LDA+UFH therapy and delivered after 24 GW. These 51 pregnancies comprised 50 live births and one stillbirth at 26 GW. Women who received HIVIg therapy were excluded from this analysis. 3.3.1 Risk factors for premature delivery before 34 GW Table 3 shows risk factors for premature delivery before 34 GW. Univariate logistic regression analyses identified, a history of two or more pregnancy losses at 10 GW or later (OR 22.8, 95%CI 1.1-475, p<0.05), LDA therapy prior to pregnancy (OR 0.27, 95%CI 0.07-0.97, p<0.05), positive tests for LA (OR 7.64, 95%CI 1.79-32.6, p<0.01), IgG aCLß2GPI (OR 19.1, 95%CI 2.25-161, p<0.01), 2 or more aPL (OR 5.38, 95%CI 1.28-22.6, p<0.05), and aPTT prolongation (OR 12.5, 95%CI 2.41-64.9, p<0.01), as risk factors for premature delivery before 34 GW Multiple logistic regression analysis demonstrated that LDA therapy prior to pregnancy (OR 0.14, 95%CI 0.03-0.69, p<0.05) was an independent factor that decreased
10 risks of premature delivery before 34 GW, whereas a positive test for two or more anti-phospholipid antibodies (OR 9.61, 95%CI 1.78-51.8, p<0.05) was an independent factor that increased risks of premature delivery. Maximum Chi-squared tests revealed a lowest p-value (p=0.001) of IgG anti-cardiolipin β2 glycoprotein I for the preterm birth before 34 GW, and a lowest p-value (p=0.023) of LDA prior to pregnancy for the preterm birth before 33 GW.
3.3.2 Risk factors for hypertensive disorders of pregnancy Table 4 shows risk factors for HDP. Univariate logistic regression analyses identified, maternal age (OR 0.80 95%CI 0.65-0.97, p<0.05), PSL therapy (OR 6.93, 95%CI 1.30-37.0, p<0.05), and low complements (OR 13.0, 95%CI 1.94-87.1, p<0.05), as risk factors for HDP. Multiple logistic regression analysis demonstrated that laboratory findings of low complements (OR 12.1, 95%CI 1.61-91.0, p<0.05) was an independent factor that increased risks of HDP, whereas maternal age (OR 0.79, 95%CI 0.63-0.997, p<0.05) was an independent factor that decreased risks of HDP. 3.3.3 Risk factors for thrombocytopenia Table 5 shows risk factors for thrombocytopenia defined as less than 12 × 104/µL platelet counts during pregnancy. Univariate logistic regression analyses identified, secondary APS (OR 5.25, 95%CI 1.43-19.2, p<0.05), a history of three or more pregnancy losses before 10 GW
(OR 0.19, 95%CI 0.04-0.98, p<0.05), PSL therapy (OR 5.5, 95%CI 1.44-21.0,
p<0.05), positive tests for IgG aCLß2GPI (OR 9.1, 95%CI 1.78-46.4, p<0.01) and two or more aPL (OR 6.29, 95%CI 1.5-26.3, p<0.05), as risk factors for thrombocytopenia.
11 Multiple logistic regression analysis demonstrated that a positive test for two or more anti-phospholipid antibodies (OR 4.90, 95%CI 1.11-21.7, p<0.05) and secondary APS (OR 3.96, 95%CI 1.002-15.7, p<0.05) were independent factors that increased risks of thrombocytopenia during pregnancy. 3.3.4 Risk factors for light-for-date neonate Table 6 shows risk factors for LFD neonate. Univariate logistic regression analyses found, secondary APS (OR 6.67, 95%CI 1.14-39.1, p<0.05) and aPTT prolongation (OR 23.6, 95%CI 1.27-439, p<0.05), as risk factors for LFD. Multiple logistic regression analysis was not performed as aPTT prolongation was observed in all seven pregnancies with LFD.
4. Discussion It is acknowledged worldwide that LDA plus UFH or low molecular heparin (LMWH) therapy is recommended as a standard therapy for APS-complicated pregnancy (ACOG, 2011; Fouda et al., 2011; Laskin et al., 2009; RCOG, 2011). In the present multicenter study, LDA+UFH or LDA+UFH+HIVIg therapy was performed in 81.5% (66/81) of APS-complicated pregnancies. UFH but not LMWH was used in these pregnancies, because LMWH therapy for APS-complicated pregnancy is not covered by medical insurance in Japan. The live-birth rate of pregnancies with LDA+UFH or LDA+UFH+HIVIg therapy was high (88.1%, 59/66). Multiple regression analysis demonstrated that use of LDA+UFH therapy significantly decreased the risk of pregnancy loss. However, the live-birth rate with LDA+UFH+HIVIg therapy (75.0%) was relatively low compared with that with LDA+UFH therapy (92.6%). This may be because eight of the 12 pregnant women who received LDA+UFH+HIVIg therapy had a history of pregnancy loss despite LDA+UFH therapy; this
12 group may be considered severe cases of APS. A randomized controlled trial has shown live-birth rates in APS-complicated pregnancies with therapy of LDA alone and LMWH alone are 72.1% and 86.3%, respectively (Alalaf, 2012). The live-birth rate with LDA alone (71.4%) or UFH alone (75.0%) in the present study corresponded with those previously reported live-birth rates. Generally, 80-90% of women with APS have live births with LDA+UFH therapy, whereas the remainder is refractory to LDA+UFH therapy failing to have healthy neonates. This condition is called aspirin-heparin resistant APS (AHRAPS) (Shimada et al., 2010). In the present study, a history of pregnancy loss despite LDA+UFH therapy increased the risk of pregnancy loss in the subsequent pregnancy. In addition to standard LDA+UFH therapy, therapies such as HIVIg may be necessary to improve pregnancy outcomes in women with AHRAPS. In the present study, the eight pregnant women with a history of pregnancy loss despite LDA+UFH therapy received LDA+UFH+HIVIg therapy, yielding the live-birth rate of 62.5% (5/8). HIVIg therapy has been first performed in a pregnant woman with a positive LA test and a history of nine recurrent miscarriages (Carreras et al., 1988). A randomized controlled trial has evaluated the efficacy of LDA+UFH plus 1 g/kg body weight of intravenous immunoglobulin (IVIg) therapy compared with LDA+UFH therapy in 16 pregnant women with APS, and found no difference in treatment efficacy (Branch et al., 2000). However, another investigator has reported the live-birth rate of 80% (8/10) in women with AHRAPS who receive 1 g/kg body weight of IVIg therapy (Triolo et al., 2004). Further randomized controlled studies are necessary to determine the efficacy of LDA+UFH+HIVIg therapy in women with AHRAPS.
13 Risk factors for pregnancy complications including premature delivery before 34 GW, HDP, thrombocytopenia, and LFD neonate were evaluated for 51 pregnancies with LDA+UFH therapy that ended after 24 GW. It was found that positive tests for two or more anti-phospholipid antibodies were independent risk factors for premature delivery before 34 GW and thrombocytopenia, and that laboratory findings of low complements and younger age were independent risk factors for HDP. In the present study, all pregnancies with positive tests for LA and IgG aCLß2GPI ended in premature delivery before 34 GW. Likewise, a study has shown that poor pregnancy outcomes are associated with a positive test for two or more aPLs (Ruffatti et al., 2009). Other investigators have found a positive test for aCLß2GPI/aß2GPI is associated with poor pregnancy outcomes (Katano et al., 1996; Matsuki et al., 2015; Simchen et al., 2011), while European and American studies have found LA but not aß2GPI as a predictor of adverse pregnancy outcomes in women with APS (Lockshin et al., 2012; Sailer et al., 2006). Commencement of LDA therapy prior to pregnancy was found to be an independent factor that decreased risks for premature delivery before 34 GW. The present study is the first report that shows an advantage of LDA therapy prior to the conception. It is hypothesized that LDA in early pregnancy suppresses COX-1 and reduces thromboxane A2 production from trophoblast cells and vasoconstriction (Askie et al., 2007; Groeneveld et al., 2013; Lambers et al., 2009). LDA therapy commencing prior to the conception in women with APS may stimulate invasion of the uterine spiral arteries and improve placental blood flow, thus reducing the risk for premature delivery. It has been reported that low complements are associated with low birth weight and prematre delivery in women with APS (De Carolis et al., 2012, 2010). The present study is
14 the first report demonstrating that low complements increase the risk for hypertension in APS-complicated pregnancy. Seventeen pregnancies from women with autoimmune diseases (secondary APS) were included in 51 study subjects, and secondary APS was also identified as a risk factor for LFD neonate in univariate logistic regression analysis. Therefore, the disease activity of autoimmune diseases might affect the risk for these pregnancy complications. The multivariate analysis demonstrated that a positive test for two or more anti-phospholipid antibodies was found to be an independent risk factor for thrombocytopenia during pregnancy, while a positive test for aCLß2GPI IgG was also associated with thrombocytopenia in the univariate analysis. Thrombocytopenia is common symptom that is not included in the APS diagnostic criteria. An association between IgG aß2GPI and thrombocytopenia has been reported in women with SLE (Cucurull et al., 1999). A recent review has shown that the direct binding of aβ2GPI antibodies or aβ2GPI-β2GPI complexes to platelets is a possible cause of thrombocytopenia (Baroni et al., 2017). The results demonstrated in the present study have important implications for clinicians. However, this study has some potential limitations. This study was designed as a retrospective study, although all subjects had undergone workup for aPL prior to pregnancy. The number of variables in multivariable analyses was restricted to two covariates based on the case number. Covariates with high OR determined by univariate analyses might be related to risks for adverse pregnancy outcomes. The subjects of this study were mixed population with varied APS-related background. The evaluation of treatment efficacy in heterogenous
15 subjects was difficult. Prospective randomized case-controlled studies are necessary to confirm the conclusions of the present study in future.
Funding This work was supported by Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan (25080501) and the Japan Agency for Medical Research and Development (AMED).
Conflict of interest None of the authors have any conflicts of interest to declare.
Data are presented as box-and-whisker plots (25th and 75th percentile; 5th and 95th percentile; and median).
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19 antiphospholipid syndrome patients with history of severe pregnancy complications. Mod. Rheumatol. 25, 215–218. doi:10.3109/14397595.2014.942503 Miyakis, S., Lockshin, M.D., Atsumi, T., Branch, D.W., Brey, R.L., Cervera, R., Derkesen, R.H.W.M., De Groot, P.G., Koike, T., Meroni, P.L., Reber, G., Shoenfeld, Y., Tincani, A., Vlachoyiannopoulos, P.G., Krilis, S.A., 2006. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306. doi:10.1111/j.1538-7836.2006.01753.x Oku, K., Amengual, O., Atsumi, T., 2014. Antiphospholipid scoring : significance in diagnosis and prognosis. Lupus 23, 1269–1272. doi:10.1177/0961203314537361 Otomo, K., Atsumi, T., Amengual, O., Fujieda, Y., Kato, M., Oku, K., Horita, T., Yasuda, S., Koike, T., 2012. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum. 64, 504–512. doi:10.1002/art.33340 RCOG, N., 2011. RCOG: the investigations and treaments of couples with recurrent first-trimester and second-trimester miscarriage. NICE Guidel. Roubey, R.A., Hoffman, M., Ginsburg, K., Liang, M., Newcomer, L., Al., E., Kittner, S., Gorelick, P., Love, P., Santoro, S., Roubey, R., Willems, G., Janssen, M., Pelsers, M., Al., E., Takeya, H., Mori, T., Gabazza, E., Al., E., Rand, J., Wu, X., Andree, H., Al., E., Rao, L., Hoang, A., Rapaport, S., Papa, N. Del, Guidali, L., Spatola, L., Al., E., Simantov, R., LaSala, J., Lo, S., Al., E., Kornberg, A., Blank, M., Kaufman, S., Shoenfeld, Y., Schved, J.-F., Gris, J.-C., Ollivier, V., Wautier, J.-L., Tobelem, G., Caen, J., Cuadrado, M.,
20 Lopez-Pedrera, C., Khamashta, M., Al., E., Ginsberg, J., Demers, C., Brill-Edwards, P., Al., E., Pradier, O., Surquin, M., Stordeur, P., Al., E., 1997. From antiphospholipid syndrome
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doi:10.1016/S0140-6736(05)63936-0 Ruffatti, A., Tonello, M., Cavazzana, A., Bagatella, P., Pengo, V., 2009. Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome
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doi:10.1111/j.1600-0412.2011.01236.x; 10.1111/j.1600-0412.2011.01236.x Triolo, G., Ferrante, A., Accardo-Palumbo, A., Ciccia, F., Cadelo, M., Castelli, A., Perino, A., Licata,
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2004.
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22 Figure legends Figure 1
Gestational weeks at delivery of live birth according to therapy modality.
23 Table 1 Live-birth rates according to therapy modality
Pregnancy outcome Pregnancy loss (number of conceptus with normal
Therapy modality
Number of
chromosome,
Number of
pregnancies
abnormal
Live
pregnancies
with PSL
chromosome,
birth
(*)
therapy (*)
unknown)
Live-birth
P-value
rate (%)
None
3 (1)
N.A.
3 (2, 0, 1)
0
0
LDA alone
7 (2)
5 (2)
2 (2, 0, 0)
5
71.4
a
a v.s. c p=0.14
UFH alone
4 (1)
2 (1)
1 (1, 0, 0)
3
75.0
b
b v.s. c LDA+danaparoid
1 (1)
1 (1)
1 (0, 1, 0)
0
0
LDA+UFH
54 (4)
24 (4)
4** (4, 0, 0)
50
92.6
LDA+UFH+HIVIg
12 (8)
11 (7)
3 (2, 1, 0)
9
75.0
81 (17)
43 (15)
14 (11, 2, 1)
67
82.7
14
67
p=0.31 c
Total total
81
c v.s. d d
p=0.11
LDA, low dose aspirin; UFH, unfractionated heparin; HIVIg, a high dose intravenous immunoglobulin; PSL, prednisolone; N.A., not applicable. (*) Parenteses indicate numbers of pregnancies from women who have experienced pregnancy loss despite LDA+UFH therapy. ** One case with stillbirth at 26 gestational weeks is included.
24 Table 2 Risk factors for pregnancy loss
Univariate
Multivariate
logistic Clinical factors
logistic
regression
Pregnan
regression
cy
Live
OR
loss
birth
P-val
(95%CI
P-val
(95%CI
(n=14)
(n=67)
ue
)
ue
)
1.06 Maternal age at pregnancy (years, mean±SD)
Secondary APS
33.3±4.
34.3±3
6
.8
(0.92 ~ 0.404
1.23)
28
1.86
8
(41.8
(0.57 ~
(57.1%)
%)
0.303
6.03)
History of thrombosis and pregnancy
History of thrombosis
7 (50%)
History of 3 or more pregnancy loss before 10 GW
17
2.94
(25.4
(0.78 ~
%)
0.111
23
0.32
2
(34.3
(0.09 ~
(14.3%)
%)
0.088
History of 2 or more pregnancy loss at 10 GW or later History of premature birth delivery 34 GW Nulliparity
11.1)
1.18) 4.07
4 (28.6%)
(0.62 ~ 6 (9%)
0.145
26.9)
13
0.69
2
(19.4
(0.16 ~
(14.3%)
%)
8
36
(57.1%)
(53.7
0.628
3.06) 1.15
0.816
(0.35 ~
OR
25 %)
3.67)
15
1.39 (0.36 ~
History of hypertensive
4
(22.4
disorders of pregnancy
(28.6%)
%)
History of pregnancy loss despite LDA+UFH therapy
0.637
5.39)
9
8.59
8.74
8
(13.4
(1.69 ~
(1.69 ~
(57.1%)
%)
0.010
43.8)
0.010
45.2)
Therapy modality
LDA+UFH
PSL
HIVIg
7 (50%)
7 (50%)
59
0.14
0.13
(88.1
(0.03 ~
(0.03 ~
%)
0.006
0.57)
36
0.86
(53.7
(0.27 ~
%)
0.800
2.73)
9
1.76
3
(13.4
(0.34 ~
(21.4%)
%)
0.501
9.10)
Positive test of anti-phospholipid antibody
Lupus anticoagulant
IgG/IgM anti-cardiolipin
33
1.36
7
(50.8
(0.40 ~
(58.3%)
%)
7 (70%)
IgG anti-cardiolipin β2 glycoprotein I
7 (50%)
Two or more anti-phospholipid antibodies
0.627
4.66)
34
1.44
(61.8
(0.35 ~
%)
0.611
5.90)
36
0.83
(54.5
(0.26 ~
%)
0.758
2.65)
35
1.65
9
(52.2
(0.52 ~
(64.3%)
%)
0.400
5.25)
0.011
0.62)
26 Laboratory findings Positive test for antinuclear antibody
55
2.40
12
(83.3
(0.48 ~
(92.3%)
%)
0.288
Activated partial thromboplastin time prolongation
Low complements
12.1) 1.50
9
36
(69.2%)
(60%)
(0.44 ~ 0.519
5.15)
37
0.56
6
(60.7
(0.16 ~
(46.2%)
%)
0.362
1.96)
GW, gestational weeks; LDA, low dose aspirin, UFH, unfractionated heparin; APS, anti-phospholipid syndrome; PSL, prednisolone; HIVIg, a high dose intravenous immunoglobulin； OR, odds ratio; CI, confidence interval.
27 Table 3 Risk factors for premature delivery before 34 GW in women with LDA+UFH therapy
Prematu Clinical factors
Univariate
Multivariate
re
Delive
logistic
logistic
delivery
ry at
regression
regression
before
34 GW
34 GW
or later
P-val
(95%C
P-val
(95%CI
(n=14)
(n=37)
ue
I)
ue
)
OR
OR
1.00 Maternal age at pregnancy (years, mean±SD)
Secondary APS
34.4±3.
34.4±4
4
.2
(0.86 ~ 0.986
1.17)
12
1.16
5
(32.4
(0.32 ~
(35.7%)
%)
0.824
4.21)
History of thrombosis and pregnancy
History of thrombosis
8
1.45
4
(21.6
(0.36 ~
(28.6%)
%)
History of 3 or more pregnancy loss before 10 GW
0.603
16
0.22
2
(43.2
(0.04 ~
(14.3%)
%)
0.068
History of 2 or more pregnancy loss at 10 GW or later History of premature delivery before 34 GW Nulliparity
5.87)
1.12) 22.8
3 (21.4%)
(1.10 ~ 0 (0%)
0.018
475)
5
1.07
2
(13.5
(0.18 ~
(14.3%)
%)
0.943
6.26)
9
19
0.41
1.70
*
28 (64.3%)
(51.4
(0.45 ~
%)
6.46)
5
1.07 (0.18 ~
History of hypertensive
2
(13.5
disorders of pregnancy
(14.3%)
%)
0.943
6.26)
Therapy modality
LDA prior to pregnancy
PSL
25
0.27
5
(67.6
(0.07 ~
(35.7%)
%)
0.045
(0.03 ~
0.97)
16
1.31
7
(43.2
(0.38 ~
(50.0%)
%)
0.666
0.14 0.015 0.69)
4.52)
Positive test of anti-phospholipid antibody
Lupus anticoagulant
IgG/IgM anti-cardiolipin IgG anti-cardiolipin β2 glycoprotein I
12
7.64
11
(32.4
(1.79 ~
(78.6%)
%)
antibodies
32.6)
18
1.06
7
(48.6
(0.31 ~
(50.0%)
%)
0.931
19.1
13
(40.5
(2.25 ~
(92.9%)
%)
0.007
161)
15
5.38
11
(40.5
(1.28 ~
(78.6%)
%)
0.022
*
3.61)
15
Two or more anti-phospholipid
0.006
* 9.61 (1.78 ~
22.6)
0.009 51.8)
Laboratory findings Positive test for antinuclear antibody Activated partial
31
0.71
11
(83.8
(0.15 ~
(78.6%)
%)
0.664
3.33)
12
12
0.003
12.5
*
29 thromboplastin time
(85.7%)
(32.4
(2.41 ~
%)
64.9)
4
1.37
2
(10.8
(0.22 ~
(14.3%)
%)
prolongation
Low complements
0.732
8.5)
* not selected for multiple logistic regression analysis GW, gestational weeks; APS, anti-phospholipid syndrome; LDA, low dose aspirin; PSL, prednisolone; OR, odds ratio; CI, confidence interval.
30 Table 4 Risk factors for hypertenive disorder of pregnancy in women with LDA+UFH therapy
Clinical factors
Univariate
Multivariate
Hypertension in
logistic
logistic
pregnancy
regression
regression
OR Present Absent (n=10)
Maternal age at pregnancy (years, mean±SD)
(n=41)
31.7±3
35.0±3
.8
.8
6
11
P-val
(95%CI
P-val
(95%CI
ue
)
ue
)
0.026
)
)
4
8
0.80
0.79
(0.65 ~
(0.63 ~
0.97)
4.09
(60.0% (26.8% Secondary APS
(0.97 ~ 0.055
17.2)
History of thrombosis and pregnancy 2.75
(40.0% (19.5% History of thrombosis
)
)
History of 3 or more
1
17
pregnancy loss before 10
)
)
History of 2 or more
1
2
pregnancy loss at 10 GW or later History of premature
(0.62 ~ 0.181
(0.02 ~ 0.092
)
2
5
1.36) 2.17
(10.0% (4.88% )
12.1) 0.16
(10.0% (41.5%
GW
OR
(0.18 ~ 0.546
26.6) 1.80
(20.0% (12.2%
(0.29 ~
delivery before 34 GW
)
)
0.524
11.0)
Nulliparity
7
21
0.292
2.22
0.048
0.997)
31 (70.0% (51.2%
History of hypertensive disorders of pregnancy
(0.50 ~
)
)
9.81)
3
4
3.96
(30.0% (9.76% )
)
5
25
(0.72 ~ 0.113
21.7)
Therapy modality 0.64
(50.0% (61.0% LDA prior to pregnancy
)
)
8
15
(0.16 ~ 0.529
6.93
(80.0% (36.6% PSL
)
)
6
17
2.57) (1.30 ~
0.023
37.0)
Positive test of anti-phospholipid antibody 2.12
(60.0% (41.5% Lupus anticoagulant
)
)
5
20
(0.52 ~ 0.297
1.05
(50.0% (48.8% IgG/IgM anti-cardiolipin IgG anti-cardiolipin β2
)
)
8
20
)
)
Two or more
6
20
anti-phospholipid antibodies
(0.26 ~ 0.945
(0.79 ~ 0.091
)
8
34
22.2) 1.58
(60.0% (48.8% )
4.18) 4.2
(80.0% (48.8%
glycoprotein I
8.67)
(0.39 ~ 0.526
6.42)
Laboratory findings Positive test for antinuclear antibody
0.82
(80.0% (82.9% )
)
(0.14 ~ 0.828
4.74)
*
32 Activated partial thromboplastin time prolongation
7
17
3.29
(70.0% (41.5% )
)
4
2
(0.74 ~ 0.116
(40.0% (4.88% Low complements
)
)
0.008
14.6) 13.0
12.1
(1.94 ~
(1.61 ~
87.1)
0.016
91.0)
* not selected for multiple logistic regression analysis GW, gestational weeks; APS, anti-phospholipid syndrome; LDA, low dose aspirin; PSL, prednisolone; OR, odds ratio; CI, confidence interval.
33 Table 5 Risk factors for thrombocytopenia during pregnancy in women with LDA+UFH therapy
Univariate
Multivariate
Thrombocytope
logistic
logistic
nia
regression
regression
Clinical factors
OR
OR
Present
Absent
P-val
(95%C
P-val
(95%CI
(n=15)
(n=36)
ue
I)
ue
)
1.11 Maternal age at pregnancy (years, mean±SD)
Secondary APS
33.2±3
34.9±4
.1
.2
(0.95 ~ 0.178
1.31)
8
5.25
9
(22.2%
(1.43 ~
0.049
(1.002 ~
(60%)
)
19.2)
6
15.7)
5
7
0.012
3.96
History of thrombosis and pregnancy 2.07
(33.3% (19.4% History of thrombosis
)
)
History of 3 or more
2
16
pregnancy loss before 10
)
History of 2 or more
2
or later History of premature delivery before 34 GW Nulliparity
0.292
)
8.02) 0.19
(13.3% (44.4%
GW pregnancy loss at 10 GW
(0.53 ~
(0.04 ~ 0.047
0.98) 5.38
(13.3%
1
)
(2.8%)
(0.45 ~ 0.184
64.52)
6
0.36
1
(16.7%
(0.04 ~
(6.7%)
)
10
18
(66.7%
(50%)
0.361
3.26) 2.00
0.280
(0.57 ~
*
34 ) 2 History of hypertensive disorders of pregnancy
7.03) 5
0.95
(13.3% (13.9% )
)
8
22
(0.16 ~ 0.958
5.56)
Therapy modality 0.73
(53.3% (61.1% LDA prior to pregnancy
)
)
11
12
(0.22 ~ 0.608
5.5
(73.3% (33.3% PSL
)
)
10
13
2.45) (1.44 ~
0.013
21.0)
*
Positive test of anti-phospholipid antibody 3.54
(66.7% (36.1% Lupus anticoagulant
IgG/IgM anti-cardiolipin IgG anti-cardiolipin β2 glycoprotein I
)
antibodies
0.051
12.6)
16
1.88
9
(44.4%
(0.55 ~
(60%)
)
13
15
(86.7% (41.7% )
0.314
6.38) 9.1
0.008
(1.78 ~ 46.4)
14
6.29
4.90
12
(38.9%
(1.5 ~
(1.11 ~
(80%)
)
14
28
0.012
26.3)
Laboratory findings Positive test for antinuclear antibody Activated partial thromboplastin time
*
)
Two or more anti-phospholipid
)
(0.99 ~
4 (0.45
(93.3% (77.8% )
)
10
14
(66.7% (38.9%
~ 0.212
35.23) 3.14
0.076
(0.89 ~
0.036
21.7)
35 prolongation
)
)
11.14) 2.75
Low complements
3
3
(20%)
(8.3%)
(0.49 ~ 0.252
15.53)
* not selected for multiple logistic regression analysis GW, gestational weeks; APS, anti-phospholipid syndrome; LDA, low dose aspirin; PSL, prednisolone; OR, odds ratio; CI, confidence interval.
36 Table 6 Risk factors for light-for-date neonate in women with LDA+UFH therapy
Clinical factors
Maternal age at pregnancy (years, mean±SD)
Appropriat
Univariate logistic
Light
e for
regression
for date
date
neonate
neonate
P-valu
OR
(n=7)
(n=44)
e
(95%CI)
33.9±5. 7
1.04 (0.85 34.5±3.7
0.709
5 Secondary APS
~ 1.27) 6.67 (1.14
(71.4%) 12 (27.3%)
0.036
~ 39.1)
History of thrombosis and pregnancy 2 History of thrombosis History of 3 or more pregnancy loss before 10 GW History of 2 or more pregnancy loss at 10 GW or later
1.36 (0.23
(28.6%) 10 (22.7%)
0.736
1
0.26 (0.03
(14.3%) 17 (38.6%)
0.237
1 (14.3%)
2 (4.50%)
0.335
0 (0%)
7 (15.9%)
0.573
~ 6.49) 2.28 (0.39
(71.4%) 23 (52.3%)
0.353
History of hypertensive disorders of pregnancy
44.75) 0.33 (0.02
5 Nulliparity
~ 2.39) 3.5 (0.27 ~
History of premature delivery before 34 GW
~ 8.1)
~ 13.0) 0.33 (0.02
0 (0%)
7 (15.9%)
0.573
~ 6.49)
Therapy modality 2 LDA prior to pregnancy
(28.6%) 28 (63.6%)
0.23 (0.04 0.099
5 PSL
(71.4%) 18 (40.9%)
~ 1.32) 3.61 (0.63
0.15
~ 20.71)
37 Positive test of anti-phospholipid antibody 3 Lupus anticoagulant
0.90 (0.18
(42.9%) 20 (45.5%)
0.898
3 IgG/IgM anti-cardiolipin
0.75 (0.15
(42.9%) 22 (50.0%)
0.726
6
antibodies
~ 3.75) 6 (0.67 ~
IgG anti-cardiolipin β2 glycoprotein I (85.7%) 22 (50.0%) Two or more anti-phospholipid
~ 4.50)
0.11
4
54.04) 1.33 (0.27
(57.1%) 22 (50.0%)
0.726
~ 6.67)
Laboratory findings 5 Positive test for antinuclear antibody Activated partial thromboplastin time prolongation
0.47 (0.08
(71.4%) 37 (84.1%)
0.422
7 (100%)
23.6 (1.27 17 (38.6%)
0.003
2 Low complements
(28.6%)
~ 2.94)
~ 439) 4 (0.58 ~
4 (9.10%)
0.16
27.7)
* not selected for multiple logistic regression analysis. GW, gestational weeks; APS, anti-phospholipid syndrome; LDA, low dose aspirin; PSL, prednisolone; OR, odds ratio; CI, confidence interval.
*
S0165-0378(17)30093-1 http://dx.doi.org/doi:10.1016/j.jri.2017.08.001 JRI 2485
To appear in:
Journal
Received date: Revised date: Accepted date:
19-4-2017 6-7-2017 2-8-2017
of
Reproductive
Immunology
Please cite this article as: Deguchi, Masashi, Yamada, Hideto, Sugiura-Ogasawara, Mayumi, Morikawa, Mamoru, Fujita, Daisuke, Miki, Akinori, Makino, Shintaro, Murashima, Atsuko, Factors associated with adverse pregnancy outcomes in women with antiphospholipid syndrome: A multicenter study.Journal of Reproductive Immunology http://dx.doi.org/10.1016/j.jri.2017.08.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Journal of Reproductive Immunology Factors associated with adverse pregnancy outcomes in women with antiphospholipid syndrome: A multicenter study
Masashi Deguchi1, Hideto Yamada1, Mayumi Sugiura-Ogasawara2, Mamoru Morikawa3, Daisuke Fujita4, Akinori Miki5, Shintaro Makino6, Atsuko Murashima7
1 Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, JAPAN. 2 Department of Obstetrics and Gynecology, Nagoya City University, Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. 3 Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-0818, Japan. 4 Department of Obstetrics and Gynecology, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569- 8686, Japan. 5 Department of Obstetrics and Gynecology, Kitasato University Medical Center, 6-100 Arai, Kitamoto City, Saitama 364-8501, Japan. 6 Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8431, Japan. 7 Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
2 Corresponding author: Professor Hideto Yamada, MD, PhD Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho Chuo-ku, Kobe 650-0017, Japan Tel: +81-78-382-6000; fax: +81-78-382-6019 E-mail: [email protected]
Highlights
LDA+UFH therapy decreased the risk of pregnancy loss in APS women
A history of pregnancy loss despite LDA+UFH increased the risk of pregnancy loss
LDA therapy prior to pregnancy decreased the risk of premature delivery
Positive tests for two or more aPLs related to premature delivery and thrombocytopenia
Low complements increased the risk of hypertenive disorder of pregnancy
Abstract The aim of this study was to understand the clinical features of antiphospholipid syndrome (APS)-complicated pregnancies and evaluate risk factors for the adverse pregnancy outcomes. This multicenter study evaluated live-birth rates according to therapy modality for APS and risk factors of pregnancy loss in 81 pregnancies. Risk factors for pregnancy complications, including premature delivery before 34 gestational weeks, hypertensive disorders of pregnancy, thrombocytopenia, and light-for-date neonate, were evaluated in 51 women who received low dose aspirin (LDA) plus unfractionated heparin (UFH) and delivered after 24 GW. The live-birth rate in APS pregnancies with LDA+UFH therapy was
3 92.6%. A multiple logistic regression analysis demonstrated that LDA+UFH therapy decreased the risk of pregnancy loss (OR 0.13, 95%CI 0.03-0.62), and that a history of pregnancy loss despite LDA+UFH therapy increased the risk of pregnancy loss (OR 8.74, 95%CI 1.69-45.2). LDA therapy prior to pregnancy decreased the risk of premature delivery (OR 0.14, 95%CI 0.03-0.69). Positive tests for two or more anti-phospholipid antibodies increased the risks of premature delivery (OR 9.61, 95%CI 1.78-51.8) and thrombocytopenia (OR 4.90, 95%CI 1.11~21.7). Laboratory findings of low complements increased the risk of hypertensive disorders of pregnancy (OR 12.1, 95%CI 1.61-91.0). Standard therapy yielded high live-birth rates. Positive tests for two or more anti-phospholipid antibodies and low complements were associated with adverse pregnancy outcomes. These results have important implications for clinicians.
Key words: antiphospholipid syndrome, pregnancy, pregnancy complications, risk factor, therapy modality
1. Introduction Antiphospholipid syndrome (APS) causes pregnancy complications (Hughes, 1993) and vascular thrombosis (Roubey et al., 1997) in patients who test positive for antiphospholipid antibody (aPL). A wide variety of pregnancy complications in APS, including recurrent early miscarriages, late pregnancy loss, hypertensive disorders of pregnancy (HDP), pre-eclampsia, placental insufficiency, fetal growth restriction, and premature delivery are recognized. Recently, antiphospholipid score, a quantitative marker representing the aPL profile, has been determined to predict thrombotic events in patients with APS (Oku et al., 2014; Otomo
4 et al., 2012). On the other hand, in terms of pregnancy complications, a positive test for lupus anticoagulant (LA) rather than anti-cardiolipin (aCL) or anti-ß2 glycoprotein I (aß2GPI) antibody has been found to be a risk factor for adverse pregnancy outcomes (Lockshin et al., 2012; Sailer et al., 2006). Other investigators have found that a positive test for aß2GPI, triple positive tests for aCL/aß2GPI/LA, a high value of aPL antibody, secondary APS, and thrombotic history are associated with adverse pregnancy outcomes (Ruffatti et al., 2011; Simchen et al., 2011). Therefore, some controversy remains about risk factors for adverse pregnancy outcomes in women with APS. This multicenter study aimed to understand the clinical features of APS-complicated pregnancies, and evaluate whether any clinical factors were associated with adverse pregnancy outcome.
2. Patients and Methods This study was approved by the institutional review boards of seven hospitals with perinatal centers in Japan, including Kobe University, Osaka Medical College, Nagoya City University, Hokkaido University, Saitama Medical University, Juntendo University, and the National Center for Child Health and Development. Clinical data were retrospectively collected from medical records of pregnant women with APS who received perinatal management and medication between November 2008 and October 2013. This study enrolled pregnancies from women who were diagnosed as having APS according to the clinical and laboratory criteria of the updated Sydney classification criteria (Miyakis et al., 2006). The clinical criteria used in the present study included vascular thrombosis and obstetrical manifestations of the following: premature delivery of a
5 morphologically normal neonate before 34 gestational weeks (GW) due to eclampsia, severe preeclampsia or placental insufficiency, unexplained miscarriage without fetal abnormality at 10 GW or later, and three or more recurrent early miscarriages. The laboratory criteria used in the present study included repeated positive tests for LA, IgG/IgM aCL, and IgG ß2 glycoprotein I-dependent anti-aCL (aCLß2GPI). A dilute Russell's viper venom time-based test (Gradipore LA Screen and LA Confirm, Gradipore Ltd., Australia) was used for LA measurements. Screen clotting times/ Confirm clotting time ratio of 1.3 (99%ile) was defined as the cut off value of LA. IgG/IgM aCL was measured using specific enzyme-linked immunosorbent assay for cardiolipin (MESACUP cardiolipin test IgG/IgM, MBL Co Ltd., Japan), based on the methods described by Harris et al. (Harris et al., 1987); 19.2 unit/ml of IgG (99%ile) and 23.4 unit/ml of IgM (99%ile) were defined as cut off values. IgG aCLß2GPI was measured using specific enzyme immunoassay for ß2GPI (Yamasa kit, Yamasa Co., Japan); 3.5 unit/ml (+6SD) was defined as the cut off value. In the present study, data for IgG aCLß2GPI were used as the measurement of aß2GPI or IgM aCLß2GPI is not commercially available in Japan. Clinical and laboratory data including maternal age, primary/secondary APS, histories of thrombosis and pregnancy, therapy modality for APS, positive testes of LA, IgG/IgM aCL, IgG aCLß2GPI, antinuclear antigen, activated partial thromboplastin time (aPTT) prolongation, and low complements (C3, C4, or CH50), and therapy modality were collected. Information about chromosome karyotype of the conceptus in cases of pregnancy loss was also obtained. Live-birth rates according to therapy modality for APS and risk factors for pregnancy loss were evaluated for all enrolled pregnancies. Risk factors for pregnancy
complications
including
premature
delivery
before
34
GW,
HDP,
6 thrombocytopenia during pregnancy, and light-for-date (LFD) neonate were evaluated for women who received standard APS therapy of low-dose aspirin (LDA) plus unfractionated heparin (UFH), and delivered after 24 GW. The present study focused on the preterm birth before 34 GW, because the updated Sydney classification criteria adopt the preterm birth before 34 GW as one of the clinical criteria. HDP was defined as an in-hospital systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, based on the average of at least apart two measurements, using the same arm. LFD was defined as a birthweight less than 10 percentile. Fisher’s exact and Mann-Whitney tests were used for comparison. Univariate and multivariate logistic regression analyses were performed to identify independent factors yielding odds ratios (OR) and 95% confidence intervals (CI). Covariates with a significant univariate test (p <0.05) were selected as candidates for multivariate analysis. The number of variables in the final model of multivariable analyses was restricted to two covariates based on the case number, to avoid overfitting in multivariable logistic regression analyses. When the sample number of one of four comparative arms was zero in the univariate analysis, Fisher’s exact test was applied to calculate p-values and OR; these covariates were not selected further for multivariable analyses. Statistical analyses were performed using GraphPad Prism version 6 and R statistics version 3; p-values <0.05 were considered significant.
3. Results In total, 81 pregnancies from 69 women with APS were enrolled in the present study: 24 pregnancies from Kobe University Hospital; 15 from Nagoya City University
7 Hospital, 14 from Hokkaido University Hospital, 13 from Osaka Medical College Hospital, 10 from National Center for Child Health and Development, three from Saitama Medical University Hospital, and three from Juntendo University Hospital. Maternal age (mean ± SD) at pregnancy was 34.1 ± 4.0 years. They had a history of median three (range 0-7) gravida, 0 (0-2) para, and two (0-7) pregnancy losses. Twenty-four women had a history of thrombosis. The 81 pregnancies consisted of 45 pregnancies from women with primary APS and 36 from women with secondary APS. Secondary APS included 35 women with systemic lupus erythematosus (SLE) and one with autoimmune hepatitis. None had hypertensive disorder or antihypertensive medications at the time of pregnancy diagnosis.
3.1 Pregnancy outcomes and therapy modality Table 1 shows live-birth rates according to therapy modality in 81 APS complicated pregnancies. According to therapy modality for APS, the 81 pregnancies were divided into six groups as the following: none (n=3), LDA alone (n=7), UFH alone (n=4), LDA plus danaparoid (LDA+danaparoid, n=1), LDA plus UFH (LDA+UFH, n=54), and LDA plus UFH plus high dose intravenous immunoglobulin (HIVIg) before 17 GW (LDA+UFH+HIVIg, n=12). Doses of 81 or 100 mg/day of LDA, median 10000 (range 5000-24000) IU/day of UFH, and 2500 IU/day of danaparoid were administered. HIVIg (20 g/day, 5 consecutive days, total 100 g) was performed at median 6 (5-16) GW. Forty-three women received median 10 (5-50) mg/day of prednisolone (PSL), and one received pulse methyl-PSL (500 mg/day, 3 days) additionally due to a flare of SLE. Three of four women who received UFH only had
8 suspected aspirin allergy. Seven women who received LDA only did not consent to continuous UFH therapy. A total 67 of 81 pregnancies ended in live births, yielding the live-birth rate of 82.7%. The live-birth rate (92.6%) in pregnancies with LDA+UFH therapy did not statically differ from 71.4% with LDA alone (p=0.14), 75.0% with UFH alone (p=0.31), or 75.0% with LDA+UFH+HIVIg (p=0.11) (Tab. 1). Eight pregnant women who had experienced pregnancy loss despite LDA+UFH therapy received LDA+UFH+HIVIg therapy in the index pregnancy, yielding the live-birth rate of 62.5% (5/8). Gestational weeks at delivery in the 67 live births were compared as shown in Figure 1. The gestational week at delivery in pregnancies with LDA+UFH (median 36, range 24-41 GW) or pregnancies with LDA+UFH+HIVIg therapy (34, 26-39 GW) was significantly (p<0.05) shorter than that with LDA alone (40, 36-41 GW). Fourteen pregnancies ended in pregnancy losses: four spontaneous miscarriages before 10 GW at median 7 (range 6-9) GW, eight spontaneous miscarriages at median 21 (10-22) GW, and two stillbirths at 26 and 27 GW. Eleven of the 14 conceptuses of pregnancy losses carried normal chromosome karyotypes; two carried abnormal karyotypes; and one was unknown. 3.2 Risk factors for pregnancy loss To identify risk factors associated with pregnancy loss in women with APS, a stepwise logistic regression analysis was performed for 67 pregnancies ending in live births and 14 pregnancies ending in miscarriages/stillbirths. Maternal age at pregnancy, primary/secondary APS, therapy modality, positive testes for aPL, antinuclear antigen, aPTT prolongation, and low complements were assessed. Univariate logistic regression analyses
9 identified, a history of pregnancy loss despite LDA+UFH therapy (OR 8.59, 95%CI 1.69-43.8, p<0.05) and LDA+UFH therapy (OR 0.14, 95%CI 0.03-0.57, p<0.01) as factors associated with pregnancy loss in the index pregnancy (Table 2). Multiple logistic regression analysis demonstrated that LDA+UFH therapy (OR 0.13, 95%CI 0.03-0.62, p<0.05) was an independent factor that decreased risks of pregnancy loss, and that a history of pregnancy loss despite LDA+UFH therapy was an independent factor that increased risks of pregnancy loss (OR 8.74, 95%CI 1.69-45.2, p<0.01). 3.3 Risk factors for pregnancy complications in women with LDA+UFH therapy Risk factors for pregnancy complications, including premature delivery before 34 GW, HDP, thrombocytopenia, and LFD neonate were evaluated for 51 pregnant women who received LDA+UFH therapy and delivered after 24 GW. These 51 pregnancies comprised 50 live births and one stillbirth at 26 GW. Women who received HIVIg therapy were excluded from this analysis. 3.3.1 Risk factors for premature delivery before 34 GW Table 3 shows risk factors for premature delivery before 34 GW. Univariate logistic regression analyses identified, a history of two or more pregnancy losses at 10 GW or later (OR 22.8, 95%CI 1.1-475, p<0.05), LDA therapy prior to pregnancy (OR 0.27, 95%CI 0.07-0.97, p<0.05), positive tests for LA (OR 7.64, 95%CI 1.79-32.6, p<0.01), IgG aCLß2GPI (OR 19.1, 95%CI 2.25-161, p<0.01), 2 or more aPL (OR 5.38, 95%CI 1.28-22.6, p<0.05), and aPTT prolongation (OR 12.5, 95%CI 2.41-64.9, p<0.01), as risk factors for premature delivery before 34 GW Multiple logistic regression analysis demonstrated that LDA therapy prior to pregnancy (OR 0.14, 95%CI 0.03-0.69, p<0.05) was an independent factor that decreased
10 risks of premature delivery before 34 GW, whereas a positive test for two or more anti-phospholipid antibodies (OR 9.61, 95%CI 1.78-51.8, p<0.05) was an independent factor that increased risks of premature delivery. Maximum Chi-squared tests revealed a lowest p-value (p=0.001) of IgG anti-cardiolipin β2 glycoprotein I for the preterm birth before 34 GW, and a lowest p-value (p=0.023) of LDA prior to pregnancy for the preterm birth before 33 GW.
3.3.2 Risk factors for hypertensive disorders of pregnancy Table 4 shows risk factors for HDP. Univariate logistic regression analyses identified, maternal age (OR 0.80 95%CI 0.65-0.97, p<0.05), PSL therapy (OR 6.93, 95%CI 1.30-37.0, p<0.05), and low complements (OR 13.0, 95%CI 1.94-87.1, p<0.05), as risk factors for HDP. Multiple logistic regression analysis demonstrated that laboratory findings of low complements (OR 12.1, 95%CI 1.61-91.0, p<0.05) was an independent factor that increased risks of HDP, whereas maternal age (OR 0.79, 95%CI 0.63-0.997, p<0.05) was an independent factor that decreased risks of HDP. 3.3.3 Risk factors for thrombocytopenia Table 5 shows risk factors for thrombocytopenia defined as less than 12 × 104/µL platelet counts during pregnancy. Univariate logistic regression analyses identified, secondary APS (OR 5.25, 95%CI 1.43-19.2, p<0.05), a history of three or more pregnancy losses before 10 GW
(OR 0.19, 95%CI 0.04-0.98, p<0.05), PSL therapy (OR 5.5, 95%CI 1.44-21.0,
p<0.05), positive tests for IgG aCLß2GPI (OR 9.1, 95%CI 1.78-46.4, p<0.01) and two or more aPL (OR 6.29, 95%CI 1.5-26.3, p<0.05), as risk factors for thrombocytopenia.
11 Multiple logistic regression analysis demonstrated that a positive test for two or more anti-phospholipid antibodies (OR 4.90, 95%CI 1.11-21.7, p<0.05) and secondary APS (OR 3.96, 95%CI 1.002-15.7, p<0.05) were independent factors that increased risks of thrombocytopenia during pregnancy. 3.3.4 Risk factors for light-for-date neonate Table 6 shows risk factors for LFD neonate. Univariate logistic regression analyses found, secondary APS (OR 6.67, 95%CI 1.14-39.1, p<0.05) and aPTT prolongation (OR 23.6, 95%CI 1.27-439, p<0.05), as risk factors for LFD. Multiple logistic regression analysis was not performed as aPTT prolongation was observed in all seven pregnancies with LFD.
4. Discussion It is acknowledged worldwide that LDA plus UFH or low molecular heparin (LMWH) therapy is recommended as a standard therapy for APS-complicated pregnancy (ACOG, 2011; Fouda et al., 2011; Laskin et al., 2009; RCOG, 2011). In the present multicenter study, LDA+UFH or LDA+UFH+HIVIg therapy was performed in 81.5% (66/81) of APS-complicated pregnancies. UFH but not LMWH was used in these pregnancies, because LMWH therapy for APS-complicated pregnancy is not covered by medical insurance in Japan. The live-birth rate of pregnancies with LDA+UFH or LDA+UFH+HIVIg therapy was high (88.1%, 59/66). Multiple regression analysis demonstrated that use of LDA+UFH therapy significantly decreased the risk of pregnancy loss. However, the live-birth rate with LDA+UFH+HIVIg therapy (75.0%) was relatively low compared with that with LDA+UFH therapy (92.6%). This may be because eight of the 12 pregnant women who received LDA+UFH+HIVIg therapy had a history of pregnancy loss despite LDA+UFH therapy; this
12 group may be considered severe cases of APS. A randomized controlled trial has shown live-birth rates in APS-complicated pregnancies with therapy of LDA alone and LMWH alone are 72.1% and 86.3%, respectively (Alalaf, 2012). The live-birth rate with LDA alone (71.4%) or UFH alone (75.0%) in the present study corresponded with those previously reported live-birth rates. Generally, 80-90% of women with APS have live births with LDA+UFH therapy, whereas the remainder is refractory to LDA+UFH therapy failing to have healthy neonates. This condition is called aspirin-heparin resistant APS (AHRAPS) (Shimada et al., 2010). In the present study, a history of pregnancy loss despite LDA+UFH therapy increased the risk of pregnancy loss in the subsequent pregnancy. In addition to standard LDA+UFH therapy, therapies such as HIVIg may be necessary to improve pregnancy outcomes in women with AHRAPS. In the present study, the eight pregnant women with a history of pregnancy loss despite LDA+UFH therapy received LDA+UFH+HIVIg therapy, yielding the live-birth rate of 62.5% (5/8). HIVIg therapy has been first performed in a pregnant woman with a positive LA test and a history of nine recurrent miscarriages (Carreras et al., 1988). A randomized controlled trial has evaluated the efficacy of LDA+UFH plus 1 g/kg body weight of intravenous immunoglobulin (IVIg) therapy compared with LDA+UFH therapy in 16 pregnant women with APS, and found no difference in treatment efficacy (Branch et al., 2000). However, another investigator has reported the live-birth rate of 80% (8/10) in women with AHRAPS who receive 1 g/kg body weight of IVIg therapy (Triolo et al., 2004). Further randomized controlled studies are necessary to determine the efficacy of LDA+UFH+HIVIg therapy in women with AHRAPS.
13 Risk factors for pregnancy complications including premature delivery before 34 GW, HDP, thrombocytopenia, and LFD neonate were evaluated for 51 pregnancies with LDA+UFH therapy that ended after 24 GW. It was found that positive tests for two or more anti-phospholipid antibodies were independent risk factors for premature delivery before 34 GW and thrombocytopenia, and that laboratory findings of low complements and younger age were independent risk factors for HDP. In the present study, all pregnancies with positive tests for LA and IgG aCLß2GPI ended in premature delivery before 34 GW. Likewise, a study has shown that poor pregnancy outcomes are associated with a positive test for two or more aPLs (Ruffatti et al., 2009). Other investigators have found a positive test for aCLß2GPI/aß2GPI is associated with poor pregnancy outcomes (Katano et al., 1996; Matsuki et al., 2015; Simchen et al., 2011), while European and American studies have found LA but not aß2GPI as a predictor of adverse pregnancy outcomes in women with APS (Lockshin et al., 2012; Sailer et al., 2006). Commencement of LDA therapy prior to pregnancy was found to be an independent factor that decreased risks for premature delivery before 34 GW. The present study is the first report that shows an advantage of LDA therapy prior to the conception. It is hypothesized that LDA in early pregnancy suppresses COX-1 and reduces thromboxane A2 production from trophoblast cells and vasoconstriction (Askie et al., 2007; Groeneveld et al., 2013; Lambers et al., 2009). LDA therapy commencing prior to the conception in women with APS may stimulate invasion of the uterine spiral arteries and improve placental blood flow, thus reducing the risk for premature delivery. It has been reported that low complements are associated with low birth weight and prematre delivery in women with APS (De Carolis et al., 2012, 2010). The present study is
14 the first report demonstrating that low complements increase the risk for hypertension in APS-complicated pregnancy. Seventeen pregnancies from women with autoimmune diseases (secondary APS) were included in 51 study subjects, and secondary APS was also identified as a risk factor for LFD neonate in univariate logistic regression analysis. Therefore, the disease activity of autoimmune diseases might affect the risk for these pregnancy complications. The multivariate analysis demonstrated that a positive test for two or more anti-phospholipid antibodies was found to be an independent risk factor for thrombocytopenia during pregnancy, while a positive test for aCLß2GPI IgG was also associated with thrombocytopenia in the univariate analysis. Thrombocytopenia is common symptom that is not included in the APS diagnostic criteria. An association between IgG aß2GPI and thrombocytopenia has been reported in women with SLE (Cucurull et al., 1999). A recent review has shown that the direct binding of aβ2GPI antibodies or aβ2GPI-β2GPI complexes to platelets is a possible cause of thrombocytopenia (Baroni et al., 2017). The results demonstrated in the present study have important implications for clinicians. However, this study has some potential limitations. This study was designed as a retrospective study, although all subjects had undergone workup for aPL prior to pregnancy. The number of variables in multivariable analyses was restricted to two covariates based on the case number. Covariates with high OR determined by univariate analyses might be related to risks for adverse pregnancy outcomes. The subjects of this study were mixed population with varied APS-related background. The evaluation of treatment efficacy in heterogenous
15 subjects was difficult. Prospective randomized case-controlled studies are necessary to confirm the conclusions of the present study in future.
Funding This work was supported by Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan (25080501) and the Japan Agency for Medical Research and Development (AMED).
Conflict of interest None of the authors have any conflicts of interest to declare.
Data are presented as box-and-whisker plots (25th and 75th percentile; 5th and 95th percentile; and median).
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19 antiphospholipid syndrome patients with history of severe pregnancy complications. Mod. Rheumatol. 25, 215–218. doi:10.3109/14397595.2014.942503 Miyakis, S., Lockshin, M.D., Atsumi, T., Branch, D.W., Brey, R.L., Cervera, R., Derkesen, R.H.W.M., De Groot, P.G., Koike, T., Meroni, P.L., Reber, G., Shoenfeld, Y., Tincani, A., Vlachoyiannopoulos, P.G., Krilis, S.A., 2006. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306. doi:10.1111/j.1538-7836.2006.01753.x Oku, K., Amengual, O., Atsumi, T., 2014. Antiphospholipid scoring : significance in diagnosis and prognosis. Lupus 23, 1269–1272. doi:10.1177/0961203314537361 Otomo, K., Atsumi, T., Amengual, O., Fujieda, Y., Kato, M., Oku, K., Horita, T., Yasuda, S., Koike, T., 2012. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum. 64, 504–512. doi:10.1002/art.33340 RCOG, N., 2011. RCOG: the investigations and treaments of couples with recurrent first-trimester and second-trimester miscarriage. NICE Guidel. Roubey, R.A., Hoffman, M., Ginsburg, K., Liang, M., Newcomer, L., Al., E., Kittner, S., Gorelick, P., Love, P., Santoro, S., Roubey, R., Willems, G., Janssen, M., Pelsers, M., Al., E., Takeya, H., Mori, T., Gabazza, E., Al., E., Rand, J., Wu, X., Andree, H., Al., E., Rao, L., Hoang, A., Rapaport, S., Papa, N. Del, Guidali, L., Spatola, L., Al., E., Simantov, R., LaSala, J., Lo, S., Al., E., Kornberg, A., Blank, M., Kaufman, S., Shoenfeld, Y., Schved, J.-F., Gris, J.-C., Ollivier, V., Wautier, J.-L., Tobelem, G., Caen, J., Cuadrado, M.,
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doi:10.1111/j.1600-0412.2011.01236.x; 10.1111/j.1600-0412.2011.01236.x Triolo, G., Ferrante, A., Accardo-Palumbo, A., Ciccia, F., Cadelo, M., Castelli, A., Perino, A., Licata,
G.,
2004.
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in
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Lupus
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22 Figure legends Figure 1
Gestational weeks at delivery of live birth according to therapy modality.
23 Table 1 Live-birth rates according to therapy modality
Pregnancy outcome Pregnancy loss (number of conceptus with normal
Therapy modality
Number of
chromosome,
Number of
pregnancies
abnormal
Live
pregnancies
with PSL
chromosome,
birth
(*)
therapy (*)
unknown)
Live-birth
P-value
rate (%)
None
3 (1)
N.A.
3 (2, 0, 1)
0
0
LDA alone
7 (2)
5 (2)
2 (2, 0, 0)
5
71.4
a
a v.s. c p=0.14
UFH alone
4 (1)
2 (1)
1 (1, 0, 0)
3
75.0
b
b v.s. c LDA+danaparoid
1 (1)
1 (1)
1 (0, 1, 0)
0
0
LDA+UFH
54 (4)
24 (4)
4** (4, 0, 0)
50
92.6
LDA+UFH+HIVIg
12 (8)
11 (7)
3 (2, 1, 0)
9
75.0
81 (17)
43 (15)
14 (11, 2, 1)
67
82.7
14
67
p=0.31 c
Total total
81
c v.s. d d
p=0.11
LDA, low dose aspirin; UFH, unfractionated heparin; HIVIg, a high dose intravenous immunoglobulin; PSL, prednisolone; N.A., not applicable. (*) Parenteses indicate numbers of pregnancies from women who have experienced pregnancy loss despite LDA+UFH therapy. ** One case with stillbirth at 26 gestational weeks is included.
24 Table 2 Risk factors for pregnancy loss
Univariate
Multivariate
logistic Clinical factors
logistic
regression
Pregnan
regression
cy
Live
OR
loss
birth
P-val
(95%CI
P-val
(95%CI
(n=14)
(n=67)
ue
)
ue
)
1.06 Maternal age at pregnancy (years, mean±SD)
Secondary APS
33.3±4.
34.3±3
6
.8
(0.92 ~ 0.404
1.23)
28
1.86
8
(41.8
(0.57 ~
(57.1%)
%)
0.303
6.03)
History of thrombosis and pregnancy
History of thrombosis
7 (50%)
History of 3 or more pregnancy loss before 10 GW
17
2.94
(25.4
(0.78 ~
%)
0.111
23
0.32
2
(34.3
(0.09 ~
(14.3%)
%)
0.088
History of 2 or more pregnancy loss at 10 GW or later History of premature birth delivery 34 GW Nulliparity
11.1)
1.18) 4.07
4 (28.6%)
(0.62 ~ 6 (9%)
0.145
26.9)
13
0.69
2
(19.4
(0.16 ~
(14.3%)
%)
8
36
(57.1%)
(53.7
0.628
3.06) 1.15
0.816
(0.35 ~
OR
25 %)
3.67)
15
1.39 (0.36 ~
History of hypertensive
4
(22.4
disorders of pregnancy
(28.6%)
%)
History of pregnancy loss despite LDA+UFH therapy
0.637
5.39)
9
8.59
8.74
8
(13.4
(1.69 ~
(1.69 ~
(57.1%)
%)
0.010
43.8)
0.010
45.2)
Therapy modality
LDA+UFH
PSL
HIVIg
7 (50%)
7 (50%)
59
0.14
0.13
(88.1
(0.03 ~
(0.03 ~
%)
0.006
0.57)
36
0.86
(53.7
(0.27 ~
%)
0.800
2.73)
9
1.76
3
(13.4
(0.34 ~
(21.4%)
%)
0.501
9.10)
Positive test of anti-phospholipid antibody
Lupus anticoagulant
IgG/IgM anti-cardiolipin
33
1.36
7
(50.8
(0.40 ~
(58.3%)
%)
7 (70%)
IgG anti-cardiolipin β2 glycoprotein I
7 (50%)
Two or more anti-phospholipid antibodies
0.627
4.66)
34
1.44
(61.8
(0.35 ~
%)
0.611
5.90)
36
0.83
(54.5
(0.26 ~
%)
0.758
2.65)
35
1.65
9
(52.2
(0.52 ~
(64.3%)
%)
0.400
5.25)
0.011
0.62)
26 Laboratory findings Positive test for antinuclear antibody
55
2.40
12
(83.3
(0.48 ~
(92.3%)
%)
0.288
Activated partial thromboplastin time prolongation
Low complements
12.1) 1.50
9
36
(69.2%)
(60%)
(0.44 ~ 0.519
5.15)
37
0.56
6
(60.7
(0.16 ~
(46.2%)
%)
0.362
1.96)
GW, gestational weeks; LDA, low dose aspirin, UFH, unfractionated heparin; APS, anti-phospholipid syndrome; PSL, prednisolone; HIVIg, a high dose intravenous immunoglobulin； OR, odds ratio; CI, confidence interval.
27 Table 3 Risk factors for premature delivery before 34 GW in women with LDA+UFH therapy
Prematu Clinical factors
Univariate
Multivariate
re
Delive
logistic
logistic
delivery
ry at
regression
regression
before
34 GW
34 GW
or later
P-val
(95%C
P-val
(95%CI
(n=14)
(n=37)
ue
I)
ue
)
OR
OR
1.00 Maternal age at pregnancy (years, mean±SD)
Secondary APS
34.4±3.
34.4±4
4
.2
(0.86 ~ 0.986
1.17)
12
1.16
5
(32.4
(0.32 ~
(35.7%)
%)
0.824
4.21)
History of thrombosis and pregnancy
History of thrombosis
8
1.45
4
(21.6
(0.36 ~
(28.6%)
%)
History of 3 or more pregnancy loss before 10 GW
0.603
16
0.22
2
(43.2
(0.04 ~
(14.3%)
%)
0.068
History of 2 or more pregnancy loss at 10 GW or later History of premature delivery before 34 GW Nulliparity
5.87)
1.12) 22.8
3 (21.4%)
(1.10 ~ 0 (0%)
0.018
475)
5
1.07
2
(13.5
(0.18 ~
(14.3%)
%)
0.943
6.26)
9
19
0.41
1.70
*
28 (64.3%)
(51.4
(0.45 ~
%)
6.46)
5
1.07 (0.18 ~
History of hypertensive
2
(13.5
disorders of pregnancy
(14.3%)
%)
0.943
6.26)
Therapy modality
LDA prior to pregnancy
PSL
25
0.27
5
(67.6
(0.07 ~
(35.7%)
%)
0.045
(0.03 ~
0.97)
16
1.31
7
(43.2
(0.38 ~
(50.0%)
%)
0.666
0.14 0.015 0.69)
4.52)
Positive test of anti-phospholipid antibody
Lupus anticoagulant
IgG/IgM anti-cardiolipin IgG anti-cardiolipin β2 glycoprotein I
12
7.64
11
(32.4
(1.79 ~
(78.6%)
%)
antibodies
32.6)
18
1.06
7
(48.6
(0.31 ~
(50.0%)
%)
0.931
19.1
13
(40.5
(2.25 ~
(92.9%)
%)
0.007
161)
15
5.38
11
(40.5
(1.28 ~
(78.6%)
%)
0.022
*
3.61)
15
Two or more anti-phospholipid
0.006
* 9.61 (1.78 ~
22.6)
0.009 51.8)
Laboratory findings Positive test for antinuclear antibody Activated partial
31
0.71
11
(83.8
(0.15 ~
(78.6%)
%)
0.664
3.33)
12
12
0.003
12.5
*
29 thromboplastin time
(85.7%)
(32.4
(2.41 ~
%)
64.9)
4
1.37
2
(10.8
(0.22 ~
(14.3%)
%)
prolongation
Low complements
0.732
8.5)
* not selected for multiple logistic regression analysis GW, gestational weeks; APS, anti-phospholipid syndrome; LDA, low dose aspirin; PSL, prednisolone; OR, odds ratio; CI, confidence interval.
30 Table 4 Risk factors for hypertenive disorder of pregnancy in women with LDA+UFH therapy
Clinical factors
Univariate
Multivariate
Hypertension in
logistic
logistic
pregnancy
regression
regression
OR Present Absent (n=10)
Maternal age at pregnancy (years, mean±SD)
(n=41)
31.7±3
35.0±3
.8
.8
6
11
P-val
(95%CI
P-val
(95%CI
ue
)
ue
)
0.026
)
)
4
8
0.80
0.79
(0.65 ~
(0.63 ~
0.97)
4.09
(60.0% (26.8% Secondary APS
(0.97 ~ 0.055
17.2)
History of thrombosis and pregnancy 2.75
(40.0% (19.5% History of thrombosis
)
)
History of 3 or more
1
17
pregnancy loss before 10
)
)
History of 2 or more
1
2
pregnancy loss at 10 GW or later History of premature
(0.62 ~ 0.181
(0.02 ~ 0.092
)
2
5
1.36) 2.17
(10.0% (4.88% )
12.1) 0.16
(10.0% (41.5%
GW
OR
(0.18 ~ 0.546
26.6) 1.80
(20.0% (12.2%
(0.29 ~
delivery before 34 GW
)
)
0.524
11.0)
Nulliparity
7
21
0.292
2.22
0.048
0.997)
31 (70.0% (51.2%
History of hypertensive disorders of pregnancy
(0.50 ~
)
)
9.81)
3
4
3.96
(30.0% (9.76% )
)
5
25
(0.72 ~ 0.113
21.7)
Therapy modality 0.64
(50.0% (61.0% LDA prior to pregnancy
)
)
8
15
(0.16 ~ 0.529
6.93
(80.0% (36.6% PSL
)
)
6
17
2.57) (1.30 ~
0.023
37.0)
Positive test of anti-phospholipid antibody 2.12
(60.0% (41.5% Lupus anticoagulant
)
)
5
20
(0.52 ~ 0.297
1.05
(50.0% (48.8% IgG/IgM anti-cardiolipin IgG anti-cardiolipin β2
)
)
8
20
)
)
Two or more
6
20
anti-phospholipid antibodies
(0.26 ~ 0.945
(0.79 ~ 0.091
)
8
34
22.2) 1.58
(60.0% (48.8% )
4.18) 4.2
(80.0% (48.8%
glycoprotein I
8.67)
(0.39 ~ 0.526
6.42)
Laboratory findings Positive test for antinuclear antibody
0.82
(80.0% (82.9% )
)
(0.14 ~ 0.828
4.74)
*
32 Activated partial thromboplastin time prolongation
7
17
3.29
(70.0% (41.5% )
)
4
2
(0.74 ~ 0.116
(40.0% (4.88% Low complements
)
)
0.008
14.6) 13.0
12.1
(1.94 ~
(1.61 ~
87.1)
0.016
91.0)
* not selected for multiple logistic regression analysis GW, gestational weeks; APS, anti-phospholipid syndrome; LDA, low dose aspirin; PSL, prednisolone; OR, odds ratio; CI, confidence interval.
33 Table 5 Risk factors for thrombocytopenia during pregnancy in women with LDA+UFH therapy
Univariate
Multivariate
Thrombocytope
logistic
logistic
nia
regression
regression
Clinical factors
OR
OR
Present
Absent
P-val
(95%C
P-val
(95%CI
(n=15)
(n=36)
ue
I)
ue
)
1.11 Maternal age at pregnancy (years, mean±SD)
Secondary APS
33.2±3
34.9±4
.1
.2
(0.95 ~ 0.178
1.31)
8
5.25
9
(22.2%
(1.43 ~
0.049
(1.002 ~
(60%)
)
19.2)
6
15.7)
5
7
0.012
3.96
History of thrombosis and pregnancy 2.07
(33.3% (19.4% History of thrombosis
)
)
History of 3 or more
2
16
pregnancy loss before 10
)
History of 2 or more
2
or later History of premature delivery before 34 GW Nulliparity
0.292
)
8.02) 0.19
(13.3% (44.4%
GW pregnancy loss at 10 GW
(0.53 ~
(0.04 ~ 0.047
0.98) 5.38
(13.3%
1
)
(2.8%)
(0.45 ~ 0.184
64.52)
6
0.36
1
(16.7%
(0.04 ~
(6.7%)
)
10
18
(66.7%
(50%)
0.361
3.26) 2.00
0.280
(0.57 ~
*
34 ) 2 History of hypertensive disorders of pregnancy
7.03) 5
0.95
(13.3% (13.9% )
)
8
22
(0.16 ~ 0.958
5.56)
Therapy modality 0.73
(53.3% (61.1% LDA prior to pregnancy
)
)
11
12
(0.22 ~ 0.608
5.5
(73.3% (33.3% PSL
)
)
10
13
2.45) (1.44 ~
0.013
21.0)
*
Positive test of anti-phospholipid antibody 3.54
(66.7% (36.1% Lupus anticoagulant
IgG/IgM anti-cardiolipin IgG anti-cardiolipin β2 glycoprotein I
)
antibodies
0.051
12.6)
16
1.88
9
(44.4%
(0.55 ~
(60%)
)
13
15
(86.7% (41.7% )
0.314
6.38) 9.1
0.008
(1.78 ~ 46.4)
14
6.29
4.90
12
(38.9%
(1.5 ~
(1.11 ~
(80%)
)
14
28
0.012
26.3)
Laboratory findings Positive test for antinuclear antibody Activated partial thromboplastin time
*
)
Two or more anti-phospholipid
)
(0.99 ~
4 (0.45
(93.3% (77.8% )
)
10
14
(66.7% (38.9%
~ 0.212
35.23) 3.14
0.076
(0.89 ~
0.036
21.7)
35 prolongation
)
)
11.14) 2.75
Low complements
3
3
(20%)
(8.3%)
(0.49 ~ 0.252
15.53)
* not selected for multiple logistic regression analysis GW, gestational weeks; APS, anti-phospholipid syndrome; LDA, low dose aspirin; PSL, prednisolone; OR, odds ratio; CI, confidence interval.
36 Table 6 Risk factors for light-for-date neonate in women with LDA+UFH therapy
Clinical factors
Maternal age at pregnancy (years, mean±SD)
Appropriat
Univariate logistic
Light
e for
regression
for date
date
neonate
neonate
P-valu
OR
(n=7)
(n=44)
e
(95%CI)
33.9±5. 7
1.04 (0.85 34.5±3.7
0.709
5 Secondary APS
~ 1.27) 6.67 (1.14
(71.4%) 12 (27.3%)
0.036
~ 39.1)
History of thrombosis and pregnancy 2 History of thrombosis History of 3 or more pregnancy loss before 10 GW History of 2 or more pregnancy loss at 10 GW or later
1.36 (0.23
(28.6%) 10 (22.7%)
0.736
1
0.26 (0.03
(14.3%) 17 (38.6%)
0.237
1 (14.3%)
2 (4.50%)
0.335
0 (0%)
7 (15.9%)
0.573
~ 6.49) 2.28 (0.39
(71.4%) 23 (52.3%)
0.353
History of hypertensive disorders of pregnancy
44.75) 0.33 (0.02
5 Nulliparity
~ 2.39) 3.5 (0.27 ~
History of premature delivery before 34 GW
~ 8.1)
~ 13.0) 0.33 (0.02
0 (0%)
7 (15.9%)
0.573
~ 6.49)
Therapy modality 2 LDA prior to pregnancy
(28.6%) 28 (63.6%)
0.23 (0.04 0.099
5 PSL
(71.4%) 18 (40.9%)
~ 1.32) 3.61 (0.63
0.15
~ 20.71)
37 Positive test of anti-phospholipid antibody 3 Lupus anticoagulant
0.90 (0.18
(42.9%) 20 (45.5%)
0.898
3 IgG/IgM anti-cardiolipin
0.75 (0.15
(42.9%) 22 (50.0%)
0.726
6
antibodies
~ 3.75) 6 (0.67 ~
IgG anti-cardiolipin β2 glycoprotein I (85.7%) 22 (50.0%) Two or more anti-phospholipid
~ 4.50)
0.11
4
54.04) 1.33 (0.27
(57.1%) 22 (50.0%)
0.726
~ 6.67)
Laboratory findings 5 Positive test for antinuclear antibody Activated partial thromboplastin time prolongation
0.47 (0.08
(71.4%) 37 (84.1%)
0.422
7 (100%)
23.6 (1.27 17 (38.6%)
0.003
2 Low complements
(28.6%)
~ 2.94)
~ 439) 4 (0.58 ~
4 (9.10%)
0.16
27.7)
* not selected for multiple logistic regression analysis. GW, gestational weeks; APS, anti-phospholipid syndrome; LDA, low dose aspirin; PSL, prednisolone; OR, odds ratio; CI, confidence interval.
*