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D. Le Thi Huong, B. Wechsler, D. Vauthier-Brouzes, P. Duhaut, N. Costedoat, M. R. Andreu, G. Lefebvre, J.-C. Piette, The second trimester Doppler ultrasound examination is the best predictor of late pregnancy outcome in systemic lupus erythematosus and/or the antiphospholipid syndrome, Rheumatology, Volume 45, Issue 3, March 2006, Pages 332–338, https://doi.org/10.1093/rheumatology/kei159
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Abstract
Objective. To examine the predictive value of clinical examination, laboratory tests and Doppler ultrasound examination in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) pregnancies.
Methods. A prospective study of 116 pregnancies followed in a single tertiary referral centre. Outcomes analysed were fetal/neonatal death and adverse pregnancy outcome. Univariate analysis was performed for: (i) medical and obstetric history; (ii) medical and obstetric clinical examination; (iii) biological data; (iv) Doppler ultrasound examination. Variables significantly associated with the outcomes in the univariate analysis were entered into a logistic regression model.
Results. Sixteen out of 116 pregnancies ended in 12 fetal deaths and 4 embryonic losses. Hence, data for 100 pregnancies were analysed. Seven fetal deaths and one neonatal death occurred, associated with abnormal end-diastolic umbilical artery Doppler flow at the second trimester (P<0.006), a history of thrombophlebitis (P<0.001) or notched uterine artery and growth restriction at the second trimester (P<0.002). Multivariate analysis retained abnormal end-diastolic umbilical artery Doppler flow (P = 0.047) and history of thrombophlebitis (P = 0.018) as significant predictors. Thirty-one adverse pregnancy outcomes occurred, associated with notched uterine artery (P<0.00003), abnormal end-diastolic umbilical artery Doppler flow (P<0.0006) and fetal growth restriction at the second trimester (P<0.008), growth restriction (P<0.00001) and notched uterine artery at the third trimester (P<0.0008), use of heparin (P<0.05) and history of thrombophlebitis (P<0.04). Notched uterine artery at the second trimester remained the only predictor in multivariate analysis (P = 0.001).
Conclusions. Results of the second trimester Doppler ultrasound examination are the best predictors for late pregnancy outcome in SLE and/or APS.
Pregnancies in women with systemic lupus erythematosus (SLE) and/or the antiphospholipid syndrome (APS) are considered at high risk for recurrent spontaneous abortions, intra-uterine growth restriction (IUGR), pre-term delivery, pre-eclampsia, HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome and vascular thrombosis. In most tertiary referral centres, at least a monthly visit is advised for clinical and obstetric examination and laboratory tests [1–4]. In France, a systematic fetal Doppler ultrasound examination is performed during each trimester in all pregnancies. The predictive value for adverse pregnancy outcome of fetal Doppler ultrasound examination has been demonstrated. Absent end-diastolic velocities of the umbilical artery predict early pregnancy-induced hypertension/pre-eclampsia and fetal or neonatal death [5]. The predictive value of abnormal uterine blood flow remains controversial [6]. Several studies have demonstrated that abnormal uterine blood flow correlates with an increased risk of pre-eclampsia and fetal growth restriction in women with hypertension [7] and also in the general population [8]. In SLE pregnancies, identified predictors of poor outcome are hypertension [9], race [1], SLE activity, especially nephritis [10], hypocomplementaemia [11], anticardiolipin antibodies (aCL) [1, 12] and lupus anticoagulant (LA) [13]. In APS, thrombocytopenia [2] and prior pregnancy loss [2, 14] have been suggested as predictors. The value of fetal Doppler ultrasound in SLE pregnancies has not been widely assessed. To our best knowledge, no study has attempted to summarize the respective value of clinical, biological and fetal Doppler ultrasound data. The aim of our prospective study conducted in a single French tertiary referral centre was to ascertain the predictive value of medical history, clinical, biological and Doppler ultrasound examination for fetal outcome in SLE/APS pregnancies. These two diseases were studied together because they are commonly associated, they share similar pregnancy complications and specialized physicians frequently take care of patients with either or both diseases.
Patients and methods
Patients
We prospectively analysed 116 consecutive pregnancies in 84 women with SLE and/or APS followed in our institution. Women with SLE fulfilled the 1997 American College of Rheumatology (ACR) criteria for SLE [15]. Diagnosis of APS was based on international criteria [16]. Lupus anticoagulant was usually detected by activated partial thromboplastin time (PTT), diluted thromboplastin time or kaolin clotting time. Abnormal coagulation times were confirmed by a 1:1 mixture of patient and control plasma to exclude clotting factor deficiencies. Anticardiolipin antibodies were measured by an enzyme-linked immunosorbent assay (ELISA) that detects IgG and IgM aCL.
One hundred and four pregnancies were planned as previously described [17]. Basically, pregnancy was authorized when SLE was inactive on antimalarial drugs and/or low-dose prednisone without immunosuppressive therapy for 1 year, and when there was no frank renal function alteration or systemic or pulmonary hypertension. Upon diagnosis of pregnancy, aspirin was systematically instituted for prevention of pre-eclampsia and spontaneous abortions in case of asymptomatic aPL. Heparin was added if a history of vascular thrombosis or a history of aPL-related spontaneous abortions with aspirin alone was present. High-dose immunoglobulins (2 g/kg in 2 days every 4 weeks) were administered in two women with a history of fetal death with aspirin plus low-molecular-weight heparin (LMWH).
Pregnancy was monitored from pregnancy diagnosis to up to 12 weeks post-partum by at least a monthly consultation (more frequently after 30 weeks of gestation, depending on disease activity and fetal status), both with an internist and an obstetrician. At each visit, weight and blood pressure were measured, fetal growth was assessed by abdominal palpation, evaluation of symphysis–fundal height and ultrasound, and urinalysis was performed using a Multistix. Monthly routine laboratory assessment consisted of total blood count, aminotransferases, uric acid, serum creatinine, aCL determination and 24-h proteinuria. In case of SLE, antinuclear antibodies, anti-double-stranded DNA (dsDNA), anti-extractable nuclear antigen (ENA) and total complement, C3 and C4, were assessed. A fetal Doppler ultrasound examination was done at least every 3 months with evaluation of the uteroplacental perfusion. If there was no history of congenital heart block (CHB) related to anti-SSA antibodies, no therapy was dedicated to its prevention.
The following pregnancy data were recorded:
Medical and obstetric history: history of SLE, SLE nephritis, pre-existing hypertension, central nervous system (CNS) involvement, use of immunosuppressants, arterial and venous thrombosis, LA, aCL, prior pregnancy outcome.
Medical and obstetric clinical examination: arterial pressure, manifestations suggesting SLE flare—a variation of the SLE disease activity index (SLEDAI) of 2 or more was considered as an SLE flare.
Biological data: with regard to the determinations made at the first pregnancy visit, the highest variation of the following parameters was taken into account: platelet count, serum acid uric, daily proteinuria, aminotransferases. A 30% decrease of the platelet count, of total complement, a 30% increase of serum uric acid, a 0.5 g daily proteinuria increase and a 2-fold increase in aminotransferases were considered significant. The presence of hypocomplementaemia and anti-dsDNA antibodies were noted in SLE pregnancies.
Fetal Doppler ultrasound examination: the umbilical artery Doppler flow was measured at the placental end and assessed visually as having normal, reduced, absent or reversed end-diastolic flow. Umbilical artery flow was considered abnormal when there was reduced, absent or reverse end-diastolic flow. Abnormal umbilical artery flow appeared to be a good predictor of adverse pregnancy outcome with a sensitivity 89%, a specificity of 86%, a positive predictive value of 86% and a negative predictive value of 89% in pre-eclampsia and in pregnancies at risk for intrauterine growth retardation [18]. The right and left uterine arteries were identified at the apparent crossover with the external iliac arteries. The presence of an early diastolic notch was recorded. Abnormal uterine velocimetry at the mid-trimester examination should single out pregnancies at risk for adverse outcome with a sensitivity up to 100%, a specificity up to 97%, a positive predictive value up to 57% and a negative predictive value up to 100% in high-risk pregnancies [19]. Hence, data for the second and third trimesters were categorized in four types: (a) abnormal umbilical artery Doppler blood flow waveforms, (b) presence of abnormal notch on one or both uterine arteries, (c) IUGR assessed on measurement of head biparietal diameter and abdominal circumference, and (d) other morphological anomalies such as oligo- or polydramnios, or abruptio placentae.
Definitions
The following definitions were used:
Gestation duration was measured from the first day of the last menstrual period, or, if not available, on the ultrasound estimate; for pregnancy caused by ovulation induction therapy, 2 weeks were added to the date of conception.
Embryonic loss: spontaneous termination of pregnancy prior to 10 weeks of gestation [20].
Fetal death: according to Branch's definition [20], death of a fetus demonstrated to be alive at or beyond 10 weeks of gestation.
Premature birth: termination of pregnancy with a live birth below 37 weeks of gestation.
Full-term birth: termination of pregnancy with a live birth between 38 and 40 weeks.
IUGR: birth weight below the tenth percentile for the stated gestation.
Hypertension: diastolic pressure above 90 mm Hg.
Pre-eclampsia: hypertension complicated with at least 0.5 g/24 h proteinuria.
Eclampsia: pre-eclampsia complicated with seizures.
Adverse pregnancy outcome: (i) fetal or neonatal death, or (ii) pre-eclampsia or eclampsia or HELLP syndrome, or (iii) premature birth of a morphologically normal neonate at or before 34 weeks of gestation because of severe pre-eclampsia or eclampsia or severe placental insufficiency, or (iv) premature or full-term birth of a growth retarded liveborn.
Statistical methods
Data analysis was performed on SAS. A Fisher's exact test was performed for all qualitative variables, and a Student's t-test for comparison of quantitative variables. Variables found to be significant in the univariate analysis were included in a logistic regression model. An odds ratio with 95% confidence interval (CI) was computed.
Results
Sixteen pregnancies out of 116 ended in spontaneous abortions which occurred before the second trimester fetal Doppler ultrasound examination. Of 16 spontaneous abortions, six occurred in women with history of thrombophlebitis, one after an amniocentesis performed for karyotype screening and one after the discovery of morphological fetal abnormalities by fetal ultrasound examination. Hence, statistical analysis was performed on the 100 remaining pregnancies.
Characteristics of the study group
Thirty-three pregnancies occurred in nulliparous and 67 in multigravid women. Among the latter, 35 were preceded by prior adverse pregnancy outcome. The maternal history is summarized in Table 1. Ten pregnancies occurred after ovulation-induction therapy, with embryo transfer in eight. Sixty-seven pregnancies occurred in women with SLE, 44 being isolated SLE and 23 associated with secondary APS, 32 occurred in primary APS and one in APS associated with ulcerative colitis. Seven fetal deaths and one neonatal death occurred. The other 92 pregnancies ended in liveborns, premature in 15 cases and full-term in 77 cases. The main maternal and fetal complications are summarized in Tables 2 and 3. The second trimester fetal Doppler ultrasound examination was abnormal in 18 pregnancies, out of which 14 were complicated by five fetal deaths, one neonatal death, five premature deliveries associated with pre-eclampsia and/or HELLP syndrome or abruptio placentae, and three deliveries of growth restricted babies. Only seven of these pregnancies progressed until the third trimester. Hence, the third trimester fetal Doppler ultrasound examination, performed in 90 pregnancies, was abnormal in 18. Thirteen out of these 18 pregnancies ended in adverse outcome: one neonatal death, one fetal death, three pre-eclampsia/HELLP syndrome and/or abruptio placentae with premature delivery and eight deliveries of growth-restricted liveborns (Fig. 1).
. | SLE without APS (n = 44) . | Secondary APS (n = 24) (SLE in 23, ulcerative colitis in 1) . | Primary APS (n = 32) . |
---|---|---|---|
Prior obstetric complications: | 3 | 15 | 17 |
≥Three embryonic losses | 0 | 0 | 10 |
Fetal death | 2 | 13 | 4 |
Premature <35 weeks | 1 | 1 | 1 |
HELLP syndrome | 0 | 2a | 1 |
Pre-eclampsia | 0 | 0 | 3b |
Prior vascular complications: | 1 | 15 | 21 |
Thrombophlebitis | 1 | 10 | 17 |
Arterial occlusion | 0 | 3 | 3 |
Both arterial and venous thrombosis | 0 | 2 | 1 |
Both prior vascular and obstetric complications | 0 | 7 | 7 |
Major organ involvement:c | 14 | 7 | 3 |
Kidney involvement | 14 | 5 | 0 |
Hypertension | 0 | 1 | 1 |
CNS involvement | 1 | 6 | 2 |
. | SLE without APS (n = 44) . | Secondary APS (n = 24) (SLE in 23, ulcerative colitis in 1) . | Primary APS (n = 32) . |
---|---|---|---|
Prior obstetric complications: | 3 | 15 | 17 |
≥Three embryonic losses | 0 | 0 | 10 |
Fetal death | 2 | 13 | 4 |
Premature <35 weeks | 1 | 1 | 1 |
HELLP syndrome | 0 | 2a | 1 |
Pre-eclampsia | 0 | 0 | 3b |
Prior vascular complications: | 1 | 15 | 21 |
Thrombophlebitis | 1 | 10 | 17 |
Arterial occlusion | 0 | 3 | 3 |
Both arterial and venous thrombosis | 0 | 2 | 1 |
Both prior vascular and obstetric complications | 0 | 7 | 7 |
Major organ involvement:c | 14 | 7 | 3 |
Kidney involvement | 14 | 5 | 0 |
Hypertension | 0 | 1 | 1 |
CNS involvement | 1 | 6 | 2 |
aHELLP with fetal death in one case. bPre-eclampsia with fetal death in two cases. cEventually associated complications.
. | SLE without APS (n = 44) . | Secondary APS (n = 24) (SLE in 23, ulcerative colitis in 1) . | Primary APS (n = 32) . |
---|---|---|---|
Prior obstetric complications: | 3 | 15 | 17 |
≥Three embryonic losses | 0 | 0 | 10 |
Fetal death | 2 | 13 | 4 |
Premature <35 weeks | 1 | 1 | 1 |
HELLP syndrome | 0 | 2a | 1 |
Pre-eclampsia | 0 | 0 | 3b |
Prior vascular complications: | 1 | 15 | 21 |
Thrombophlebitis | 1 | 10 | 17 |
Arterial occlusion | 0 | 3 | 3 |
Both arterial and venous thrombosis | 0 | 2 | 1 |
Both prior vascular and obstetric complications | 0 | 7 | 7 |
Major organ involvement:c | 14 | 7 | 3 |
Kidney involvement | 14 | 5 | 0 |
Hypertension | 0 | 1 | 1 |
CNS involvement | 1 | 6 | 2 |
. | SLE without APS (n = 44) . | Secondary APS (n = 24) (SLE in 23, ulcerative colitis in 1) . | Primary APS (n = 32) . |
---|---|---|---|
Prior obstetric complications: | 3 | 15 | 17 |
≥Three embryonic losses | 0 | 0 | 10 |
Fetal death | 2 | 13 | 4 |
Premature <35 weeks | 1 | 1 | 1 |
HELLP syndrome | 0 | 2a | 1 |
Pre-eclampsia | 0 | 0 | 3b |
Prior vascular complications: | 1 | 15 | 21 |
Thrombophlebitis | 1 | 10 | 17 |
Arterial occlusion | 0 | 3 | 3 |
Both arterial and venous thrombosis | 0 | 2 | 1 |
Both prior vascular and obstetric complications | 0 | 7 | 7 |
Major organ involvement:c | 14 | 7 | 3 |
Kidney involvement | 14 | 5 | 0 |
Hypertension | 0 | 1 | 1 |
CNS involvement | 1 | 6 | 2 |
aHELLP with fetal death in one case. bPre-eclampsia with fetal death in two cases. cEventually associated complications.
. | Number of pregnancies . |
---|---|
SLE flare in 67 SLE pregnancies | 18 (27%) |
Kidney involvement | 4 |
Arthritis | 12 |
Skin involvement | 2 |
Ulcerative colitis flare in one case of ulcerative colitis | 1 |
Hypertension: | 9 |
with pre-eclampsia and/or HELLP syndrome | 8 |
Gestational diabetes in 47 steroid-treated pregnancies | 6 (13%) |
Septicaemia | 2 |
Increased serum acid uric | 37 |
Decreased platelet count | 8 |
Increased aminotransferases | 6 |
Hypocomplementaemia in 67 SLE pregnancies | 5 (7%) |
Anti-dsDNA antibodies in 67 SLE pregnancies | 16 (24%) |
Increased proteinuria >0.5 g/day | 9 |
Superficial thrombophlebitis | 1 |
Post-partum haemorrhage | 4 |
Osteoporosis fracture in 47 heparin-treated pregnancies | 0 |
. | Number of pregnancies . |
---|---|
SLE flare in 67 SLE pregnancies | 18 (27%) |
Kidney involvement | 4 |
Arthritis | 12 |
Skin involvement | 2 |
Ulcerative colitis flare in one case of ulcerative colitis | 1 |
Hypertension: | 9 |
with pre-eclampsia and/or HELLP syndrome | 8 |
Gestational diabetes in 47 steroid-treated pregnancies | 6 (13%) |
Septicaemia | 2 |
Increased serum acid uric | 37 |
Decreased platelet count | 8 |
Increased aminotransferases | 6 |
Hypocomplementaemia in 67 SLE pregnancies | 5 (7%) |
Anti-dsDNA antibodies in 67 SLE pregnancies | 16 (24%) |
Increased proteinuria >0.5 g/day | 9 |
Superficial thrombophlebitis | 1 |
Post-partum haemorrhage | 4 |
Osteoporosis fracture in 47 heparin-treated pregnancies | 0 |
. | Number of pregnancies . |
---|---|
SLE flare in 67 SLE pregnancies | 18 (27%) |
Kidney involvement | 4 |
Arthritis | 12 |
Skin involvement | 2 |
Ulcerative colitis flare in one case of ulcerative colitis | 1 |
Hypertension: | 9 |
with pre-eclampsia and/or HELLP syndrome | 8 |
Gestational diabetes in 47 steroid-treated pregnancies | 6 (13%) |
Septicaemia | 2 |
Increased serum acid uric | 37 |
Decreased platelet count | 8 |
Increased aminotransferases | 6 |
Hypocomplementaemia in 67 SLE pregnancies | 5 (7%) |
Anti-dsDNA antibodies in 67 SLE pregnancies | 16 (24%) |
Increased proteinuria >0.5 g/day | 9 |
Superficial thrombophlebitis | 1 |
Post-partum haemorrhage | 4 |
Osteoporosis fracture in 47 heparin-treated pregnancies | 0 |
. | Number of pregnancies . |
---|---|
SLE flare in 67 SLE pregnancies | 18 (27%) |
Kidney involvement | 4 |
Arthritis | 12 |
Skin involvement | 2 |
Ulcerative colitis flare in one case of ulcerative colitis | 1 |
Hypertension: | 9 |
with pre-eclampsia and/or HELLP syndrome | 8 |
Gestational diabetes in 47 steroid-treated pregnancies | 6 (13%) |
Septicaemia | 2 |
Increased serum acid uric | 37 |
Decreased platelet count | 8 |
Increased aminotransferases | 6 |
Hypocomplementaemia in 67 SLE pregnancies | 5 (7%) |
Anti-dsDNA antibodies in 67 SLE pregnancies | 16 (24%) |
Increased proteinuria >0.5 g/day | 9 |
Superficial thrombophlebitis | 1 |
Post-partum haemorrhage | 4 |
Osteoporosis fracture in 47 heparin-treated pregnancies | 0 |
Complications . | Number of pregnancies . |
---|---|
Deaths | 8 |
Fetal death | 7 |
Neonatal death | 1 |
Deliveries | 92 |
Premature | 15 |
Secondary to pre-eclampsia/HELLP syndrome | 6 |
Full-term | 77 |
Growth restriction | 18 |
in premature liveborns | 4 |
in full-term liveborns | 14 (1 twin) |
Complications . | Number of pregnancies . |
---|---|
Deaths | 8 |
Fetal death | 7 |
Neonatal death | 1 |
Deliveries | 92 |
Premature | 15 |
Secondary to pre-eclampsia/HELLP syndrome | 6 |
Full-term | 77 |
Growth restriction | 18 |
in premature liveborns | 4 |
in full-term liveborns | 14 (1 twin) |
Complications . | Number of pregnancies . |
---|---|
Deaths | 8 |
Fetal death | 7 |
Neonatal death | 1 |
Deliveries | 92 |
Premature | 15 |
Secondary to pre-eclampsia/HELLP syndrome | 6 |
Full-term | 77 |
Growth restriction | 18 |
in premature liveborns | 4 |
in full-term liveborns | 14 (1 twin) |
Complications . | Number of pregnancies . |
---|---|
Deaths | 8 |
Fetal death | 7 |
Neonatal death | 1 |
Deliveries | 92 |
Premature | 15 |
Secondary to pre-eclampsia/HELLP syndrome | 6 |
Full-term | 77 |
Growth restriction | 18 |
in premature liveborns | 4 |
in full-term liveborns | 14 (1 twin) |
Fetal and neonatal deaths
One neonatal death occurred, in addition to seven fetal deaths which occurred between 24 and 39 weeks. All except one of these eight women had APS with a history of thrombophlebitis. One woman had SLE with history of CHB due to anti-SSA antibodies. Three women had had prior spontaneous abortion. Except for two cases, all of these women with APS were treated with LMWH at a dosage varying between 5000 and 8000 units daily. Heparin was started secondarily, or its dose increased in two cases because of IUGR and/or abnormal umbilical Doppler blood flow examination, but it did not prevent fetal death in one case.
The second trimester Doppler ultrasound examination was abnormal in six cases. Abnormal end-diastolic velocities of umbilical artery Doppler flow together with notched uterine arteries were observed in three cases, and associated with IUGR in two cases. LMWH compliance was poor in two of these cases. Notched uterine arteries and fetal hydrops preceded one fetal death. Uterine arteries were solely notched in two cases. However, fetal death occurred a few days after a sudden pre-eclampsia in one case; in the other case, subsequent Doppler ultrasound examination showed onset of an abnormal end-diastolic umbilical artery Doppler flow before neonatal death. Biological monitoring showed in two cases a 125% and an 180% increased uric acid compared with the base level, associated with pre-eclampsia in one case. The second trimester examination was normal but a sudden polyhydramnios occurred in the third trimester before fetal death in one case.
As shown in Table 4, univariate analysis showed that fetal and neonatal deaths correlated with abnormal end-diastolic umbilical artery Doppler flow at the second trimester examination (P<0.006), history of thrombophlebitis (P<0.001), presence of notched uterine artery or growth restriction at the second trimester examination (P<0.002) and use of prednisone during pregnancy (P<0.06). Prior severity of SLE attested by use of immunosuppressive therapy and/or renal and/or CNS involvement, and history of obstetric complications did not correlate with fetal/neonatal death. No biological criteria reached statistical significance. In multivariate analysis, the only two predictors were abnormal end-diastolic umbilical artery Doppler flow at the second trimester examination [odds ratio OR, 7.44; 95% CI 1.02–54.00, P = 0.047] and history of thrombophlebitis (OR 13.78; 95% CI 1.56–121.38, P = 0.018). Table 5 summarizes the prediction of fetal/neonatal death by fetal Doppler ultrasound examination.
Potential predictor . | Fetal or neonatal deaths (n = 8) . | Livebirths (n = 92) . | P . | Odds ratio (95% CI) . |
---|---|---|---|---|
Medical history | ||||
SLE | 3 (37.5%) | 64 (69.6%) | 0.11 | 0.26 (0.06–1.17) |
APS | 7 (87.5%) | 49 (53.3%) | 0.07 | 6.14 (0.73–51.95) |
Multigravida | 4 (50%) | 63 (68.5%) | 0.43 | 0.46 (0.11–1.97) |
Prior normal pregnancy | 2 (25%) | 32 (34.8%) | 0.71 | 0.62 (0.12–3.28) |
Prior abnormal pregnancy | 4 (50%) | 48 (52.2%) | 1 | 0.92 (0.22–3.89) |
Prior thrombophlebitis | 7 (87.5%) | 24 (26.1%) | 0.001 | 19.83 (2.32–169.65) |
Prior arterial thrombosis | 0 | 9 (9.8%) | 1 | 0.52 (0.03–9.68) |
Prior hypertension | 0 | 3 (3.3%) | 1 | 1.50 (0.07–31.62) |
Prior nephritis | 0 | 20 (21.7%) | 0.35 | 0.21 (0.01–3.76) |
Prior CNS involvement | 0 | 9 (9.8%) | 1 | 0.52 (0.03–9.68) |
Prior use of prednisone | 2 (25%) | 51 (55.4%) | 0.14 | 0.27 (0.05–1.40) |
Prior use of immunosuppressants | 0 | 11 (12%) | 0.59 | 0.42 (0.02–7.72) |
Clinical data | ||||
Hypertension | 1 (12.5%) | 8 (8.7%) | 0.54 | 1.50 (0.16–13.77) |
SLE flare | 2 (25%) | 15 (16.3%) | 0.62 | 1.71 (0.31–9.30) |
Biological data | ||||
Anti-SSA present | 1 (12.5%) | 26 (28.3%) | 0.68 | 0.36 (0.04–3.09) |
Lupus anticoagulant present | 5 (62.5%) | 30 (32.6%) | 0.12 | 3.44 (0.77–15.38) |
Anticardiolipin present | 7 (87.5%) | 62 (67.4%) | 0.43 | 3.39 (0.40–28.80) |
Serum uric acid +30% | 3 (37.5%) | 34 (37.0%) | 1 | 1.02 (0.23–4.55) |
Platelets –30% | 0 | 8 (8.7%) | 1 | 0.58 (0.03–11.04) |
Hypocomplementaemia | 0 | 5 (5.4%) | 1 | 0.94 (0.05–18.41) |
Anti-dsDNA | 1 (12.5%) | 15 (16.3%) | 1 | 0.73 (0.08–6.40) |
Increased aminotransferases | 1 (12.5%) | 5 (5.4%) | 0.40 | 2.49 (0.25–24.32) |
Proteinuria +0.5 g/day | 1 (12.5%) | 8 (8.7%) | 0.54 | 1.50 (0.16–13.77) |
Therapy | ||||
Low-dose aspirin | 8 (100%) | 82 (89.1%) | 1 | 2.16 (0.12–40.26) |
Heparin | 5 (62.5%) | 42 (45.6%) | 0.47 | 1.98 (0.45–8.80) |
Prednisone | 2 (25%) | 58 (63%) | 0.06 | 0.19 (0.04–1.02) |
Second trimester Doppler ultrasound | ||||
Abnormal umbilical artery | 3 (37.5%) | 3 (3.26%) | 0.006 | 17.8 (2.84–111.68) |
Notched uterine artery | 5 (62.5%) | 10 (10.9%) | 0.002 | 13.67 (2.83–66.00) |
Growth retardation | 2 (25%) | 2 (2.2%) | 0.03 | 15.00 (1.79–125.85) |
Other anomaly | 1 (12.5%) | 2 (2.2%) | 0.22 | 6.43 (0.52–79.95) |
Potential predictor . | Fetal or neonatal deaths (n = 8) . | Livebirths (n = 92) . | P . | Odds ratio (95% CI) . |
---|---|---|---|---|
Medical history | ||||
SLE | 3 (37.5%) | 64 (69.6%) | 0.11 | 0.26 (0.06–1.17) |
APS | 7 (87.5%) | 49 (53.3%) | 0.07 | 6.14 (0.73–51.95) |
Multigravida | 4 (50%) | 63 (68.5%) | 0.43 | 0.46 (0.11–1.97) |
Prior normal pregnancy | 2 (25%) | 32 (34.8%) | 0.71 | 0.62 (0.12–3.28) |
Prior abnormal pregnancy | 4 (50%) | 48 (52.2%) | 1 | 0.92 (0.22–3.89) |
Prior thrombophlebitis | 7 (87.5%) | 24 (26.1%) | 0.001 | 19.83 (2.32–169.65) |
Prior arterial thrombosis | 0 | 9 (9.8%) | 1 | 0.52 (0.03–9.68) |
Prior hypertension | 0 | 3 (3.3%) | 1 | 1.50 (0.07–31.62) |
Prior nephritis | 0 | 20 (21.7%) | 0.35 | 0.21 (0.01–3.76) |
Prior CNS involvement | 0 | 9 (9.8%) | 1 | 0.52 (0.03–9.68) |
Prior use of prednisone | 2 (25%) | 51 (55.4%) | 0.14 | 0.27 (0.05–1.40) |
Prior use of immunosuppressants | 0 | 11 (12%) | 0.59 | 0.42 (0.02–7.72) |
Clinical data | ||||
Hypertension | 1 (12.5%) | 8 (8.7%) | 0.54 | 1.50 (0.16–13.77) |
SLE flare | 2 (25%) | 15 (16.3%) | 0.62 | 1.71 (0.31–9.30) |
Biological data | ||||
Anti-SSA present | 1 (12.5%) | 26 (28.3%) | 0.68 | 0.36 (0.04–3.09) |
Lupus anticoagulant present | 5 (62.5%) | 30 (32.6%) | 0.12 | 3.44 (0.77–15.38) |
Anticardiolipin present | 7 (87.5%) | 62 (67.4%) | 0.43 | 3.39 (0.40–28.80) |
Serum uric acid +30% | 3 (37.5%) | 34 (37.0%) | 1 | 1.02 (0.23–4.55) |
Platelets –30% | 0 | 8 (8.7%) | 1 | 0.58 (0.03–11.04) |
Hypocomplementaemia | 0 | 5 (5.4%) | 1 | 0.94 (0.05–18.41) |
Anti-dsDNA | 1 (12.5%) | 15 (16.3%) | 1 | 0.73 (0.08–6.40) |
Increased aminotransferases | 1 (12.5%) | 5 (5.4%) | 0.40 | 2.49 (0.25–24.32) |
Proteinuria +0.5 g/day | 1 (12.5%) | 8 (8.7%) | 0.54 | 1.50 (0.16–13.77) |
Therapy | ||||
Low-dose aspirin | 8 (100%) | 82 (89.1%) | 1 | 2.16 (0.12–40.26) |
Heparin | 5 (62.5%) | 42 (45.6%) | 0.47 | 1.98 (0.45–8.80) |
Prednisone | 2 (25%) | 58 (63%) | 0.06 | 0.19 (0.04–1.02) |
Second trimester Doppler ultrasound | ||||
Abnormal umbilical artery | 3 (37.5%) | 3 (3.26%) | 0.006 | 17.8 (2.84–111.68) |
Notched uterine artery | 5 (62.5%) | 10 (10.9%) | 0.002 | 13.67 (2.83–66.00) |
Growth retardation | 2 (25%) | 2 (2.2%) | 0.03 | 15.00 (1.79–125.85) |
Other anomaly | 1 (12.5%) | 2 (2.2%) | 0.22 | 6.43 (0.52–79.95) |
Potential predictor . | Fetal or neonatal deaths (n = 8) . | Livebirths (n = 92) . | P . | Odds ratio (95% CI) . |
---|---|---|---|---|
Medical history | ||||
SLE | 3 (37.5%) | 64 (69.6%) | 0.11 | 0.26 (0.06–1.17) |
APS | 7 (87.5%) | 49 (53.3%) | 0.07 | 6.14 (0.73–51.95) |
Multigravida | 4 (50%) | 63 (68.5%) | 0.43 | 0.46 (0.11–1.97) |
Prior normal pregnancy | 2 (25%) | 32 (34.8%) | 0.71 | 0.62 (0.12–3.28) |
Prior abnormal pregnancy | 4 (50%) | 48 (52.2%) | 1 | 0.92 (0.22–3.89) |
Prior thrombophlebitis | 7 (87.5%) | 24 (26.1%) | 0.001 | 19.83 (2.32–169.65) |
Prior arterial thrombosis | 0 | 9 (9.8%) | 1 | 0.52 (0.03–9.68) |
Prior hypertension | 0 | 3 (3.3%) | 1 | 1.50 (0.07–31.62) |
Prior nephritis | 0 | 20 (21.7%) | 0.35 | 0.21 (0.01–3.76) |
Prior CNS involvement | 0 | 9 (9.8%) | 1 | 0.52 (0.03–9.68) |
Prior use of prednisone | 2 (25%) | 51 (55.4%) | 0.14 | 0.27 (0.05–1.40) |
Prior use of immunosuppressants | 0 | 11 (12%) | 0.59 | 0.42 (0.02–7.72) |
Clinical data | ||||
Hypertension | 1 (12.5%) | 8 (8.7%) | 0.54 | 1.50 (0.16–13.77) |
SLE flare | 2 (25%) | 15 (16.3%) | 0.62 | 1.71 (0.31–9.30) |
Biological data | ||||
Anti-SSA present | 1 (12.5%) | 26 (28.3%) | 0.68 | 0.36 (0.04–3.09) |
Lupus anticoagulant present | 5 (62.5%) | 30 (32.6%) | 0.12 | 3.44 (0.77–15.38) |
Anticardiolipin present | 7 (87.5%) | 62 (67.4%) | 0.43 | 3.39 (0.40–28.80) |
Serum uric acid +30% | 3 (37.5%) | 34 (37.0%) | 1 | 1.02 (0.23–4.55) |
Platelets –30% | 0 | 8 (8.7%) | 1 | 0.58 (0.03–11.04) |
Hypocomplementaemia | 0 | 5 (5.4%) | 1 | 0.94 (0.05–18.41) |
Anti-dsDNA | 1 (12.5%) | 15 (16.3%) | 1 | 0.73 (0.08–6.40) |
Increased aminotransferases | 1 (12.5%) | 5 (5.4%) | 0.40 | 2.49 (0.25–24.32) |
Proteinuria +0.5 g/day | 1 (12.5%) | 8 (8.7%) | 0.54 | 1.50 (0.16–13.77) |
Therapy | ||||
Low-dose aspirin | 8 (100%) | 82 (89.1%) | 1 | 2.16 (0.12–40.26) |
Heparin | 5 (62.5%) | 42 (45.6%) | 0.47 | 1.98 (0.45–8.80) |
Prednisone | 2 (25%) | 58 (63%) | 0.06 | 0.19 (0.04–1.02) |
Second trimester Doppler ultrasound | ||||
Abnormal umbilical artery | 3 (37.5%) | 3 (3.26%) | 0.006 | 17.8 (2.84–111.68) |
Notched uterine artery | 5 (62.5%) | 10 (10.9%) | 0.002 | 13.67 (2.83–66.00) |
Growth retardation | 2 (25%) | 2 (2.2%) | 0.03 | 15.00 (1.79–125.85) |
Other anomaly | 1 (12.5%) | 2 (2.2%) | 0.22 | 6.43 (0.52–79.95) |
Potential predictor . | Fetal or neonatal deaths (n = 8) . | Livebirths (n = 92) . | P . | Odds ratio (95% CI) . |
---|---|---|---|---|
Medical history | ||||
SLE | 3 (37.5%) | 64 (69.6%) | 0.11 | 0.26 (0.06–1.17) |
APS | 7 (87.5%) | 49 (53.3%) | 0.07 | 6.14 (0.73–51.95) |
Multigravida | 4 (50%) | 63 (68.5%) | 0.43 | 0.46 (0.11–1.97) |
Prior normal pregnancy | 2 (25%) | 32 (34.8%) | 0.71 | 0.62 (0.12–3.28) |
Prior abnormal pregnancy | 4 (50%) | 48 (52.2%) | 1 | 0.92 (0.22–3.89) |
Prior thrombophlebitis | 7 (87.5%) | 24 (26.1%) | 0.001 | 19.83 (2.32–169.65) |
Prior arterial thrombosis | 0 | 9 (9.8%) | 1 | 0.52 (0.03–9.68) |
Prior hypertension | 0 | 3 (3.3%) | 1 | 1.50 (0.07–31.62) |
Prior nephritis | 0 | 20 (21.7%) | 0.35 | 0.21 (0.01–3.76) |
Prior CNS involvement | 0 | 9 (9.8%) | 1 | 0.52 (0.03–9.68) |
Prior use of prednisone | 2 (25%) | 51 (55.4%) | 0.14 | 0.27 (0.05–1.40) |
Prior use of immunosuppressants | 0 | 11 (12%) | 0.59 | 0.42 (0.02–7.72) |
Clinical data | ||||
Hypertension | 1 (12.5%) | 8 (8.7%) | 0.54 | 1.50 (0.16–13.77) |
SLE flare | 2 (25%) | 15 (16.3%) | 0.62 | 1.71 (0.31–9.30) |
Biological data | ||||
Anti-SSA present | 1 (12.5%) | 26 (28.3%) | 0.68 | 0.36 (0.04–3.09) |
Lupus anticoagulant present | 5 (62.5%) | 30 (32.6%) | 0.12 | 3.44 (0.77–15.38) |
Anticardiolipin present | 7 (87.5%) | 62 (67.4%) | 0.43 | 3.39 (0.40–28.80) |
Serum uric acid +30% | 3 (37.5%) | 34 (37.0%) | 1 | 1.02 (0.23–4.55) |
Platelets –30% | 0 | 8 (8.7%) | 1 | 0.58 (0.03–11.04) |
Hypocomplementaemia | 0 | 5 (5.4%) | 1 | 0.94 (0.05–18.41) |
Anti-dsDNA | 1 (12.5%) | 15 (16.3%) | 1 | 0.73 (0.08–6.40) |
Increased aminotransferases | 1 (12.5%) | 5 (5.4%) | 0.40 | 2.49 (0.25–24.32) |
Proteinuria +0.5 g/day | 1 (12.5%) | 8 (8.7%) | 0.54 | 1.50 (0.16–13.77) |
Therapy | ||||
Low-dose aspirin | 8 (100%) | 82 (89.1%) | 1 | 2.16 (0.12–40.26) |
Heparin | 5 (62.5%) | 42 (45.6%) | 0.47 | 1.98 (0.45–8.80) |
Prednisone | 2 (25%) | 58 (63%) | 0.06 | 0.19 (0.04–1.02) |
Second trimester Doppler ultrasound | ||||
Abnormal umbilical artery | 3 (37.5%) | 3 (3.26%) | 0.006 | 17.8 (2.84–111.68) |
Notched uterine artery | 5 (62.5%) | 10 (10.9%) | 0.002 | 13.67 (2.83–66.00) |
Growth retardation | 2 (25%) | 2 (2.2%) | 0.03 | 15.00 (1.79–125.85) |
Other anomaly | 1 (12.5%) | 2 (2.2%) | 0.22 | 6.43 (0.52–79.95) |
Tests . | Sensitivity (%) . | Specificity (%) . | Positive predictive value (%) . | Negative predictive value (%) . |
---|---|---|---|---|
Abnormal umbilical artery | 37.5 | 94.7 | 50 | 96.7 |
Notched uterine artery | 62.5 | 89.1 | 33.3 | 96.4 |
Growth retardation | 25 | 97.8 | 50 | 93.7 |
Tests . | Sensitivity (%) . | Specificity (%) . | Positive predictive value (%) . | Negative predictive value (%) . |
---|---|---|---|---|
Abnormal umbilical artery | 37.5 | 94.7 | 50 | 96.7 |
Notched uterine artery | 62.5 | 89.1 | 33.3 | 96.4 |
Growth retardation | 25 | 97.8 | 50 | 93.7 |
Tests . | Sensitivity (%) . | Specificity (%) . | Positive predictive value (%) . | Negative predictive value (%) . |
---|---|---|---|---|
Abnormal umbilical artery | 37.5 | 94.7 | 50 | 96.7 |
Notched uterine artery | 62.5 | 89.1 | 33.3 | 96.4 |
Growth retardation | 25 | 97.8 | 50 | 93.7 |
Tests . | Sensitivity (%) . | Specificity (%) . | Positive predictive value (%) . | Negative predictive value (%) . |
---|---|---|---|---|
Abnormal umbilical artery | 37.5 | 94.7 | 50 | 96.7 |
Notched uterine artery | 62.5 | 89.1 | 33.3 | 96.4 |
Growth retardation | 25 | 97.8 | 50 | 93.7 |
Adverse pregnancy outcome
Thirty-one adverse pregnancy outcomes occurred. Besides eight fetal/neonatal deaths, they consisted of pre-eclampsia/HELLP syndrome in seven pregnancies, severe prematurity in two and growth restriction in 14.
The second trimester Doppler ultrasound examination was abnormal in 14 cases, six associated with fetal or neonatal deaths, five with pre-eclampsia/HELLP syndrome and three with growth restriction. Anomalies consisted of six cases of abnormal end-diastolic umbilical artery Doppler flow associated in four cases with IUGR. In all but one of these cases there was a history of thrombophlebitis related to APS. Doppler abnormalities preceded pre-eclampsia and/or HELLP syndrome in two cases. In six cases, the second Doppler ultrasound examination showed notched uterine arteries with normal umbilical artery flow. This anomaly persisted subsequently in all cases progressing beyond the third trimester. Three abnormal second trimester Doppler ultrasound examinations normalized subsequently; abnormalities consisted of isolated notched uterine arteries in two cases and abruptio placentae in one case. The third trimester Doppler ultrasound examination was abnormal in 13 pregnancies (of which seven had abnormal second trimester Doppler ultrasound examination). One case of abnormal end-diastolic umbilical artery Doppler flow with notched uterine arteries ended in neonatal death. Eleven consisted of notched uterine arteries, associated with IUGR in seven cases, abruptio placentae in two cases and placenta praevia in two cases. One sudden isolated polyhydramnios preceded one fetal death. Pregnancies ended in two fetal/neonatal deaths, three cases of pre-eclampsia/HELLP syndrome and delivery of eight growth-restricted babies.
An adverse pregnancy outcome occurred in eight cases although the second and third Doppler ultrasound examinations were normal. Adverse outcomes consisted of one HELLP syndrome, one very premature delivery and delivery of six growth-restricted babies. Results of univariate analysis are given in Table 6. An adverse pregnancy outcome was associated with notched uterine artery (P<0.00003), absent end-diastolic umbilical artery Doppler flow (P<0.0006) and IUGR (P<0.008) at the second trimester examination, with IUGR (P<0.0002) and notched uterine artery (P<0.0008) at the third trimester examination, with use of heparin (P<0.005) and with history of thrombophlebitis (P<0.04). In multivariate analysis, the only predictor was the presence of a notched uterine artery at the second trimester examination with an OR of 13.84 (95% CI 3.41–56.16, P = 0.001). Table 7 summarizes prediction of adverse pregnancy outcome by fetal Doppler ultrasound examination.
Potential predictor . | Adverse pregnancy outcome (n = 31) . | Uncomplicated pregnancy (n = 69) . | P . | Odds ratio (95% CI) . |
---|---|---|---|---|
Medical history | ||||
SLE | 22 (71%) | 45 (65.2%) | 0.57 | 1.30 (0.52–3.27) |
APS | 20 (64.5%) | 36 (52.2%) | 0.25 | 1.67 (0.69–3.99) |
Multigravida | 21 (67.7%) | 46 (66.7%) | 0.92 | 1.05 (0.42–2.60) |
Prior normal pregnancy | 10 (32.2%) | 24 (34.8%) | 0.80 | 0.89 (0.36–2.20) |
Prior abnormal pregnancy | 18 (58%) | 34 (49.3%) | 0.42 | 1.42 (0.61–3.35) |
Prior thrombophlebitis | 14 (45.2%) | 17 (24.6%) | 0.04 | 2.52 (1.03–6.16) |
Prior arterial thrombosis | 3 (9.7%) | 6 (8.7%) | 1 | 1.12 (0.26–4.82) |
Prior hypertension | 1 (3.2%) | 2 (2.9%) | 1 | 1.11 (0.10–12.80) |
Prior nephritis | 5 (16.13%) | 15 (21.7%) | 0.52 | 0.69 (0.22–2.11) |
Prior CNS involvement | 3 (9.7%) | 6 (8.7%) | 1 | 1.12 (0.26–4.82) |
Prior use of prednisone | 16 (51.6%) | 37 (53.6%) | 0.85 | 0.92 (0.39–2.16) |
Prior use of immunosuppressants | 3 (9.7%) | 8 (11.6%) | 1 | 0.82 (0.20–3.31) |
Clinical data | ||||
Hypertension | 5 (16.13%) | 4 (5.8%) | 0.13 | 3.12 (0.77–12.56) |
SLE flare | 6 (19.3%) | 13 (18.8%) | 1 | 1.03 (0.35–3.03) |
Biological data | ||||
Anti-SSA present | 8 (25.8%) | 19 (27.5%) | 0.86 | 0.91 (0.35–2.40) |
Lupus anticoagulant present | 11 (35.5%) | 24 (34.8%) | 0.94 | 1.03 (0.42–2.50) |
Anticardiolipin present | 21 (67.7%) | 48 (69.5%) | 0.85 | 0.9 (0.36–2.29) |
Serum uric acid +30% | 14 (45.1%) | 23 (33.3%) | 0.26 | 1.65 (0.69–3.92) |
Platelets –30% | 4 (12.9%) | 4 (5.8%) | 0.25 | 2.41 (0.56–10.33) |
Hypocomplementaemia | 1 (3.2%) | 4 (5.8%) | 1 | 0.54 (0.06–5.06) |
Anti-dsDNA | 1 (3.2%) | 2 (2.9%) | 1 | 1.11 (0.10–12.80) |
Increased aminotransferases | 4 (12.9%) | 2 (2.9%) | 0.07 | 4.96 (0.86–28.71) |
Proteinuria +0.5 g/day | 4 (12.9%) | 5 (7.2%) | 0.45 | 1.9 (0.47–7.61) |
Therapy | ||||
Low-dose aspirin | 29 (93.5%) | 61 (88.4%) | 0.72 | 1.9 (0.38–9.53) |
Heparin | 19 (61.3%) | 28 (40.6%) | 0.055 | 2.32 (0.97–5.52) |
Prednisone | 19 (61.3%) | 41 (59.4%) | 0.86 | 1.08 (0.45–2.58) |
Second trimester Doppler ultrasound | ||||
Umbilical artery | 6 (19.3%) | 0 | 0.0006 | 35.4 (1.93–651.72) |
Uterine artery | 12 (38.7%) | 3 (4.3%) | 0.00003 | 13.89 (3.55–54.36) |
Growth retardation | 4 (12.9%) | 0 | 0.008 | 22.74 (1.18–436.72) |
Other anomaly | 2 (6.4%) | 1 (1.4%) | 0.2 | 4.69 (0.41–53.78) |
Third trimester Doppler ultrasound | ||||
Umbilical artery | 1 (4.7%) | 0 | 0.24 | 9.88 (0.39–251.86) |
Uterine artery | 8 (38.1%) | 4 (5.9%) | 0.0008 | 9.69 (2.54–37.03) |
Growth retardation | 7 (33.3%) | 0 | 0.00002 | 69.83 (3.77–1292.6) |
Other anomaly | 2 (9.1%) | 2 (3.0%) | 0.25 | 3.25 (0.43–22.54) |
Potential predictor . | Adverse pregnancy outcome (n = 31) . | Uncomplicated pregnancy (n = 69) . | P . | Odds ratio (95% CI) . |
---|---|---|---|---|
Medical history | ||||
SLE | 22 (71%) | 45 (65.2%) | 0.57 | 1.30 (0.52–3.27) |
APS | 20 (64.5%) | 36 (52.2%) | 0.25 | 1.67 (0.69–3.99) |
Multigravida | 21 (67.7%) | 46 (66.7%) | 0.92 | 1.05 (0.42–2.60) |
Prior normal pregnancy | 10 (32.2%) | 24 (34.8%) | 0.80 | 0.89 (0.36–2.20) |
Prior abnormal pregnancy | 18 (58%) | 34 (49.3%) | 0.42 | 1.42 (0.61–3.35) |
Prior thrombophlebitis | 14 (45.2%) | 17 (24.6%) | 0.04 | 2.52 (1.03–6.16) |
Prior arterial thrombosis | 3 (9.7%) | 6 (8.7%) | 1 | 1.12 (0.26–4.82) |
Prior hypertension | 1 (3.2%) | 2 (2.9%) | 1 | 1.11 (0.10–12.80) |
Prior nephritis | 5 (16.13%) | 15 (21.7%) | 0.52 | 0.69 (0.22–2.11) |
Prior CNS involvement | 3 (9.7%) | 6 (8.7%) | 1 | 1.12 (0.26–4.82) |
Prior use of prednisone | 16 (51.6%) | 37 (53.6%) | 0.85 | 0.92 (0.39–2.16) |
Prior use of immunosuppressants | 3 (9.7%) | 8 (11.6%) | 1 | 0.82 (0.20–3.31) |
Clinical data | ||||
Hypertension | 5 (16.13%) | 4 (5.8%) | 0.13 | 3.12 (0.77–12.56) |
SLE flare | 6 (19.3%) | 13 (18.8%) | 1 | 1.03 (0.35–3.03) |
Biological data | ||||
Anti-SSA present | 8 (25.8%) | 19 (27.5%) | 0.86 | 0.91 (0.35–2.40) |
Lupus anticoagulant present | 11 (35.5%) | 24 (34.8%) | 0.94 | 1.03 (0.42–2.50) |
Anticardiolipin present | 21 (67.7%) | 48 (69.5%) | 0.85 | 0.9 (0.36–2.29) |
Serum uric acid +30% | 14 (45.1%) | 23 (33.3%) | 0.26 | 1.65 (0.69–3.92) |
Platelets –30% | 4 (12.9%) | 4 (5.8%) | 0.25 | 2.41 (0.56–10.33) |
Hypocomplementaemia | 1 (3.2%) | 4 (5.8%) | 1 | 0.54 (0.06–5.06) |
Anti-dsDNA | 1 (3.2%) | 2 (2.9%) | 1 | 1.11 (0.10–12.80) |
Increased aminotransferases | 4 (12.9%) | 2 (2.9%) | 0.07 | 4.96 (0.86–28.71) |
Proteinuria +0.5 g/day | 4 (12.9%) | 5 (7.2%) | 0.45 | 1.9 (0.47–7.61) |
Therapy | ||||
Low-dose aspirin | 29 (93.5%) | 61 (88.4%) | 0.72 | 1.9 (0.38–9.53) |
Heparin | 19 (61.3%) | 28 (40.6%) | 0.055 | 2.32 (0.97–5.52) |
Prednisone | 19 (61.3%) | 41 (59.4%) | 0.86 | 1.08 (0.45–2.58) |
Second trimester Doppler ultrasound | ||||
Umbilical artery | 6 (19.3%) | 0 | 0.0006 | 35.4 (1.93–651.72) |
Uterine artery | 12 (38.7%) | 3 (4.3%) | 0.00003 | 13.89 (3.55–54.36) |
Growth retardation | 4 (12.9%) | 0 | 0.008 | 22.74 (1.18–436.72) |
Other anomaly | 2 (6.4%) | 1 (1.4%) | 0.2 | 4.69 (0.41–53.78) |
Third trimester Doppler ultrasound | ||||
Umbilical artery | 1 (4.7%) | 0 | 0.24 | 9.88 (0.39–251.86) |
Uterine artery | 8 (38.1%) | 4 (5.9%) | 0.0008 | 9.69 (2.54–37.03) |
Growth retardation | 7 (33.3%) | 0 | 0.00002 | 69.83 (3.77–1292.6) |
Other anomaly | 2 (9.1%) | 2 (3.0%) | 0.25 | 3.25 (0.43–22.54) |
Potential predictor . | Adverse pregnancy outcome (n = 31) . | Uncomplicated pregnancy (n = 69) . | P . | Odds ratio (95% CI) . |
---|---|---|---|---|
Medical history | ||||
SLE | 22 (71%) | 45 (65.2%) | 0.57 | 1.30 (0.52–3.27) |
APS | 20 (64.5%) | 36 (52.2%) | 0.25 | 1.67 (0.69–3.99) |
Multigravida | 21 (67.7%) | 46 (66.7%) | 0.92 | 1.05 (0.42–2.60) |
Prior normal pregnancy | 10 (32.2%) | 24 (34.8%) | 0.80 | 0.89 (0.36–2.20) |
Prior abnormal pregnancy | 18 (58%) | 34 (49.3%) | 0.42 | 1.42 (0.61–3.35) |
Prior thrombophlebitis | 14 (45.2%) | 17 (24.6%) | 0.04 | 2.52 (1.03–6.16) |
Prior arterial thrombosis | 3 (9.7%) | 6 (8.7%) | 1 | 1.12 (0.26–4.82) |
Prior hypertension | 1 (3.2%) | 2 (2.9%) | 1 | 1.11 (0.10–12.80) |
Prior nephritis | 5 (16.13%) | 15 (21.7%) | 0.52 | 0.69 (0.22–2.11) |
Prior CNS involvement | 3 (9.7%) | 6 (8.7%) | 1 | 1.12 (0.26–4.82) |
Prior use of prednisone | 16 (51.6%) | 37 (53.6%) | 0.85 | 0.92 (0.39–2.16) |
Prior use of immunosuppressants | 3 (9.7%) | 8 (11.6%) | 1 | 0.82 (0.20–3.31) |
Clinical data | ||||
Hypertension | 5 (16.13%) | 4 (5.8%) | 0.13 | 3.12 (0.77–12.56) |
SLE flare | 6 (19.3%) | 13 (18.8%) | 1 | 1.03 (0.35–3.03) |
Biological data | ||||
Anti-SSA present | 8 (25.8%) | 19 (27.5%) | 0.86 | 0.91 (0.35–2.40) |
Lupus anticoagulant present | 11 (35.5%) | 24 (34.8%) | 0.94 | 1.03 (0.42–2.50) |
Anticardiolipin present | 21 (67.7%) | 48 (69.5%) | 0.85 | 0.9 (0.36–2.29) |
Serum uric acid +30% | 14 (45.1%) | 23 (33.3%) | 0.26 | 1.65 (0.69–3.92) |
Platelets –30% | 4 (12.9%) | 4 (5.8%) | 0.25 | 2.41 (0.56–10.33) |
Hypocomplementaemia | 1 (3.2%) | 4 (5.8%) | 1 | 0.54 (0.06–5.06) |
Anti-dsDNA | 1 (3.2%) | 2 (2.9%) | 1 | 1.11 (0.10–12.80) |
Increased aminotransferases | 4 (12.9%) | 2 (2.9%) | 0.07 | 4.96 (0.86–28.71) |
Proteinuria +0.5 g/day | 4 (12.9%) | 5 (7.2%) | 0.45 | 1.9 (0.47–7.61) |
Therapy | ||||
Low-dose aspirin | 29 (93.5%) | 61 (88.4%) | 0.72 | 1.9 (0.38–9.53) |
Heparin | 19 (61.3%) | 28 (40.6%) | 0.055 | 2.32 (0.97–5.52) |
Prednisone | 19 (61.3%) | 41 (59.4%) | 0.86 | 1.08 (0.45–2.58) |
Second trimester Doppler ultrasound | ||||
Umbilical artery | 6 (19.3%) | 0 | 0.0006 | 35.4 (1.93–651.72) |
Uterine artery | 12 (38.7%) | 3 (4.3%) | 0.00003 | 13.89 (3.55–54.36) |
Growth retardation | 4 (12.9%) | 0 | 0.008 | 22.74 (1.18–436.72) |
Other anomaly | 2 (6.4%) | 1 (1.4%) | 0.2 | 4.69 (0.41–53.78) |
Third trimester Doppler ultrasound | ||||
Umbilical artery | 1 (4.7%) | 0 | 0.24 | 9.88 (0.39–251.86) |
Uterine artery | 8 (38.1%) | 4 (5.9%) | 0.0008 | 9.69 (2.54–37.03) |
Growth retardation | 7 (33.3%) | 0 | 0.00002 | 69.83 (3.77–1292.6) |
Other anomaly | 2 (9.1%) | 2 (3.0%) | 0.25 | 3.25 (0.43–22.54) |
Potential predictor . | Adverse pregnancy outcome (n = 31) . | Uncomplicated pregnancy (n = 69) . | P . | Odds ratio (95% CI) . |
---|---|---|---|---|
Medical history | ||||
SLE | 22 (71%) | 45 (65.2%) | 0.57 | 1.30 (0.52–3.27) |
APS | 20 (64.5%) | 36 (52.2%) | 0.25 | 1.67 (0.69–3.99) |
Multigravida | 21 (67.7%) | 46 (66.7%) | 0.92 | 1.05 (0.42–2.60) |
Prior normal pregnancy | 10 (32.2%) | 24 (34.8%) | 0.80 | 0.89 (0.36–2.20) |
Prior abnormal pregnancy | 18 (58%) | 34 (49.3%) | 0.42 | 1.42 (0.61–3.35) |
Prior thrombophlebitis | 14 (45.2%) | 17 (24.6%) | 0.04 | 2.52 (1.03–6.16) |
Prior arterial thrombosis | 3 (9.7%) | 6 (8.7%) | 1 | 1.12 (0.26–4.82) |
Prior hypertension | 1 (3.2%) | 2 (2.9%) | 1 | 1.11 (0.10–12.80) |
Prior nephritis | 5 (16.13%) | 15 (21.7%) | 0.52 | 0.69 (0.22–2.11) |
Prior CNS involvement | 3 (9.7%) | 6 (8.7%) | 1 | 1.12 (0.26–4.82) |
Prior use of prednisone | 16 (51.6%) | 37 (53.6%) | 0.85 | 0.92 (0.39–2.16) |
Prior use of immunosuppressants | 3 (9.7%) | 8 (11.6%) | 1 | 0.82 (0.20–3.31) |
Clinical data | ||||
Hypertension | 5 (16.13%) | 4 (5.8%) | 0.13 | 3.12 (0.77–12.56) |
SLE flare | 6 (19.3%) | 13 (18.8%) | 1 | 1.03 (0.35–3.03) |
Biological data | ||||
Anti-SSA present | 8 (25.8%) | 19 (27.5%) | 0.86 | 0.91 (0.35–2.40) |
Lupus anticoagulant present | 11 (35.5%) | 24 (34.8%) | 0.94 | 1.03 (0.42–2.50) |
Anticardiolipin present | 21 (67.7%) | 48 (69.5%) | 0.85 | 0.9 (0.36–2.29) |
Serum uric acid +30% | 14 (45.1%) | 23 (33.3%) | 0.26 | 1.65 (0.69–3.92) |
Platelets –30% | 4 (12.9%) | 4 (5.8%) | 0.25 | 2.41 (0.56–10.33) |
Hypocomplementaemia | 1 (3.2%) | 4 (5.8%) | 1 | 0.54 (0.06–5.06) |
Anti-dsDNA | 1 (3.2%) | 2 (2.9%) | 1 | 1.11 (0.10–12.80) |
Increased aminotransferases | 4 (12.9%) | 2 (2.9%) | 0.07 | 4.96 (0.86–28.71) |
Proteinuria +0.5 g/day | 4 (12.9%) | 5 (7.2%) | 0.45 | 1.9 (0.47–7.61) |
Therapy | ||||
Low-dose aspirin | 29 (93.5%) | 61 (88.4%) | 0.72 | 1.9 (0.38–9.53) |
Heparin | 19 (61.3%) | 28 (40.6%) | 0.055 | 2.32 (0.97–5.52) |
Prednisone | 19 (61.3%) | 41 (59.4%) | 0.86 | 1.08 (0.45–2.58) |
Second trimester Doppler ultrasound | ||||
Umbilical artery | 6 (19.3%) | 0 | 0.0006 | 35.4 (1.93–651.72) |
Uterine artery | 12 (38.7%) | 3 (4.3%) | 0.00003 | 13.89 (3.55–54.36) |
Growth retardation | 4 (12.9%) | 0 | 0.008 | 22.74 (1.18–436.72) |
Other anomaly | 2 (6.4%) | 1 (1.4%) | 0.2 | 4.69 (0.41–53.78) |
Third trimester Doppler ultrasound | ||||
Umbilical artery | 1 (4.7%) | 0 | 0.24 | 9.88 (0.39–251.86) |
Uterine artery | 8 (38.1%) | 4 (5.9%) | 0.0008 | 9.69 (2.54–37.03) |
Growth retardation | 7 (33.3%) | 0 | 0.00002 | 69.83 (3.77–1292.6) |
Other anomaly | 2 (9.1%) | 2 (3.0%) | 0.25 | 3.25 (0.43–22.54) |
Tests . | Sensitivity (%) . | Specificity (%) . | Positive predictive value (%) . | Negative predictive value (%) . |
---|---|---|---|---|
Second trimester examination | ||||
Abnormal umbilical artery | 19.3 | 100 | 100 | 73.4 |
Notched uterine artery | 38.7 | 95.6 | 80 | 77.6 |
Growth retardation | 12.9 | 100 | 100 | 71.8 |
Third trimester examination | ||||
Notched uterine artery | 38.1 | 94 | 66.6 | 82.8 |
Growth retardation | 33.3 | 100 | 100 | 82.7 |
Tests . | Sensitivity (%) . | Specificity (%) . | Positive predictive value (%) . | Negative predictive value (%) . |
---|---|---|---|---|
Second trimester examination | ||||
Abnormal umbilical artery | 19.3 | 100 | 100 | 73.4 |
Notched uterine artery | 38.7 | 95.6 | 80 | 77.6 |
Growth retardation | 12.9 | 100 | 100 | 71.8 |
Third trimester examination | ||||
Notched uterine artery | 38.1 | 94 | 66.6 | 82.8 |
Growth retardation | 33.3 | 100 | 100 | 82.7 |
Tests . | Sensitivity (%) . | Specificity (%) . | Positive predictive value (%) . | Negative predictive value (%) . |
---|---|---|---|---|
Second trimester examination | ||||
Abnormal umbilical artery | 19.3 | 100 | 100 | 73.4 |
Notched uterine artery | 38.7 | 95.6 | 80 | 77.6 |
Growth retardation | 12.9 | 100 | 100 | 71.8 |
Third trimester examination | ||||
Notched uterine artery | 38.1 | 94 | 66.6 | 82.8 |
Growth retardation | 33.3 | 100 | 100 | 82.7 |
Tests . | Sensitivity (%) . | Specificity (%) . | Positive predictive value (%) . | Negative predictive value (%) . |
---|---|---|---|---|
Second trimester examination | ||||
Abnormal umbilical artery | 19.3 | 100 | 100 | 73.4 |
Notched uterine artery | 38.7 | 95.6 | 80 | 77.6 |
Growth retardation | 12.9 | 100 | 100 | 71.8 |
Third trimester examination | ||||
Notched uterine artery | 38.1 | 94 | 66.6 | 82.8 |
Growth retardation | 33.3 | 100 | 100 | 82.7 |
Normal outcome
Biological abnormalities were common, particularly increased serum uric acid. It remained isolated in 18 cases and accompanied hypertension in two cases and renal flare in one. Three SLE nephritis flared-ups accompanied two cases with arthritis. Among the 69 uncomplicated pregnancy outcomes, the second Doppler ultrasound examination was abnormal in three pregnancies, showing abruptio placentae in one case, which disappeared on subsequent examination after heparin withdrawal, and transient notched uterine arteries in two cases. The third Doppler ultrasound examination was also abnormal in five pregnancies with uncomplicated outcome. In one case, notched uterine arteries persisted, associated with placenta praevia, but a healthy baby was born at 36 weeks. One twin-to-twin transfusion syndrome occurred, leading to Caesarean section at 35 weeks. In addition, notched uterine arteries were noted in three cases, associated with placenta praevia in one case, hypertension in one case, increased serum uric acid in two cases and increased aminotransferases in one case. Healthy babies were born at 36–39 weeks. The pregnancy outcome is summarized in Fig. 1 according to the results of the second and third trimester Doppler ultrasound examinations.
Discussion
Our prospective study analysed 100 high-risk pregnancies in SLE and APS. In pregnancies having progressed beyond the second trimester, pre-eclampsia and/or HELLP syndrome occurred in 7% of the cases and fetal or neonatal death in 8%. Pre-eclampsia/HELLP syndrome are common in APS and SLE pregnancies, especially in those with history of nephritis. Pre-eclampsia may occur in 3–30% of SLE pregnancies and in up to 64% of patients with pre-existing nephropathy [21]. In APS, pre-eclampsia and/or HELLP syndrome is observed in 3–51% of APS pregnancies with higher rates in series including women with SLE and/or prior thrombophlebitis [2, 4, 22, 23]. In our study, SLE flare occurred in 25% of the cases, but led to increased prednisone dosage in less than half of the cases. The flare rate was lower than the one observed 10 yr before [1] but similar to those observed in recent series in which most pregnancies were planned [17]. In this context, we observed that clinical SLE flare, the presence of hypocomplementaemia and/or anti-dsDNA did not influence pregnancy outcome, in contrast with previous studies.
We found that an abnormal umbilical artery waveform on second trimester Doppler examination and history of thrombophlebitis were independent predictors of fetal and neonatal death in SLE and APS pregnancies progressing beyond 22 weeks. Seven out of eight fetal/neonatal deaths occurred in women with a history of thrombophlebitis. It has to be underlined that no clinical signs were associated with six out of eight fetal/neonatal deaths. One woman had pre-eclampsia, the other mild SLE flare. The sole biological anomaly was elevated uric acid in two fetal deaths. Six out of eight fetal/neonatal deaths were associated with abnormal second trimester Doppler ultrasound examinations. The anomalies consisted of notched uterine arteries in 62% of cases, abnormal umbilical artery Doppler waveform in 37% and IUGR in 25%. In one case, absence of IUGR despite absent end-diastolic velocities of the umbilical artery suggested an acute phenomenon due to poor LMWH compliance. In a series of 28 APS pregnancies treated with prednisone and aspirin, Caruso et al. [24] found that an abnormal resistance index of the uterine arteries at 18–24 weeks predicted major obstetric complications. In 21 SLE/APS pregnancies, Benifla et al. [25] found that abnormal uterine blood flow velocity waveforms at Doppler examination performed between 20 and 30 weeks predicted later adverse fetal and neonatal events. In 170 APS pregnancies treated with aspirin plus enoxaparin, Venkat-Raman et al. [26] found that persistent notched uterine arteries at 22–24 weeks predicted later development of pre-eclampsia and growth restriction, but not non-proteinuric hypertension. The likelihood ratio for pre-eclampsia was 12.8 (CI 2.2–75), and 13.6 (CI 1.9–96) for growth restriction.
In our study, we observed that the only predictor of adverse pregnancy outcome by multivariate analysis was uterine artery notches on second trimester examination, with an OR of 13.84. Similar to observations in our analysis of potential predictors of fetal/neonatal deaths, it is striking that no clinical or biological test appeared to be a significant predictor. Studies comparing the usefulness of clinical, biological and Doppler ultrasound examination together are scarce in SLE/APS pregnancies. In 56 SLE/APS pregnancies, Kerslake et al. [27] showed that absent end-diastolic flow at 20 weeks appeared a better predictor than presence of aPL for detection of fetal death. In 77 APS pregnancies, Carmona et al. [28] found that fetal outcome correlated with pre-conceptional use of aspirin and abnormal umbilical artery Doppler velocimetry at 23–26 weeks.
In conclusion, a history of thrombophlebitis and results of the second trimester Doppler ultrasound examination are the best predictors of late fetal outcome in SLE/APS pregnancy. History of thrombophlebitis should lead to initiation of aspirin plus therapeutic dose of heparin upon diagnosis of pregnancy. At present, LMWH appears to be the best anticoagulant for pregnant women because of its better biodisponibility, its longer half-life and its decreased risk of thrombocytopenia and of osteoporosis [29]. As end-diastolic umbilical artery Doppler flow may be abnormal at 20 weeks, it would appear to be necessary to perform examination earlier in order to adapt therapy. Increased LMWH dose aimed at 0.5–1 anti-Xa activity might improve umbilical artery Doppler flow and fetal growth. However, in 65 pregnancies in women with history of adverse pregnancy outcome and acquired or congenital thrombophilia, Bar et al. [30] concluded that a combination of aspirin and LMWH versus aspirin alone improved maternal circulation parameters on the third trimester Doppler examination but did not correlate with pregnancy outcome. It is of note that in pregnant women anti-Xa heparin levels are correlated with weight, irrespective of the gestational age and this may mandate dose adjustment in response to weight changes during pregnancy [31].
The authors have declared no conflicts of interest.
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Author notes
Department of Internal Medicine and 1Department of Gynecology-Obstetrics, Groupe Hospitalier Pitié-Salpêtrière, 83 bd de l’Hôpital, 75013 Paris, France.
- antiphospholipid syndrome
- pregnancy
- heparin
- thrombophlebitis
- physical examination
- systemic lupus erythematosus
- doppler ultrasound
- diastole
- embryo
- fetal death
- fetal growth retardation
- fetus
- pregnancy trimester, second
- pregnancy trimester, third
- umbilical artery
- obstetrics
- uterine artery
- late stage of pregnancy
- neonatal death
- adverse pregnancy outcome
- univariate analysis
- fluid flow
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