Methods
This was an observational, retrospective, single center cohort study. All the records of women who attended the Lupus & Antiphospholipid Pregnancy clinic from January 2008 to July 2014 were searched. All the pregnancies in women with persisting aPL were identified.
aPL positivity was defined according to the current classification criteria and confirmed at least 12 weeks apart in all the included women before the index pregnancy. Women with equivocal or unconfirmed aPL positivity were excluded from our analysis. Our final cohort included 170 pregnancies, which occurred in 96 women with aPL.
Anticardiolipin antibodies (isotypes immunoglobulin G and M) were quantified by indirect ELISA with the use of AEUSKULISA Cardiolipin-GM reagents (Grifols UK, Cambridge, UK). Anti β2-glycoprotein I antibodies (isotypes immunoglobulin G and M) were quantified by indirect ELISA with the use of QUANTA Lite reagents (INOVA Diagnostics Inc, San Diego, CA). Lupus anticoagulant detection that was in compliance with published guidelines was determined by dilute Russell’s viper venom time and dilute activated partial thromboplastin time, accompanied by appropriate confirmatory tests. Patients on oral anticoagulation therapy additionally received screening with Taipan snake venom time with the use of Diagen Taipan venom (Diagnostic Reagents, Thames, UK) with an Ecarin time confirmatory test using Echis carinatus venom (Diagnostic Reagents).
Patients were divided in 2 groups: Group A included aPL patients who received hydroxychloroquine treatment during pregnancy. Group B included patients without hydroxychloroquine treatment.
The following baseline data were registered and compared between the 2 groups: frequency of aPL only, primary APS, aPL with SLE and APS with SLE, mean disease duration, history of pregnancy morbidity and/or thrombosis, conventional risk factors for cardiovascular events (hypertension, body mass index ≥30 kg/m 2 , hyperlipemia, diabetes mellitus, smoking>5 cigarettes/daily), aPL profile, and the presence of other autoantibodies (antinuclear antibodies, anti–double stranded DNA, anti-extractable nuclear antigens antibodies).
For each pregnancy, the following data were collected: treatment, pregnancy outcome and maternal/fetal/neonatal complications.
Neonatal outcomes that were recorded included survival, gestational age at delivery, neonatal weight, and occurrence of intrauterine growth restriction.
Pregnancy morbidity was defined according to the current classification criteria for APS.
Therapy other than hydroxychloroquine varied according to the clinical manifestations and can be summarized in the following manner: women without previous pregnancy morbidity or thrombosis received low-dose aspirin. Low–molecular-weight heparin (LMWH) at thromboprophylactic doses was associated only if previous failure of low-dose aspirin alone. Women with previous fetal death or previous early delivery because of severe preeclampsia or placental insufficiency received low-dose aspirin plus LMWH at thromboprophylactic doses. Patients with thrombotic APS who undergo long-term anticoagulation were treated with low-dose aspirin and LMWH at therapeutic doses.
Statistical analysis was performed with SPSS software (version 17; SPSS Inc, Chicago, IL) and included logistic regression analysis and χ 2 and Fisher exact tests with a generalized link function to correct pregnancy outcomes for >1 pregnancy in the same woman.
A stepwise forward conditional procedure that included biologic relevant and significant risk factors that were obtained from the univariate analysis was then used for the logistic regression analysis to identify significant independent risk factors. Computed variables included age, aPL profile, presence of SLE, history of pregnancy morbidity and/or thrombosis, presence of other autoantibodies (antinuclear antibodies, anti–double stranded DNA, anti-extractable nuclear antigens antibodies, treatment during pregnancy (low-dose aspirin, LMWH, steroids, and/or immunosuppressant use).
Patients
Previous obstetric and thrombotic events, concomitant autoimmune conditions, and autoantibodies are shown in Table 1 .
| Variable | Hydroxychloroquine | % | Without hydroxychloroquine | % | Significance |
|---|---|---|---|---|---|
| Patient, n | 31 | 65 | |||
| Pregnancies, n | 51 | 119 | |||
| Pregnancies per woman, n (range) | 1.65 (1-5) | 1.83 (1-7) | |||
| Ethnicity, n (%) | |||||
| White | 17 (54.8) | 39 (60) | |||
| Black | 6 (19.4) | 10 (15.4) | |||
| Other | 8 (25.8) | 16 (24.6) | |||
| Mean age, y ± SD (range) | 32.5 ± 4.6 (21-42) | 35.6 ± 5.2 (18-42) | NS | ||
| Antiphospholipid antibodies only, n | 6 | 19.4 | 15 | 23.1 | NS |
| Primary antiphospholipid syndrome, n | 5 | 16.1 | 45 | 69.2 | P <.001 |
| Systemic lupus erythematosus + antiphospholipid antibodies, n | 11 | 35.5 | 0 | 0.0 | P <.001 |
| Systemic lupus erythematosus and antiphospholipid syndrome, n | 9 | 29.0 | 5 | 7.7 | P =.006 |
| Mean disease duration, y ± SD | 5.3 ± 4.1 | — | 2.7 ± 2.4 | — | P = .042 |
| Previous thrombosis, n | 10 | 32.3 | 19 | 29.2 | NS |
| Venous | 5 | 16.1 | 13 | 20.0 | NS |
| Arterial | 5 | 16.1 | 7 | 10.8 | NS |
| Previous pregnancy morbidity, n | |||||
| Any | 7 | 22.6 | 35 | 53.8 | P = .004 |
| Spontaneous abortions before week 10 | 4 | 12.9 | 18 | 27.7 | NS |
| Fetal Loss beyond week 10 | 0 | 0.0 | 4 | 6.2 | NS |
| Placenta-mediated complication a | 3 | 9.7 | 11 | 16.9 | NS |
| Antinuclear antibodies, n | 23 | 74.2 | 13 | 20.0 | P < .001 |
| Anti-extractable nuclear antigens antibodies (anti-Ro/anti– lupus anticoagulant), n | 15 | 48.4 | 6 | 9.2 | P < .001 |
| Lupus anticoagulant positivity, n | 21 | 67.7 | 49 | 75.4 | NS |
| Anticardiolipin antibodies positivity, n | 14 | 45.2 | 35 | 53.8 | NS |
| Immunoglobulin G/immunoglobulin M (GPL/MPL) | |||||
| Mean ± SD b | 68.8 ± 22.1/49.2 ± 8.7 | 61.3 ± 20.7/47.9 ± 9.1 | NS | ||
| Median (range) b | 72.6 (41-110)/48.9 (40-75) | 69.7 (40-107)/49.1 (40-77) | NS | ||
| Antibeta2-glycoprotein I positivity (GPL/MPL), n | 6 | 19.4 | 6 | 9.2 | NS |
| Immunoglobulin G/immunoglobulin M | |||||
| Mean ± SD b | 35.3 ± 20.7/30.8 ± 18.6 | 36.3 ± 18.7/29.4 ± 12.6 | NS | ||
| Median (range) b | 22 (15-75)/20 (14-70) | 20.5 (15-65)/18 (14-59) | NS | ||
| Cardiovascular risk factors, n | |||||
| Smoking >5 cigarettes | 3 | 9.7 | 1 | 1.5 | NS |
| Diabetes mellitus | 0 | 0.0 | 4 (Gestational) | 6.2 | NS |
| Hyperlipidemia | 0 | 0.0 | 0 | 0.0 | NS |
| Hypertension | 2 | 6.5 | 10 | 15.4 | NS |
a Placenta-mediated complication; preeclampsia, abruption placentae, intrauterine growth restriction
Hydroxychloroquine group (group A)
Between January 2008 and July 2014, 51 pregnancies occurred in 31 women who had been treated with hydroxychloroquine for at least 6 months before pregnancy (mean time treatment before pregnancy, 41.7 ± 9.2 months) and continued throughout gestation (only 1 patient started hydroxychloroquine at the time of a positive pregnancy test). Indications for hydroxychloroquine treatment were SLE as defined by the American College of Rheumatology criteria (n = 20; 64.5% of group A). One patient did not meet 4 American College of Rheumatology classification criteria for SLE but had arthralgias and was positive for anti-SSA/Ro antibodies (n = 1; 3.2%). In patients with primary APS, the indication was lupus-like syndrome (ie, severe fatigue and arthralgia without serologic positivity for SLE (n = 10; 32.3%).
At study entry, 7 women (22%) were primigravid, and 24 were multiparous. Six pregnancies occurred after in vitro fertilization treatment. The median age of patients at the time of delivery was 32 years (range, 21–42 years).
In 26 pregnancies, the women received hydroxychloroquine 200 mg twice daily; in 25 pregnancies, the women received hydroxychloroquine 200 mg once daily. When low-dose aspirin or heparins was excluded, hydroxychloroquine was used in 30 pregnancies as sole immunomodulation treatment.
Other treatments are reported in Table 2 .
| Variable | Hydroxychloroquine | % | Without hydroxychloroquine | % | Significance |
|---|---|---|---|---|---|
| Pregnancies, n | 51 | 119 | |||
| Live births, n | 34 | 66.7 | 60 | 57.1 | P = .05 |
| Antiphospholipid antibody–related pregnancy morbidity, n | 20 | 47.1 | 75 | 63.0 | P = .004 |
| Preterm live births <37 weeks, n | 2 | 3.9 | 16 | 13.4 | P = .06 |
| Spontaneous abortions before the week 10, n | 16 | 31.4 | 46 | 38.7 | NS |
| Fetal loss beyond the week 10, n | 1 | 2.0 | 13 | 10.9 | P = .05 |
| Placenta mediated complication, n | 1 | 2.0 | 13 | 10.9 | P = .05 |
| Preeclampsia | 1 | 2.0 | 8 | 6.7 | NS |
| Abruption placentae | 0 | 0 | 3 | 2.5 | NS |
| Intrauterine growth restriction | 0 | 0 | 2 | 1.7 | NS |
| Mode of delivery, n | |||||
| Vaginal | |||||
| Spontaneous | 19 | 37.3 | 17 | 14.3 | P = .011 |
| Induced | 3 | 5.9 | 9 | 7.6 | NS |
| Cesarean | 10 | 19.6 | 23 | 19.3 | NS |
| Median gestation duration, wk (range) | 27.6 (6-40) | — | 21.51 (6-40) | P = .034 | |
| Birthweight, kg (range) a | 3 (1.3-5) | — | 2.3 (1.4-4.1) | — | P = .04 |
| Prednisolone, | 21 | 41.2 | 13 | 11.0 | P < .001 |
| mean mg/d | 5 | 5 | NS | ||
| Azathioprine, n | 15 | 29.4 | 5 | 4.2 | P < .001 |
| Mean mg/d | 100 | 150 | NS | ||
| Low-dose aspirin, n | 100 | 100 | 100 | 100 | NS |
| Low–molecular-weight heparin, n | 37 | 72.5 | 94 | 79.0 | NS |
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