Abstract
Objective
To evaluate the effect of an educational tool on preeclampsia knowledge, as well as aspirin (ASA) use and adherence in pregnant SLE women.
Methods
A two-arm parallel randomized controlled trial was conducted recruiting pregnant SLE women up to 17 weeks’ gestation. Participants were randomly assigned to receive either usual-care alone or usual-care plus the tool (laminated card incorporating infographics on preeclampsia in SLE and ASA for prevention). The primary outcome was difference in preeclampsia knowledge scores at the second-trimester visit.
Results
Of 73 women included, 38 were randomized to the intervention. In the primary analysis of ongoing pregnancies, increase in the mean preeclampsia knowledge scores was 4.0 points (95% CI: 2.4, 5.6) in the intervention group and 2.0 points (95% CI: 0.3, 3.9) in controls, with a mean difference of 1.8 points higher (95% CI: −0.5, 4.2) favouring the intervention. Including end-of-pregnancy scores of women with fetal loss (six in each group), the difference was 4.8 points (95% CI: 3.3, 6.9) in the intervention group and 1.9 points (95% CI: 0.3, 3.6) in controls, with a mean increase of 2.5 points (95% CI: 0.3, 4.8) more for the intervention. Using electronic pharmacy data, there was a trend for higher ASA adherence in the intervention group (81%) vs controls (65%; difference 15%, 95% CI: −9, 37%).
Conclusion
Women with SLE who received an educational tool had greater improvement in preeclampsia knowledge vs controls. This tool may improve ASA use in SLE pregnancies and help optimize outcomes.
Trial registration
ClinicalTrials.gov, http://clinicaltrials.gov, NCT03749044.
Keywords: systemic lupus erythematosus, pregnancy, preeclampsia, knowledge, educational tool, aspirin, adherence, clinical trial
Rheumatology key messages.
Preeclampsia knowledge is poor in pregnant women with SLE.
Women with SLE who received our educational tool had greater improvement in preeclampsia knowledge vs controls at the second pregnancy visit.
Compared with usual care, there was a trend for higher ASA adherence in the intervention vs control group (81% vs 65%).
Introduction
Pregnant women with systemic lupus erythematosus (SLE) have more than twice the risk of preeclampsia, a placenta-mediated complication, compared with women without SLE [1]. Since preeclampsia is a leading cause of maternal/fetal morbidity and mortality around the world [2, 3], prevention is of utmost importance.
Prior studies have shown that increasing preeclampsia knowledge may be associated with improved outcomes in non-SLE populations [4–8]; furthermore, aspirin (ASA) prophylaxis reduces the incidence of preeclampsia in high-risk women, such as those with SLE [9–11]. Currently, international guidelines recommend low-dose ASA (81–162 mg daily) during pregnancy for all women with SLE [12, 13]. However, a recent publication suggested suboptimal use, with only 25% of SLE pregnancies on ASA [14].
We developed the ‘Preeclampsia in Lupus pregnAnCy EducatioNal Tool on ASA use and knowledge (PLACENTA)’ to enhance preeclampsia knowledge and ASA use in SLE. We conducted the ‘PREeclamPsia knowledge and Aspirin adheRence in lupus prEgnancies (PREPARE)’ randomized controlled trial (RCT) to assess the effect of the educational tool on preeclampsia knowledge, as well as ASA use and adherence in pregnant women with SLE.
Methods
Trial design
This was a two-arm parallel RCT conducted at four Canadian Systemic Lupus International Collaborating Clinics (SLICC) sites (Montreal, Quebec, Halifax, and Calgary), between May 2018 and August 2023. SLICC is an international network that performs collaborative research to improve clinical outcomes in SLE patients. Study eligibility criteria included being pregnant with single or multiple intrauterine pregnancies, diagnosis of SLE based on the SLICC classification criteria [15], English- or French-speaking, gestational age up to 166/7 weeks, age between 18 and 45 years, and participation in the ‘Lupus prEGnAnCY (LEGACY)’ biobank, an international prospective cohort of unselected SLE pregnancies at SLICC sites. Only the first pregnancy enrolled into LEGACY was recruited in the RCT, after patients gave written informed consent. This RCT was approved by the McGill University Health Centre Research Ethics Board.
At each study site, investigators completed questionnaires evaluating practice patterns and usual care regarding preeclampsia education and ASA prescription. At baseline, participants completed self-reported questionnaires (in English or French) assessing preeclampsia knowledge, ASA use and adherence (Supplementary Figs S1–S3, available at Rheumatology online). Demographic, obstetrical and medical data were prospectively collected by site investigators at each study visit. Gestational age was calculated using the first day of last menstrual period or best assessment via fetal ultrasound. Study visits occurred every trimester and/or at an end-of-pregnancy visit. Target visit windows were <17 weeks of gestation for first (baseline), 20–24 weeks for second and 30–34 weeks for third visits, as well as 8–12 weeks after delivery and/or pregnancy termination or loss for the end-of-pregnancy visit.
Intervention
Participants were randomized in a 1:1 ratio to receive the PLACENTA tool (Fig. 1) plus usual care (intervention) or usual care only (control). We used stratified block randomization with randomly selected block sizes performed through the LEGACY REDCap database. Intervention status was blinded to the treating physicians and all outcome assessors.
Figure 1.
Flow diagram of trial participants (n = 73). ASA: aspirin
The PLACENTA tool was developed in English and French by modifying (after appropriate agreement) the existing educational sheet by You et al. (2012) developed in collaboration with the Preeclampsia Foundation (Fig. 1) [16]. The original tool was designed for non-SLE patients of all literacy levels and improved their preeclampsia knowledge in a previous RCT [16].
One side of the PLACENTA tool explains preeclampsia, maternal and fetal risks associated with preeclampsia, symptoms of preeclampsia, and proper actions to take once symptoms arise. The other side (originally blank in the version by You et al.) presents additional SLE-relevant information (i.e. preeclampsia risk in SLE, estimated efficacy of low-dose ASA for preeclampsia prevention in high-risk women, how often to take ASA). The content of the PLACENTA tool was drawn from existing literature and developed by the principal investigator (E.V.), a rheumatologist with expertise in reproductive care. The graphical display of the SLE-specific content was reviewed and optimized in consultation with relevant end-users, including pregnant patients with SLE (not included in this RCT) and a patient advocate.
Participants randomized to the intervention arm received the PLACENTA tool after completing baseline questionnaires. The tool was distributed by an unblinded member of the research team (who did not perform outcome assessments) who advised subjects to read it, without providing any additional or standardized information.
Outcome measures and primary outcome
All participants completed the preeclampsia knowledge questionnaire, ASA use survey and ASA adherence assessment at each visit. Our primary outcome was change in preeclampsia knowledge in the intervention vs control group, from baseline to second-trimester visit, as measured by the preeclampsia knowledge questionnaire. Secondary outcomes were prevalence of ASA use at baseline in patients only receiving usual care, the difference in ASA use and adherence between the two arms at second-trimester visit, and change in ASA adherence from baseline to second visit.
Preeclampsia knowledge questionnaire
The preeclampsia knowledge questionnaire was adapted from a content-validated questionnaire included in a 2014 preeclampsia awareness survey [17] and a previously validated preeclampsia questionnaire [8, 16]. The adapted questionnaire used in the current trial had 28 close-ended questions about severity, symptoms, risks/adverse events related to preeclampsia, and appropriate actions for the patient, should symptoms arise. Two open-ended questions asked patients to describe preeclampsia in their own words, and to indicate at least one medication that could reduce the risk of preeclampsia (Supplementary Fig. S1, available at Rheumatology online).
The questionnaires were scored out of 30 by two independent raters blinded to intervention assignment. Each correct question was worth 1 point (Supplementary Materials, available at Rheumatology online for additional details on open-ended question scoring). Participants were blinded to their own scores throughout the study and correct answers were not shared.
Aspirin use survey
The ASA use survey asked if pregnant woman were currently taking ASA, if they had taken ASA at some point during pregnancy, and if they were told to take ASA by their physicians prior to the current visit (Supplementary Fig. S2, available at Rheumatology online). If they answered ‘yes’ to any of these questions, participants were asked whether a prescription was given for ASA, the frequency of over-the-counter ASA use and refills at the pharmacy. As well, they underwent ASA adherence assessment using the Adherence to Refills and Medications Scale (ARMS) (Supplementary Fig. S3, available at Rheumatology online) [18].
Information on ASA use was assessed at all visits. At each assessment, participants with ongoing pregnancy were defined as users if they were taking ASA during pregnancy, prior to the visit. Patients who experienced fetal loss were defined as users if they had taken ASA at any point during pregnancy prior to the visit (though they could have stopped ASA after pregnancy end, before the study visit).
Statistical analyses
We estimated that a total of 72 participants with 36 subjects in each group would yield 80% power (at a two-sided α of 0.05) to detect a 3-point difference in mean preeclampsia questionnaire scores (in the intervention vs control group) given an expected mean score of 15 (out of 30) and a standard deviation of 4.5 in women unexposed to the intervention, based on the prior study by You et al. [16] We calculated that 72 participants would provide 80% power to detect at least 30% difference of proportion of ASA users between the two groups at second visit with a two-sided α of 0.05, assuming 55% users in controls.
Mean and standard deviation for continuous variables and proportions for discrete variables were reported. Primary analyses were conducted in an intention-to-treat principle including all randomized participants whose pregnancy was ongoing at the second-trimester visit. A sensitivity analysis included patients who experienced pregnancy loss before the second-trimester visit; for this purpose, score difference from baseline to second visit was calculated, wherein second visit scores included second-trimester scores for women with ongoing pregnancy and scores from end-of-pregnancy visits for women whose pregnancy ended before the second-trimester visit.
For the open-ended question (to describe preeclampsia in their own words), we evaluated inter-rater reliability (IRR) between the two independent raters, using the absolute agreement intraclass correlation coefficient (ICC) with two-way model and fixed raters (i.e. ICC 2,1).
Difference in mean preeclampsia knowledge scores from baseline to second visit in the two arms was assessed with Student’s paired t-test with relevant 95% CI or bootstrap paired sample test reporting the bias-corrected and accelerated (BCa) 95% CI (which protects against skew in the resampled bootstrap distribution), when relevant. Univariate linear regression or robust regression with Huber weighting was performed to obtain the difference in mean score change between the two groups, from baseline to second visit. For robust regression, BCa 95% CIs were constructed using bootstrap with residual resampling.
ASA user proportions and differences between the two arms and 95% CI were reported. ASA adherence analysis included patients who answered whether they were told by their physicians to take ASA during pregnancy or were prescribed ASA. A Mann–Whitney U-test was used to evaluate difference in ARMS scores between the two groups. As a validation exercise, interval-based proportion of days covered (PDC) was calculated with ASA dispensation information from the participants’ electronic pharmacy records for those enrolled at the coordinating site in Montréal, who indicated not purchasing over-the-counter ASA. Interval period spanned from baseline visit date to second-trimester visit or pregnancy end date. We compared proportions of patients with PDC ≥80% between the two arms from baseline to the second visit date. Mean change in ARMS scores from baseline to second visit in patients reporting ASA use at both visits was assessed with Student’s paired t-test or bootstrap paired sample test with BCa 95% CI, when relevant.
We performed sensitivity analyses to account for missing data (<5%) for the main analyses (Supplementary Results & Tables S1 and S2, available at Rheumatology online). All tests were two-sided with the significance level set at 0.05. Analyses were conducted in R version 4.3.1 (2023-06-16).
Results
Participants were recruited from May 2018 to August 2023. Ninety-two pregnant women with suspected or diagnosed SLE underwent screening. In total, 15 women (16%) were excluded (as ineligible) and four (4%) declined to participate (Fig. 2).
Figure 2.
Preeclampsia in Lupus pregnAnCy EducatioNal Tool on ASA use and knowledge (PLACENTA). The ‘Illustrated Symptoms’ preeclampsia graphics are provided courtesy of our partners at the Preeclampsia Foundation and can be accessed at www.preeclampsia.org/signs-and-symptoms. Please note, since the time of this study, the educational tool in the above figure has been updated and the most recent version can be accessed at the above link. ASA: aspirin
Of 73 participants, 30 (41%) were primarily French speaking (from Montreal and Quebec City). Baseline characteristics were well-balanced (Table 1).
Table 1.
Baseline characteristics of study population (n = 73)
| Characteristic | Intervention | Control |
|---|---|---|
| (n = 38) | (n = 35) | |
| Age, mean (s.d.), years | 33 (4) | 34 (4) |
| SLE duration, median (IQR), years | 8 (5, 12) | 9 (4, 16) |
| Gravidity, median (IQR) | 2 (1, 2) | 2 (1, 4) |
| Gestational age, median (IQR), days | 70 (55, 89) | 62 (52, 102) |
| Post-secondary education, n (%) | ||
| No | 6 (16) | 7 (20) |
| Yes | 31 (84)a | 28 (80) |
| Ethnicity, n (%) | ||
| White | 16 (42) | 16 (46) |
| Native North American | 2 (5) | 1(3) |
| Hispanic | 5 (13) | 1 (3) |
| Black | 6 (16) | 4 (11) |
| Asian | 4 (11) | 6 (17) |
| Other | 5 (13) | 7 (20) |
| Body mass index, median (IQR), kg/m2 | 23.7 (20.8, 27.4) | 24.4 (22.1, 28.6) |
| Pre-gestational hypertension, n (%) | 2 (6) | 4 (11) |
| Antiphospholipid syndromeb, n (%) | ||
| Any pregnancy morbidity and aPL | 0 (0) | 2 (6) |
| Vascular thrombosis and aPL | 1 (3) | 2 (6) |
| Any pregnancy morbidity and vascular thrombosis and aPL | 1 (3) | 1 (3) |
| Any aPL positive, n (%) | 9 (24) | 9 (26) |
| Prior eclampsia or preeclampsia, n (%) | 1 (3) | 3 (9) |
| Prior or current lupus nephritis, n (%) | 13 (34) | 10 (29) |
| Current medication use, n (%) | ||
| Glucocorticoids | 7 (18) | 3 (9) |
| Antimalarials | 37 (97) | 32 (91) |
| Immunosuppressives | ||
| Azathioprine or tacrolimus | 16 (42) | 18 (51) |
| Biologics | 2 (5) | 0 (0) |
| Other | 0 (0) | 0 (0) |
| Heparin | ||
| Prophylactic | 3 (8) | 4 (11) |
| Therapeutic | 2 (5) | 3 (9) |
Education information not available for one subject.
As defined by the revised Sapporo classification criteria. aPL: antiphospholipid antibodies; IQR: interquartile range.
According to the site investigator surveys, none (0/4) ever handed out a specific educational pamphlet or document to patients. Two of the four sites referred to other types of educational tools (e.g. websites) while the other two never did. Sites spent dedicated time for placenta-mediated complication counselling always (3/4) or most of the time (1/4). One had a dedicated nurse and most (3/4) did not know if the obstetrician-gynaecologists at their institution handed out educational pamphlets/documents and/or referred to other tools.
Preeclampsia knowledge scores
At baseline (n = 73), mean preeclampsia knowledge score was 15.4/30 (s.d. 6.5) points in the before intervention group and 15.1 (s.d. 6.0) points in the control group (score range across both groups 0–27). Most participants (76% in intervention and 71% in control group) had heard of preeclampsia, but participants in both arms scored poorly for the open-ended question asking for patients’ own definition of preeclampsia [median score in intervention 0.3 points (interquartile range, IQR 0.0–0.6) and control 0.0 points (IQR 0.0–0.5)]. The proportions indicating ‘Unsure’ for questions about preeclampsia symptoms were high in both groups (Table 2). Most knew what actions to take if they were to experience symptoms (i.e. calling their physicians and/or going to the hospital) (Table 3). At baseline, 68% (26/38) and 66% (23/35) of women in the intervention and control group, respectively, knew that ASA could be taken during pregnancy to reduce the risk of preeclampsia. The ICC (2, 1) for inter-rater reliability for the open-ended preeclampsia knowledge scores between the two independent raters was 0.97 (95% CI: 0.96, 0.98).
Table 2.
Baseline proportion of participants correctly answering to questions related to describing the symptoms of preeclampsia
| Which represent symptoms of preeclampsia? | Intervention |
Control |
||
|---|---|---|---|---|
| (n = 38) |
(n = 35) |
|||
| Correct answer | ‘Unsure’ | Correct answer | ‘Unsure’ | |
| Swelling of hands or face, n (%) | 20 (53) | 16 (42) | 18 (51) | 13 (37) |
| Swelling of feet, n (%) | 2 (5) | 16 (42) | 3 (9) | 16 (46) |
| Headache, n (%) | 27 (71) | 10 (26) | 21 (60) | 12 (34) |
| Seeing spots/flashing lights, n (%) | 21 (55) | 14 (37) | 18 (51) | 14 (40) |
| Nausea/vomiting, n (%) | 19 (50) | 15 (39) | 16 (46) | 15 (43) |
| Uterine contractions, n (%) | 10 (26) | 19 (50) | 5 (14) | 19 (54) |
| Back pain, n (%) | 9 (24) | 21 (55) | 8 (23) | 21 (60) |
| Chest pain, n (%) | 12 (32) | 20 (53) | 9 (26) | 19 (54) |
| Sleepiness, n (%) | 5 (13) | 19 (50) | 5 (14) | 23 (63)a |
| Pain with urination, n (%) | 10 (26) | 26 (68) | 10 (29) | 20 (57) |
One participant left this question blank, so the participant was assumed to have indicated ‘Unsure’.
Table 3.
Baseline proportion of participants correctly answering regarding appropriate actions to take when facing preeclampsia symptoms
| Which are appropriate actions? | Intervention |
Control |
||
|---|---|---|---|---|
| (n = 38) |
(n = 35) |
|||
| Correct answer | Unsure | Correct answer | Unsure | |
| Call my doctor, n (%) | 33 (87) | 3 (8) | 34 (97) | 1 (3) |
| Go to the hospital, n (%) | 33 (87) | 5 (13) | 28 (80) | 3 (9) |
| Lie down, n (%) | 15 (39) | 14 (37) | 12 (34) | 14 (40) |
| Drink a glass of water, n (%) | 17 (45) | 14 (37) | 13 (37) | 12 (34) |
| Wait one day to see if the symptoms improve, n (%) | 26 (68) | 11 (29) | 24 (69) | 9 (26)a |
One patient did not complete this question, so the participant was assumed to have indicated ‘Unsure’.
In the primary analysis of women with ongoing pregnancy (n = 58), mean preeclampsia knowledge score at second-trimester visit was 20.4 points (s.d. 5.1) in the intervention group, and 17.1 points (s.d. 4.2) in controls. Increases in the mean preeclampsia knowledge scores from baseline to second trimester in the intervention group was 4.0 points (95% CI: 2.4, 5.6) and 2.0 points (95% CI: 0.3, 3.9) in controls (Table 4).
Table 4.
Results of the primary and sensitivity analyses related to preeclampsia knowledge scores
| Intervention | Control | Overall | |
|---|---|---|---|
| Primary analysis—ongoing pregnancies at second-trimester visita | |||
| n | 29 | 29 | 58 |
| Preeclampsia knowledge score, mean (s.d.) | |||
| Baseline | 16.4 (6.3) | 14.9 (5.5) | — |
| Second-trimester visit | 20.4 (5.1) | 17.1 (4.2) | — |
| Difference in scores between second-trimester visit and baseline (95% CI) | 4.0 (2.4, 5.6) | 2.0 (0.3, 3.9) | — |
| Between group difference in scores from baseline to second-trimester visit (95% CI) | — | — | 1.8 (−0.5, 4.2) |
| Sensitivity analysis—including pregnancy loss at 2nd visitb | |||
| n | 35 | 33 | 68 |
| Preeclampsia knowledge score, mean (s.d.) | |||
| Baseline | 15.4 (6.6) | 15.1 (5.8) | — |
| Second trimester visit | 20.3 (4.7) | 17.0 (4.1) | — |
| Difference in scores between 2nd visit and baseline (95% CI) | 4.8 (3.3, 6.9) | 1.9 (0.3, 3.6) | — |
| Between group difference in scores from baseline to 2nd visit (95% CI) | — | — | 2.5 (0.3, 4.8) |
Excluding 12 subjects with fetal loss prior to second-trimester visit (six in each group) and two lost to follow-up patients in the intervention group as well as one participant with an incomplete questionnaire in the intervention group.
Excluding two participants with fetal loss with partially completed questionnaires in the control group and one participant with an incomplete questionnaire and two lost to follow-up patients in the intervention group.
In the secondary analysis including end-of-pregnancy scores of women who experienced fetal loss before second-trimester visit (n = 68), increase in mean preeclampsia knowledge scores from baseline to second visit was 4.8 points (95% CI: 3.3, 6.9) in the intervention group and 1.9 points (95% CI: 0.3, 3.6) in controls (Table 4).
In women with ongoing pregnancy at the second-trimester visit (n = 58), the mean difference in knowledge scores from baseline to second trimester in the intervention group was 1.8 points higher (95% CI: −0.5, 4.2) than that of controls, using linear regression (Table 4). Including end-of-pregnancy scores of women with fetal loss before the second-trimester visit (n = 68), linear regression showed that the mean score difference in the intervention group from baseline to second visit was 2.5 points higher (95% CI: 0.3, 4.8) than that in controls (Table 4).
Aspirin use
At baseline, 28/38 (74%) women receiving the intervention were using ASA compared with 22/35 (63%) of controls. One patient receiving the intervention did not complete the ASA survey at the second-trimester visit. Excluding this patient, all women who had ongoing pregnancy at second-trimester visit were using ASA (29/29, 100%) in the intervention group while 26/29 (90%) were users in the control group (difference 10%, 95% CI: −3, 26%). Assuming the patient with missing survey was an ASA user, the difference was 10% (95% CI: –3, 26%) and as a non-user, the difference was 7% (95% CI: −8, 23%).
Among the 12 participants who experienced fetal loss before the second-trimester visit, a control participant did not complete the ASA survey at the end-of-pregnancy visit. She had fetal loss within 10 weeks of pregnancy, had the end-of-pregnancy visit at the 10th gestational week, and was not using ASA at baseline, so we used the last-observation-carried-forward method [19] and defined her as a non-user. Then, 5/6 (83%) control patients with fetal loss had ASA use during pregnancy while all six patients in the intervention group with fetal loss prior to second-trimester visit reported having used ASA at any time during pregnancy.
There were non-users at baseline who became ASA users at the second visit, particularly in the intervention vs control groups (see Supplementary Materials, available at Rheumatology online). In addition, we did not observe any substantial differences in ASA doses between the intervention and control groups (see Supplementary Materials, available at Rheumatology online).
Aspirin adherence
All patients who completed the survey at the second visit reported being recommended or prescribed ASA. In ongoing pregnancy, median ARMS score at the second-trimester visit was 12.0 points in both groups (IQR 11.0–12.0; n = 29 each group) (W = 427.5, P = 0.91). Including patients who had fetal loss, median ARMS score was 11.0 points (IQR 11.0–12.5) and 12.0 points (IQR 11.0–12.0) in the intervention (n = 35) and control groups (n = 34), respectively (W = 609, P = 0.86).
Mean change in ARMS scores from baseline to second visit in patients (including those with fetal loss) reporting ASA use at both visits was −0.62 (95% CI: −1.19, −0.23) in the intervention group (n = 26) and −0.71 (95% CI: −1.74, 0.32) in the control group (n = 21), with lower ARMS scores indicating better adherence.
ASA dispensation information in the electronic pharmacy records was available for 26 Montreal patients in each group (including women with fetal loss), all indicating no over-the-counter ASA use. Twenty-one of 26 (81%) receiving the intervention and 17/26 (65%) receiving usual care had PDC ≥80% (difference 15%, 95% CI: −9, 37%).
Discussion
Preeclampsia knowledge
As the first RCT to assess preeclampsia knowledge in pregnant SLE women receiving usual care, we observed poor preeclampsia knowledge at baseline with an overall mean score of 50% (15/30, range 0–27/30). This is congruent with previously reported mean scores in the general population ranging from 40% to 60% [8, 17]. Most patients at baseline (49/73, 67%) were aware that ASA in pregnancy can reduce preeclampsia risk. Patients were incorrect or uncertain for most questions about preeclampsia symptoms (e.g. swelling of feet). Yet, the vast majority (87–97%) of women from each trial arm correctly identified what to do when symptoms arose (e.g. call their doctor or go to the hospital). Previous research likewise reported that pregnant women without SLE lacked knowledge about preeclampsia symptoms but almost all were aware of the appropriate actions to take when they experienced symptoms [17]. Yet, suboptimal preeclampsia knowledge about early preeclampsia symptoms may be hindering women from receiving timely medical care. Of note, none of the study investigators ever handed specific educational pamphlet or document regarding preeclampsia to their SLE pregnant patients prior to this trial, highlighting a potential care gap that could be filled with the PLACENTA tool.
Statistically significant improvement in knowledge scores from baseline to second-trimester visit were observed in both the intervention and control arms in analyses including and excluding women with fetal loss (despite the control group not being handed any additional information sheet). However, women receiving the PLACENTA tool demonstrated higher score difference from baseline to the second visit (including women with fetal loss) than women only receiving usual care (difference in differences 2.5 points, 95% CI: 0.3, 4.8). Improvement in preeclampsia knowledge in the intervention group is concordant with the results of the prior RCT showing efficacy of the original educational tool in women without SLE [16]. Nevertheless, scores at the second visit were relatively low (∼20/30 or 67% for intervention and ∼17/30 or 57% for control group). Therefore, it is important to seek additional ways to further optimize preeclampsia knowledge in SLE, such as standardizing delivery method of the tool.
Aspirin use and adherence
At baseline, most (68%) pregnant SLE women in this Canadian sample were using ASA (with <20% in both groups using ASA prior to pregnancy). This is a greater proportion than what we previously observed (25%) in pregnancies from the international SLICC inception cohort from 2000 to 2017 [15], potentially reflecting improved adherence to guidelines over time and/or different clinical practices in Canada compared with other SLICC countries. Including women with fetal loss and/or preterm birth, 91% of women at second visit, 96% at third visit and 100% at end-of-pregnancy visit were using and/or had used ASA in the usual care arm, suggesting high use of ASA in SLE pregnancies followed at Canadian SLICC sites.
We saw a trend towards higher ASA use among women with ongoing pregnancy at second trimester in the intervention group compared with controls (difference 10%, 95% CI: −3, 26%). This trend was observed among patients managed at lupus tertiary care centres, where baseline ASA use was high. This suggests that the educational tool might yield better results in non-academic settings, where baseline ASA use may be lower. Early ASA initiation/use in high-risk pregnancies (i.e. <16 weeks) is of paramount importance to reduce the risk of placenta-mediated complications by optimizing placental implantation. An educational intervention like the PLACENTA tool, which demonstrates a trend in increased ASA use from the first to the second trimester—when it is most critical—has the potential to improve outcomes as ASA reduces by half the risk of placenta-mediated complications in high-risk pregnancies [11].
At the second-trimester visit, there was no significant between-group difference in ARMS scores among women with ongoing pregnancy who were recommended or prescribed ASA, even with the inclusion of end-of-pregnancy ARMS scores of women with fetal loss. However, when the PDC was assessed in women enrolled at the coordinating centre, we observed a trend for a higher proportion of subjects with PDC ≥80% in the intervention (81%) vs control group (65%), though the CI included the null (difference 15%, 95% CI: −9, 37%).
Strengths of the trial
Our trial yielded much-needed data on preeclampsia knowledge and patterns of ASA use and adherence in pregnant women with SLE receiving usual care, rarely explored in previous research, representing a crucial research gap considering the high-risk profile of SLE patients. Also, this trial was the first to have adapted a validated preeclampsia educational tool for SLE patients and evaluated it in a RCT. Since the tool has improved knowledge in women of varying health literacy in a previous RCT [16] and the SLE-specific content was optimized for comprehensiveness while consulting end-users, we expect the knowledge improvement observed in this trial to be generalizable to different SLE populations including those with limited health literacy. Using the PLACENTA tool may substantially help clinicians save time and deliver information efficiently [20], as well as improve patient knowledge [20, 21].
Another important strength of the trial is the recruitment of patients across Canada. Although it was not feasible for the trial to accrue as many patients needed to statistically adjust for site-specific effects, owing to the low frequency of SLE, we considered this potential confounding effect with the site investigator questionnaires but observed similar counselling practices across centres. Finally, the inter-rater reliability for preeclampsia knowledge scores of 0.97 (95% CI: 0.96, 0.98) indicated high concordance and reliability [22].
Potential limitations
Although very few patients did not complete the outcome assessments, missed study visits, or were lost to follow-up, we nevertheless performed sensitivity analyses to account for this. Even though we employed very conservative assumptions, these sensitivity analyses still showed a trend of higher preeclampsia knowledge score difference in those receiving the intervention.
One important limitation was the use of patient-reported ASA use and adherence, which could have been affected by reporting bias. Patients completing assessments over the phone with a member of the research staff (instead of filling a form) during the pandemic (occurring in <10%) may have been affected to a greater extent. To account for a potential information bias with self-reported ASA adherence, we used electronic drug dispensation data. We observed a trend of a higher proportion of women achieving PDC ≥80% in the intervention arm vs controls, although this analysis was restricted to participants enrolled at the coordinating centre in Montreal.
Conclusion
Our RCT is the first to report preeclampsia knowledge of pregnant women with SLE receiving usual care and to evaluate the effect of a specifically designed educational tool on preeclampsia knowledge as well as ASA use and adherence in SLE pregnancies. With the PLACENTA educational tool, we observed greater improvement in preeclampsia knowledge scores, a trend towards higher ASA use from baseline to second visit, and an increase in self-reported ASA adherence in ASA users from baseline to second visit, although patients in both arms reported high ASA adherence regardless of the intervention. Interestingly, we observed a trend for higher ASA adherence when defined using electronic pharmacy data. Our findings support the use of the PLACENTA educational tool in the care of SLE pregnant patients to improve preeclampsia knowledge and ASA use, to ultimately optimize outcomes in this at-risk population.
Supplementary Material
Acknowledgements
The authors are grateful for the relentless work of amazing research staff including Mary Ford, Luisa Ciofani, Popi Panaritis, Michele Tobaly, Nathalie Amiable, Emmanuelle Rollet-Labelle, Amély Cazes, Stephanie Reidy, Michaela Speirs, Karen Spitzer, Denisse Bonilla, Heather Waldhauser and Chynace Van Lambalgen.
Contributor Information
Joo-Young (Esther) Lee, Centre for Outcomes Research and Evaluation (CORE), Research Institute of McGill University Health Centre, Montréal, QC, Canada.
Arielle Mendel, Centre for Outcomes Research and Evaluation (CORE), Research Institute of McGill University Health Centre, Montréal, QC, Canada; Division of Rheumatology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
Isabelle Malhamé, Division of General Internal Medicine, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
Megan R W Barber, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Ann E Clarke, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Paul R Fortin, Centre ARThrite—CHU de Québec, - Université Laval, Quebec, QC, Canada.
John G Hanly, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada.
Alexandra Legge, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada.
Christine Peschken, University of Manitoba, Winnipeg, MB, Canada.
Carl A Laskin, University of Toronto, Toronto, ON, Canada.
Zahi Touma, University of Toronto, Toronto, ON, Canada.
Murray B Urowitz, University of Toronto, Toronto, ON, Canada.
Sasha Bernatsky, Centre for Outcomes Research and Evaluation (CORE), Research Institute of McGill University Health Centre, Montréal, QC, Canada; Division of Rheumatology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
Évelyne Vinet, Centre for Outcomes Research and Evaluation (CORE), Research Institute of McGill University Health Centre, Montréal, QC, Canada; Division of Rheumatology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
Supplementary material
Supplementary material is available at Rheumatology online.
Data availability
The available data supporting the findings of this study are available within the article and its supplementary materials.
Contribution statement
A.C., P.F., J.H., C.P., C. L., M.U., S.B. and E.V. designed the study; M.B., A.C., P.F., J.H., A.L., S.B., A.M. and E.V. recruited participants; E.L. and E.V. conducted the analysis. All authors contributed to the finalization of the manuscript. There was no use of artificial intelligence (AI) to generate content or images, write code, process data, or for translation.
Funding
This randomized controlled trial was funded by the Canadian Initiative for Outcomes in Rheumatology Care (CIORA) in 2017, under the grant name ‘Aspirin patterns of use and adherence for prevention of preeclampsia in SLE pregnancies’. This work was also supported by a Fonds de Recherche Santé Québec salary award to E.V.
Disclosure statement: The authors have declared no conflicts of interest.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The available data supporting the findings of this study are available within the article and its supplementary materials.