Pregnancy outcomes in systemic lupus erythematosus: experience from a Caribbean center

Abstract Background Systemic Lupus Erythematosus (SLE) is a chronic autoimmune multi-system disorder frequently affecting black women of childbearing age. No published data exist on the obstetric outcomes in a Caribbean population. Objective We analyzed pregnancy outcomes in an Afro-Caribbean cohort of women with SLE at a tertiary university hospital. Methods A retrospective cohort study was performed of all pregnant women with SLE prior to pregnancy from January 1990 to December 2021 at the University Hospital of the West Indies (UHWI), Jamaica. Maternal rheumatologic, obstetric, fetal/neonatal data were analyzed. Descriptive statistical analyses were performed. To determine if outcomes were associated with various factors, Spearman’s rho was followed by logistic regression analysis to estimate unadjusted odds ratios with statistical significance at p < 0.05. Results A total of 56 pregnancies in 47 women were identified with SLE. Live births were 87.5%, with 10.7% spontaneous miscarriages and no neonatal deaths. Prednisone was the most used drug in 67.9% of patients. 85% of women had an adverse outcome with an adverse fetal outcome occurring in 55% of cases. Prednisone was associated with an adverse fetal/neonatal outcome (Spearman’s rho = 0.38; p = .004). Conclusion In this first Caribbean series on SLE in pregnancy, reasonably successful pregnancy outcomes are achievable in Afro-Caribbean women managed in multidisciplinary centers.


Introduction
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune multi-system disorder with a propensity to affect black women of childbearing age [1]. The Jamaican prevalence rate in 1979 was quoted as 5-17/10 5 [2,3], which is likely considerably underestimated [4]. More recently Barbados, a population similar to Jamaica, had an unadjusted incidence rate of 15/10 5 in adult women [5]. To the best of our knowledge, this is the first study to report pregnancy outcomes of patients with SLE in the Caribbean -a unique low-to-middle income populace, primarily of African ancestry. Adverse outcomes have been reported to be prevalent in African populations [6], however, most of the reported literature has been from developed countries with a predominantly Caucasian population [7].
Excepting women with chronic renal disease or alkylating agent treatment, the fertility rate in persons with SLE is unaffected [8,9]. Frequently, obstetric care providers are faced with the challenges encountered with this condition in pregnancy. Adverse pregnancy outcomes include gestational hypertension, preeclampsia, preterm birth (PTB), intrauterine growth restriction (IUGR), fetal loss, spontaneous miscarriage [10], congenital heart block and neonatal lupus erythematosus [11]. Lupus flares may increase, especially with high disease activity pre-pregnancy [11].
Optimization of disease control preconceptionally is paramount [12], with six months of disease quiescence recommended [11]. Better outcomes are linked to the choice of suppressive therapy [12]; hydroxychloroquine (HCQ) reduces the risk of flares, PTB and perinatal issues [11]. Prednisone and azathioprine are safe in pregnancy and should be continued if used pre-conceptionally [13]. Multidisciplinary management is key to favorable outcomes [11].
Multiple adverse outcomes of SLE in African-origin populations such as ours are reported [14]. No published data exist on outcomes of SLE from pregnancy in Caribbean populations. Given the profile above, our study aims to analyze such outcomes at a tertiary university hospital and assess factors associated with adverse maternal and fetal/neonatal outcomes. This further assesses local risks, assists in counseling patients prior to pregnancy and ultimately helps to optimize management before and during pregnancy.

Methods
A retrospective cohort study was performed. All pregnant patients diagnosed with SLE attending the maternal-fetal medicine (MFM) clinic and admitted to the antenatal ward at the UHWI, Kingston, Jamaica, from January 1990 to December 2021, were identified from a database search. Medical charts were reviewed to capture data, which was recorded on a predefined data collection form. Our center is a university-teaching hospital that has 1614 deliveries per year, serving a primarily urban population.
Ethical approval was obtained from the Ethics Committee of the University of the West Indies, Mona, Jamaica -ECP 160, 15/16. Informed consent was not sought because this consisted of a review of medical records.
All the patient's antenatal records were available however the pre-pregnancy records were sometimes limited as during this study period, the records were not electronic.
Inclusion required SLE diagnosed prior to pregnancy. Maternal data collected included patient demographics, SLE complications and flares, medications during pregnancy, and preexisting comorbid conditions. Laboratory data, when available, included levels of: Anti-nuclear antibodies (ANA) and double-stranded DNA (dsDNA), anti-Ro/SSA, anti-La/SSB, lupus anticoagulant, anticardiolipin, complement 3 (C3) and 4 (C4) levels, urea, creatinine, 24-h urine protein and urine casts. Pregnancy outcome data were medicallyindicated termination of pregnancy and spontaneous miscarriages, live births, stillbirths, PTB, IUGR, and preeclampsia. Neonatal outcomes included APGAR scores, birth weight, special care nursery (SCN) admissions, all recorded on confidential individual data sheets with no identifying information.

Definitions
Preterm birth was defined as a live birth occurring before 37 completed weeks of gestation, stillbirth as no signs of life occurring after 24 completed weeks of gestation. The hypertensive disorders of pregnancy (HDP) included gestation hypertension and preeclampsia. Gestational hypertension was noted as systolic blood pressure (BP) !140 mmHg and/or diastolic !90 mmHg on two separate occasions at least six hours apart after 20 weeks of gestation. Pre-eclampsia was new-onset hypertension and/or proteinuria (greater than 0.3 g/day or 1þ on urine dipstick) with evidence of end-organ damage after 20 weeks of gestation. Lupus nephritis was the presence of red cell casts in urine or proven by biopsy.

Statistical analysis
Descriptive statistics were proportions, as well as means, and medians with the respective standard deviations (SD) and interquartile range (IQR). Adverse maternal outcomes were coded dichotomously as yes/no based on any complication occurring during the pregnancy; similar dichotomous coding was used for adverse fetal/neonatal outcomes. Spearman's Rho correlation was used to the associate these adverse outcomes with the continuous variables age of conception, duration of SLE and body mass index (BMI), as well as categorical variables on prednisone and on hydroxychloroquine. This was followed by logistic regression analysis to estimate unadjusted odds ratios (OR) and 95% confidence intervals (CI) of relevant factors. Statistical significance at p < 0.05, all analyzed with SPSS (version 20.0, SPSS, Inc., Chicago, IL).

Results
A total of 56 pregnancies in 47 women were identified (Table 1). Their mean age at the time of conception was 28.4 ± 5.8 years with the mean duration of SLE being 5.4 ± 4.7 years. Most women were parous and booked in the early second trimester. Despite early booking, approximately 85% had an adverse maternal outcome and 55% with an adverse fetal outcome. Approximately 1 in 3 women (30.4%) were not on medication during pregnancy. For those on medication, the most used was prednisone, followed by HCQ. There was only one case of a known teratogen used (i.e. methotrexate).
Of the results available for ANA, 62.5% of known results were positive. dsDNA was positive in 5 women, and negative in 18 women, while the remaining had no documented results. Only 4 women (of 22 documented results) were anti-Ro positive. All cases of hypocomplementemia resulted in live births. For the 3 cases of low C3 levels, all were preterm deliveries with one neonate requiring SCN admission. The 2 cases of low C4 levels saw both neonates admitted to SCN with 1 being preterm.
Most women had a live birth (88%) with a late preterm delivery (mean gestational age at delivery was 36.0 ± 2.7 weeks) and a mean birth weight of 2.68 ± 0.65 kg. Low APGAR scores were an uncommon occurrence. Of the 53 women in which data were available regarding the mode of delivery, 39 (73.6%) delivered vaginally.
Hypertensive disorder of pregnancy (HDP) was seen in 28.6% of cases. Other maternal complications included impaired renal function, diabetes mellitus (gestational and steroid-induced), uncontrolled seizures with autoimmune haematological conditions, particularly anemia and thrombocytopenia (see Table 2). Other complications which involved hospitalizations included the above conditions, as well as preterm prelabour rupture of membranes (PPROM), threatened preterm labor and community-acquired pneumonia ( Table 2). No complications were seen in 16.1% of pregnant women.
Of the fetal/neonatal outcomes investigated, more than 50% of adverse cases included preterm delivery and low birth weight infants (less than 2500 g at birth). There were 8 cases of IUGR: 4 were delivered at term, 3 preterm and 1 was a stillbirth. There were no cases of congenital lupus, congenital heart block or maternal death.
Upon further statistical analysis, associations with the adverse maternal and fetal outcomes were assessed, specifically for age at conception, SLE duration, BMI and medications used. A significant positive association was only identified between adverse fetal outcome and prednisone use (Spearman's rho ¼0.38; p ¼ .004), followed by logistic regression analysis which revealed an increased risk of adverse fetal outcome with an odds ratio of 5.63 (95% CI 1.63 À 19.42, p ¼ .006).

Discussion
This study represents the first such conducted in an Afro-Caribbean population focusing on both maternal  and fetal/neonatal adverse outcomes in pregnancy and associated factors.
While this study spanned 31 years, a small cohort of women met the criteria with a total of 56 pregnancies, lower than a Danish study having 150 pregnancies in 20 years [15]. However, a study conducted in Japan from 2000 to 2009 with a similar cohort (total of 55 pregnancies) observed an older mean age at the conception of 30.6 ± 4.8 years and a mean disease duration of 6.6 ± 5.3 years [16], compared to our findings of 28.4 ± 5.8 years and 5.4 ± 4.7 years respectively. At our institution, it is advised that pregnant women have their first antenatal visit between 8 to 16 weeks of gestation, hence a low incidence of late booking with a mean gestational age of 15.1 ± 6.3 weeks. This allowed for close monitoring of the pregnancy and early institution of multidisciplinary management involving MFM, rheumatology and nephrology services if indicated. While six months of disease-free activity is encouraged pre-conceptionally [11,12], only 10 subjects could recall their disease-free interval i.e. 8 women being flare-free and 2 experiencing flares within this time. These 2 received standard treatment including steroids and hydroxychloroquine. There were 2 cases of chronic hypertension found. The mean BMI obtained was 28.5 ± 7.0 kg/m 2 representing the overweight category, in keeping with our general population of 28.2 ± 6.6 kg/m 2 [17].
Notably, prednisone was the most used drug during pregnancy. While corticosteroids have been proven to be beneficial in symptom relief and reduction in mortality, they should be reserved for acute exacerbations [18]. Chronic glucocorticoid use in pregnancy has been shown to increase the risk of IUGR, HDP, gestational diabetes and PPROM [19,20]. Historically, there has been an association between prednisone use and cleft lip/palate [21], however, none were seen in the neonates from our study.
The anti-malarial hydroxychloroquine is a mainstay drug in SLE management [18]. It improves disease activity, reduces flares, improves survival rates (particularly with co-existing renal disease) and reduces the incidence of congenital heart block through its antiinflammatory and immunomodulatory pathways [13,22,23]. Women with SLE have been shown to have a 3 to 4-fold increased risk of developing pre-eclampsia, and HCQ reduces this risk by about 89.4% [23].
Approximately one-third of women were not on medications during their pregnancy. This may be attributed to noncompliance with medication during pregnancy for fear of feto-toxicity or lack of flares that occurred antenatally [13]. To counter this, proper counseling regarding HCQ's safety and efficacy in pregnancy should be emphasized [13]. To add, all pregnancies in this cohort were unplanned. Furthermore, there has been an increasing trend of initiating women on HCQ therapy while pregnant, however, the overall use remains low [24].
Over the period studied, the SLE diagnostic criteria evolved. In 1982, the American College of Rheumatology (ACR) criteria was first constituted [25]. The most current is the European League Against Rheumatism (EULAR) and ACR in 2019 in which patients must have an elevated ANA titer, followed by weighted items where a score of 10 gives the diagnosis of SLE [8,26]. In our cohort, ANA was positive in 26.8%, negative in 7.1% and not documented in 66.1%. With the varied diagnostic criteria having been used throughout the study period, it is unclear if this would have affected the accuracy of diagnosis given the different specificities and sensitivities of each criterion. The rheumatological records were not available for most women making it difficult to determine the pre-conception course.
The presence of a lupus antibody is associated with adverse fetal outcomes [27]. We observed 42.8% of women had pregnancies positive for a lupus antibody (ANA, dsDNA, anti-Ro and lupus anticoagulant). Hypocomplementemia represents active SLE disease with low C3 being associated with adverse pregnancy outcomes including fetal loss and IUGR [28,29]. Only 3 pregnancies (5.4%) had decreased C3 and there were 2 (3.6%) decreased C4in which one woman had both decreased C3 and C4 levels. We noted that all cases of low C3 were live PTB. Furthermore, the only case that had both decreased C3 and C4 levels had a live PTB requiring SCN admission.
Five women had significant proteinuria with only 1 having abnormal urine casts visible on urine microscopy. These casts represent glomerular and tubular dysfunction of the nephrons, with a high specificity of 97% but low sensitivity [30,31]. All five women with confirmed lupus nephritis predating pregnancy had abnormal urine samples. There were no cases of newonset lupus nephritis in pregnancy. Small numbers precluded analysis of pregnancy outcomes in those with lupus nephritis.
Previous studies report an incidence of live birth in SLE pregnancies from 56 to 79% [32,33]. The incidence of live births in our study was 87.5%, mirroring that found by Ideguchi et al. in 2013 which gave a rate of 84% [16]. Close rheumatologic monitoring of the mother with use of immunosuppressants and increased fetal surveillance could have possibly contributed to this favorable outcome. The outcomes of 4 women could not be included in this analysis because their records could not be accessed.
Several studies report a miscarriage incidence in SLE between 11% and 24% [34]. Our incidence of miscarriage was 10.7%. There is a higher risk of IUGR compared to low-risk females (28.5% vs 17.5%) [35]. We observed an IUGR rate of 14.3% -lower than the rate reported in normal pregnancies. This may reflect the small size of our cohort.
Prematurity in SLE is reported in up to 50% of cases [11], and a preterm delivery risk ratio of 2.33 [36]. In our study the rate was 19.6%, likely contributing to the 25% rate of SCN admissions. Pregnancies complicated by pre-eclampsia and renal disease increase the risk of iatrogenic prematurity [37]. Our 5 women with lupus nephritis all had iatrogenic preterm delivery.
Eighty-five (85%) of our women had an adverse maternal outcome. 28% of these women had HDP, greater than the general obstetric population of 10-15% [37]. Ray et al. found that Jamaican women had twice the risk of pre-eclampsia and indicated pre-term birth without a previous medical condition [38]. Furthermore, HDP is strongly associated with stillbirths and prematurity, independent of the presence of active SLE [39]. Hospitalizations were prevalent secondary to a range of obstetric conditions as outlined in Table 2, with this risk being greater with active disease [40].
More than 50% of fetuses/neonates had adverse outcomes. One woman was medically terminated and presented at 8 weeks gestation while being on weekly doses of methotrexatea known abortogenic, teratogenic and embryotoxic drug. Low birth weight was seen in 28.5% of cases, with rates up to 30% in those with lupus nephritis [37].
The main statistically significant finding from our study was that the use of prednisone was associated with adverse maternal and fetal/neonatal outcomes. This has been shown in previous studies where higher doses (greater than 10 mg of prednisone daily) increase the risk of HDP, PTB, PPROM, IUGR and gestational diabetes [41]. Unfortunately, the dosing administered to our subjects was not available. As such, we should encourage the use of HCQ more in practice than giving prednisone first line. HCQ has also been found to extend pregnancy duration by about 2.4 weeks [42]. This is highly significant since our study gave a mean gestational age at delivery of 36.0 ± 2.7 weeks, i.e. PTBs. Furthermore, the use of HCQ results in a lower dose of prednisone being required, especially for those with end-stage renal disease [43]. While there were no associations found among adverse outcomes and age at conception, SLE duration, BMI and HCQ use, having less accessible files may have corrected this statistical error.
The main strength of this study is it is the first within a predominantly Afro-Caribbean cohort of women with SLE in pregnancy. Information gleaned from this study will heighten awareness amongst healthcare providers of the potential complications that these women face, encourage preconception care and promote the institution of early multidisciplinary care.
Limitations of this study were the small sample size and lack of access to complete medical charts. Some maternal data were self-reported and thus prone to recall bias. As the study was retrospective, the chance of type II errors was increased. These limitations could be overcome with the use of electronic medical files now instituted, and a future prospective study. As the study period spans three decades, diagnostic criteria and modes of therapies have evolved, and may have impacted the pregnancy outcomes. Unfortunately, though desirable, our low numbers limited a more indepth periodic analysis.

Future research
The establishment of a lupus registry to further evaluate and access data [4]. A prospective study comparing the pregnancy outcomes relative to medication regimes could be undertaken. Inclusion of other tertiary institutions that provide obstetric care to Jamaican women with SLE to create more generalizable results. The implementation of low-dose aspirin for pre-eclampsia prophylaxis, particularly in the past 10 years, should also be assessed locally or regionally, in an effort to increase awareness and incorporate this cost-effective method into routine use [44][45][46]. The impact of pre-pregnancy counseling may also be studied, and contraception should be emphasized, in conjunction with close rheumatologic care. analysis. SG, SSB, TH and NJ wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
This research received no specific grant from any funding agency in the public commercial or non-for-profit sectors.

Data availability statement
The data that support the findings of this study are available from the corresponding author, TH, upon request.