Cross-sectional analysis of adverse outcomes in 1,029 pregnancies of Afro-Caribbean women in Trinidad with and without systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that predominantly affects females of child-bearing age (female:male ratio approximately 9:1), with both genetic and environmental determinants, and is particularly common in Afro-Caribbean populations. SLE has a well-recognised association with second-trimester miscarriage; studies have also examined other adverse pregnancy outcomes including prematurity and pregnancy loss [1–16]. Some of these studies, however, are based on small numbers and/or tertiary referral centres with many high-risk patients, and few studies involved a comparison group [2, 8].

Risk factors that have been previously identified for adverse pregnancy outcome in women with SLE (particularly second-trimester miscarriage) include antibodies to phospholipids (lupus anticoagulant and anticardiolipin antibodies), lupus activity and renal disease [1–3, 5–9, 11, 12, 17, 18]. Many studies may underestimate the rates of early miscarriage, however, as patients may not have been referred after a pregnancy was lost.

Trinidad was selected as an ideal place for study of pregnancy outcomes as large family sizes are common combined with a young age of reproduction. There are no known previous such studies in the Caribbean. There are no national data for Trinidad available on miscarriages, although data are provided on other reproductive outcomes such as live births and stillbirths [19]. At the last census in 2000, the population of Trinidad & Tobago was 1.26 million. Estimating the prevalence of SLE in Northern Trinidad is difficult as we do not have exact denominator data. Typical prevalence rates in Afro-Caribbean women in the United Kingdom, however, are around 200 per 100,000 adult women, which are six to eight times higher than in Europeans [20, 21]. Preliminary work carried out by the authors suggested there may be approximately 373 cases of SLE in Northern Trinidad (see Discussion), with a population denominator of approximately 170,000 adult females [22] – thus giving a crude SLE prevalence of approximately 219 per 100,000 in females in Trinidad.

Health services in Trinidad are mainly public sector with some private hospitals and clinics. Primary healthcare services include 102 nationwide health centres. Secondary healthcare is available at eight district hospitals and three large government hospitals in Port of Spain, San Fernando and Arima. Tertiary healthcare is available in Port of Spain. One of the main facilities is the Mount Hope Medical Complex, which houses a 340-bed general purpose hospital, including a 110-bed maternity hospital. Overall there is reasonable access to healthcare, even in low-income groups.

The aim of the study was to examine adverse pregnancy outcomes (miscarriage, stillbirth, ectopic pregnancy and preterm delivery) in a large group of Trinidadian Afro-Caribbean women with SLE and without SLE.

The response rate for eligible SLE cases in the case–control study was 122/131 (93%). Two women with SLE refused to participate and seven did not attend for interview. Of eligible women without SLE, the response rate was 70% (203/290). Initial comparison of nonresponders in women without SLE did not show significant differences in age or socioeconomic status. There was no association of district with risk of SLE.

The present study is the first to examine pregnancy outcome in women with SLE in Trinidad, where large family sizes and early age of reproduction make it an ideal environment to study the relationship between SLE and foetal outcomes. Access to healthcare was equal for women with SLE and for women in the comparison group, even in low-income groups.

We found that pregnancies conceived by Afro-Caribbean Trinidadian women with SLE were more likely to end in foetal death (OR, 2.4; 95% CI, 1.2–4.7). The strongest effect was on risk of stillbirth, where pregnancies conceived by women with SLE were greater than eight times more likely to end in this way (OR, 8.5; 95% CI, 2.5–28.8). There was also some evidence of an increased risk of ectopic pregnancy among pregnancies conceived by women with SLE. Finally, we found that pregnancies conceived by women with SLE also appeared more likely to end in preterm delivery. This effect was strongest among those conceived after SLE diagnosis, which were greater than three times more likely to end in preterm delivery than those conceived by women without SLE (OR, 3.4; 95% CI, 1.2–10.0).

Details regarding pregnancy outcomes in general within Trinidad are unavailable, but recent national data suggest that the overall crude live birth rate of 18,490 per 629,315 (2.9%) total female population [19] is approximately twice as high as in North America [27]. At the time of writing there were no national data available on miscarriage in Trinidad, although the national stillbirth rate was estimated as 1.2% total births, which is slightly higher than European figures (approximately 0.5% of total births around the time of this study) [28].

The live birth rate (42%) among women conceiving after a diagnosis of SLE is lower than that reported in other studies (84–87%) [1, 3, 5]; however, this may reflect higher disease activity and comorbidity in Trinidad. Furthermore, termination of pregnancy is currently illegal in Trinidad and therefore is likely to have been misreported as miscarriage – combined with the fact that most foetal deaths were reported as first-trimester miscarriage (17.6%), this misreporting might suggest that the higher pregnancy loss rate in our study could be explained by a higher proportion of induced abortion in this age group. Our findings for foetal death overall (24% in women diagnosed with SLE and 16% in women without SLE) is slightly higher than those in other studies (7–16%) [1, 3, 5, 8]. Early foetal loss may not, however, have been counted in these studies. Few other studies have reported on ectopic pregnancy in relation to SLE (or it is not clear whether ectopic was included as 'foetal loss') – but an increased risk of ectopic pregnancy was found in SLE patients in one study that did, based on a study of only 17 women (42 pregnancies) with SLE [29]. The increased risk of ectopic pregnancy is possibly explained by reduced tubal motility.

First-trimester miscarriage rates are reported as 18% in women with SLE and 13% in women without SLE, although these may be overestimated values owing to the inclusion of induced abortions, as discussed above. North American studies report first-trimester miscarriage as between 7% and 10% based on moderate numbers of pregnancies in women with SLE (63–267 pregnancies) [1, 3, 5]. Other European studies have reported similar proportions to those found here. Evidence of first-trimester miscarriage has been reported as 5% in a cohort of 46 women with SLE (60 pregnancies); however, this was in a tertiary centre with intensive management protocol for these high-risk pregnancies [6]. A study in France also estimated a spontaneous miscarriage rate of 16% in European women with SLE in 62 pregnancies (38 women) [12], although this included cases with SLE nephropathy. Spontaneous (first and second) miscarriage rates in pregnant women from Saudi Arabia with lupus nephropathy (inactive and active) are reported as between 25% and 32%, with higher rates in patients with antibodies to phospholipids, although this study included only 24 patients [10].

High stillbirth rates in women with SLE have been reported in a number of other studies, with particular high risk in patients with lupus nephritis and/or altered immunological profiles including antiphospholipid syndrome [5, 10, 12, 16, 17]. Some studies include a definition of stillbirth as spontaneous abortion at gestation ≥ 20 weeks [12, 17], however, which will inflate the estimates. In a study that defined stillbirth as spontaneous abortion at > 24 weeks (as used here), the prevalence is estimated as 3/19 (16%) pregnancies in women with lupus nephritis. Risk of stillbirth also appears to be increased in women who became pregnant after SLE was diagnosed (3/44 (6.8%) compared with one out of 10 pregnancies before SLE was diagnosed) [7]. In general these figures are difficult to interpret as estimates are based on very low numbers studied, but the general finding of an increased risk of stillbirth is similar to that reported here.

Other studies have identified risk of preterm birth in women with SLE [6–9, 12], although in some cases prematurity can be medically induced due to complications such as maternal preeclampsia [14]. We did not analyse cause of preterm birth separately in this study.

Although the present study showed an important relationship between SLE and both foetal death and preterm birth, the study does have limitations, which need to be considered.

First, we were only studying women with SLE who had survived, and it is unknown what the reproductive outcomes of those (more severe cases) who died before survey might have been, and whether this might have impacted onto the results.

Next, there was a differential response rate in cases (93%) and control individuals (70%) in the case – control study from which these data came; however, analyses of socioeconomic status such as car and home ownership did not differ between control individuals who agreed to participate and those that refused. It is possible that there may be bias from residual differences between controls who responded and those that did not; however, after obtaining a household listing of all inhabitants, a strict protocol was followed to identify a possible control. Every attempt was made to ensure that selection included working cases (up to three calls were made to identify eligible control individuals at different times of the day and weekends). No SLE cases or controls were excluded because they were pregnant at the time of the survey.

In epidemiological studies, the capture – recapture technique examines the degree of overlap between two (or more) methods of ascertainment and uses a simple formula to estimate the predicted total size of the population. From capture – recapture methods, we estimate a total of 373 cases of SLE are resident in Northern Trinidad; this includes both sexes. In reality, this is likely to be an underestimate as the probability of being on the dermatology register and on the books of the Lupus Society is associated with one another. Assuming 90% of SLE cases are female, we estimate a total of 335 female adult cases in Northern Trinidad. Allowing for incorrect addresses, exclusions on nonAfro-Caribbean individuals and deaths, the total estimated number of eligible SLE cases in Northern Trinidad is 167, of whom we have ascertained 122 (73%).

Although there is potential over-reporting of 'miscarriage', as termination for nonmedical reasons is illegal, this is unlikely to be differential between women with SLE and women without SLE. We are aware that this misclassification is likely to inflate estimates of foetal loss, particularly first-trimester miscarriage.

Our analyses did not show evidence of either high titres of IgG ACL or IgM ACL with sporadic mid-trimester miscarriage, foetal loss, or stillbirth among SLE cases. There was evidence of an association of high titres of IgG ACL and IgM ACL among women reporting three or more miscarriages, and among women with three consecutive miscarriages, but this was experienced by just five of the 97 women with SLE who reported ever being pregnant. We also found an association of high IgM ACL and IgG ACL with ectopic pregnancy, although this was based on small numbers, and an association of high IgM ACL with preterm delivery. Treatment of women with SLE during pregnancy with aspirin and/or heparin is not, however, standard clinical practice in Trinidad. These findings suggest that raised ACL antibodies cannot explain the results for foetal death reported in the present paper, although the investigation of the role of ACL antibodies in preterm and ectopic pregnancies warrants further attention.

Only 27/122 (22%) women who had ever been pregnant had ever had a history of nephritis; however, specific information at time of pregnancy was not available. No women without SLE had documented renal involvement. In any case, adjusting for history of renal involvement in the analyses made little difference. The percentage of immunosuppressive medication in women with SLE treated with corticosteroids, treated with other immunosuppressive medication, and treated with nonsteroidal antiinflammatory drugs was 96%, 84% and 52%, respectively – compared with values for control individuals of 4%, 16% and 48%, respectively. The prevalence of diagnosed hypertension was higher in control individuals than in cases (56% versus 44%), although this was not significant.

This well-conducted large population-based case-control study of SLE provided data on 1,029 pregnancies, which allowed us to examine adverse pregnancy outcomes in a systematic way. In women with SLE, we found a significantly increased risk for still birth and all foetal death (not accounted for by raised titres of ACL). We also found evidence for increased (nonsignificant) risk of all miscarriage, and ectopic pregnancies. Risk of preterm birth was significantly increased among pregnancies conceived after SLE diagnosis.

Further studies may help clarify whether ectopic pregnancy risk is raised in women with SLE, and the role of ACL in preterm and ectopic pregnancies. Women with SLE known to have APL syndrome which is associated with recurrent fetal loss and preterm delivery may benefit from antithrombotic treatment including low dose aspirin [31], where early identification of patients of particular risk (e.g. APL syndrome) for closer patient management between rheumatologist and obstetrician may help improve outcomes further. We suggest further work could be carried out in monitoring of high obstetric risk in women with SLE.