Autoimmune rheumatic diseases (ARDs) primarily affect women during their reproductive years, and pregnancy can be enormously challenging in these women. Increased prevalence of adverse pregnancy outcomes (APOs) in these women, such as preterm birth (PTB), small for gestational age (SGA), and preeclampsia, is well recognized. Additionally, there is evidence to suggest that pregnancy may contribute to the progression of preclinical autoimmune disease and APOs might be the clue to such progression.1 In women without ARDs, multiple studies have underscored a link between APOs and the mother’s increased risk of future cardiovascular disease (CVD).2-5 However, it is unclear whether similar risks exist in women with ARDs, such as systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and rheumatoid arthritis (RA), and whether CVD-related events somehow translate into APOs in these women. Quantifying and understanding underlying mechanisms are crucial, as cardiovascular (CV) morbidity and mortality are higher in several ARDs.6,7

In this issue of The Journal of Rheumatology, Dhital et al explore the relationship between CV events (CVEs) that occurred during pregnancy and the risks of APOs (PTB, SGA, or a composite of either) among women with ARDs in a large, retrospective population cohort of pregnant women who gave birth to singleton liveborn infants, using relevant linked databases.8 They found higher CVEs in pregnant women with ARDs (1.4%) and APS (5.5%) compared to those who had neither (0.3%). Rates of APOs were also higher in women with ARDs (26.9%) and APS (21.2%) than in those without (15.2%). Additionally, CVEs were linked to a higher risk of composite APOs for all groups under study, with adjusted risk ratios ranging from 1.2 to 1.4. Compared to the control group (those without CVEs or ARDs/APS), the adjusted risk differences of APOs per 100 births were 7.8 (95% CI 7.1-8.6), 8.7 (95% CI 8.0-9.4), and 27.8 (95% CI 19.3-36.3) for non-ARD/APS with CVEs, ARD without CVEs, and ARD with CVEs, respectively.

In general, the study by Dhital et al underscores the knowledge that pregnant women with ARDs and APS face significantly increased risks of APOs.8 Specifically, other studies have shown a 2- to 3-fold increase in PTB and a 2-fold increase in SGA in women with ARDs,9,10 and a 1.4 and 1.9-fold higher risk of SGA and PTB, respectively, in APS.11,12 However, the study by Dhital et al suffers from the typical deficits arising from a retrospective analysis of a database not purpose-built to study the relationship between APOs and CVEs.8,13 In particular, the lack of any information on disease activity several months preceding pregnancy and during pregnancy; details of pharmacological management, comorbidities, and prior APOs; and the predominant inclusion of a Hispanic population curtails the study’s applicability and generalizability. Further, this study did not evaluate preeclampsia, an APO associated with an increased risk of several CVEs that extends beyond the postpartum period and is linked to the risk of CVD later in life.2,3,5

Overall, however, the study by Dhital et al is a timely reminder for us to focus on care to improve prepregnancy CV health in women with ARDs and prevent CVD (eg, ischemic heart diseases, cerebrovascular diseases, and peripheral vascular disease).8 At present, extensive research has established a link between APOs and increased maternal risk of CVD and mortality in women without ARDs2-5,14; a similar appraisal in those with ARDs and APS is still a work in progress.

Several pathophysiological factors related to increased CVD risk and APOs in the context of pregnancy are at play in both those with and without ARDs (Figure). Maternal cardiometabolic adaptation during a normal pregnancy is a given, and results in hyperlipidemia, an increase in cardiac output, a hypercoagulable state, and a significant increase in insulin resistance. It is speculated that the stress of pregnancy could uncover pathophysiologic mechanisms, and women can face a marked increased risk of CVD. Further, comorbidities such as obesity, hyperlipidemia, diabetes mellitus (DM), and hypertension are frequently observed in women with ARDs, further increasing their risk of CVD. The endothelial dysfunction and uncontrolled systemic inflammation are thought to be linked to APOs such as PTB, fetal growth restriction, and preeclampsia, and are collectively referred to as maternal placental syndromes. These syndromes may potentially increase the risk of CVD in later life.15

The relationship between cardiovascular risk factors, adverse pregnancy outcomes, and subsequent cardiometabolic health.

Owing to its proinflammatory nature, obesity further increases the risk of preeclampsia in pregnant women. This additional burden disrupts the delicate balance between the CV and metabolic aspects during pregnancy, leading to endothelial dysfunction, oxidative stress, and ultimately, an increased risk of atherosclerosis and resultant CV complications.16 In addition to being linked to diseases such as obesity and CV stress, preexisting DM may cause vascular damage and is closely related to APOs.17 Because gestational DM (GDM) causes inflammation, hyperlipidemia, and metabolic syndrome and is associated with increased carotid intima-media thickness (IMT)—a recognized early marker of atherosclerosis—it significantly enhances the risk of CVD in these women.16,17

Preeclampsia could be among the earliest clinically apparent indicators of CVD. In individuals with ARDs, particularly those with SLE, preeclampsia significantly raises the risk for mortality from CVD when compared to other ARDs. Early preeclampsia enhances the risk of developing hypertension, which in turn raises the risk of premature CVD and morbidity in SLE, even in the absence of traditional CV risk factors.18 A major coronary event is significantly more likely to occur in the context of preterm delivery or SGA infant in addition to preeclampsia. Along with the preexisting CV risk factors and the preeclamptic process itself, the increased cardiometabolic stress during pregnancy raises the chance of preeclampsia, PTB, and eventual CVD by causing long-lasting endothelial dysfunction.19 Further, there is a greater risk of atherosclerosis following preterm pregnancies in women with recurrent preeclampsia compared to those without. Preterm delivery, higher atherogenic lipid profile, and hypertension in women with PTB may further increase the risk of maternal CVD.

Abnormal placentation in APS is related to activation of the complement system and inflammation. This activation causes placental vascular thrombosis, placental infarction, and endothelial dysfunction by triggering the production of antiangiogenic factors. These placental issues may result in APOs linked to CVD in women with APS.20

RA is a well-recognized independent risk factor for CVD, particularly when it is active. Women with RA are at a greater risk of CVD as preeclampsia and peripartum cardiomyopathy are linked to RA. Comorbidities such as hypertension and DM in women with RA might worsen the CV burden.

There is an increased risk of CVDs from substance use during pregnancy. The risk is also reported to be higher in those women with ARDs being treated for infertility through assisted reproductive technologies. Exogenous glucocorticoid use raises the risk of GDM, poor pregnancy outcomes, and subsequent cardiac events. They also increase the risk of preterm delivery due to premature rupture of the membranes.

It is clear from the above discussion that early detection of APOs and their risk factors in women with ARDs using cost-effective screening methods and implementing relevant preventive strategies may help reduce CVD (Table). Such approaches should consider both traditional and nontraditional risk factors for CVD. Preconception lifestyle modifications are crucial for maintaining good CV health and can include ensuring adequate rest; reducing stress; controlling blood pressure, DM, and weight; and quitting smoking. Over time, these preventive strategies are likely to have a compounding beneficial effect on CV health, leading to long-term improvements and reduced risk of CVD. Women with ARDs who are considering becoming pregnant should be given prioritization for such preventive therapies, particularly if they have a history of APOs or preexisting CVD. Ideally, such preventive strategies should begin in the preconceptional stage. Similarly, early detection and efficient preventive measures can significantly reduce the risk of CVD linked to APOs, which can be the first manifestation of preclinical or clinical ARDs.1

Management strategies in ARD with possible APOs having a CV risk profile.

In the study by Dhital et al, individuals who experienced a CVE during pregnancy faced a 1.2- to 1.7-fold increased risk of PTB, SGA, or both, regardless of whether they had ARDs or APS.8 However, since individuals with ARDs already have a higher frequency of CVEs and baseline risks of APOs, the absolute potential effect of CVEs on the development of APOs appears to be even more clinically significant. Although the overall incidence of CVEs in ARD and APS pregnancies in this study was low,8 appreciating the excess risks associated with these events is crucial for pregnancy counseling, early risk stratification, and developing customized management approaches.

In conclusion, APOs are linked with long-term maternal CVD risk due to shared but complex pathophysiologic pathways. Early identification of high-risk individuals allows for the assessment of later-life CVD risk and the implementation of appropriate risk-reduction strategies. The intricate link between ARDs, CV risk, and pregnancy necessitates a multidisciplinary approach, with focused research and patient-centered care being crucial for improving outcomes. There is also a need for prospective, dedicated registries exploring relevant issues in pregnancy in women with ARDs.

The authors declare no funding or support for this work.

The authors declare no conflicts of interest relevant to this article.