Association of Pregnancy With Recurrence of Spontaneous Coronary Artery Dissection Among Women With Prior Coronary Artery Dissection

This nested case-control study uses data from the Mayo Clinic Spontaneous Coronary Artery Dissection Registry to investigate the association of pregnancy with spontaneous coronary artery dissection recurrence among women with a history of coronary artery dissection.


Introduction
Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of acute coronary syndrome that occurs in women of childbearing age. 1,2 It is the cause of ST-elevation myocardial infarction (MI) in 1 of 5 women younger than age 50 years 3 and a foremost cause of heart attack among pregnant women. 1,4,5 Acute SCAD causes MI or sudden cardiac death due to obstruction by a coronary artery wall hematoma alone or a hematoma and an intimal-medial tear. 1,6 Enhanced awareness and technological improvements in the catheterization laboratory have facilitated the diagnosis of SCAD, 1 which for some patients has been previously overlooked.
More than 80% of patients with SCAD are women with a mean age of 42 to 52 years at the time of SCAD occurrence. 1,2 Most patients with a history of SCAD do not have the traditional risk factors, such as tobacco use, hyperlipidemia, diabetes, or a sedentary lifestyle. 7 Approximately one-third of patients have a history of hypertension. 8,9 Most patients have abnormalities in the peripheral arteries, such as fibromuscular dysplasia (FMD), aneurysms, and dissections. 1,10-13 Only a small proportion of patients have an inherited connective tissue disease (5%-8%) 14,15 or family members with SCAD (1%). [16][17][18] Despite the observation based on follow-up imaging that nearly all coronary dissections heal, the morbidity of SCAD is substantial, with an estimated 30-day rate of major adverse cardiac events of 8.8% 8 and 10-year estimated rate of major adverse cardiac events as high as 47%. 6 Much of the long-term risk is related to SCAD recurrence, which occurs in 12% to 29% of patients. 6,19 SCAD recurrence is defined as an MI or cardiac arrest due to SCAD in another, usually different, coronary artery. 1 Risk factors for SCAD recurrence and effective prevention strategies are unknown and remain a principal concern for patients and clinicians. 19,20 The onset of SCAD symptoms has been associated with the pregnant and postpartum condition, exertion, and emotional or psychological stress. 1,2,21,22 The female sex hormonal milieu likely contributes to its pathophysiology as evidenced by the marked female preponderance, association with pregnancy, and post-SCAD chest pain associated with menses. 1,2,22 Subsequent reproductive decisions are challenging because of concern for adverse events, and the current expert consensus is to discourage pregnancy after SCAD. 1 We aimed to describe short-and long-term outcomes in women with post-SCAD pregnancy to better inform future counseling of childbearing women after SCAD.

Study Population
In response to patient advocacy for more research about SCAD in 2009, the Mayo Clinic initiated an ongoing international registry and biorepository of patients with SCAD, 23,24 which were used for this nested case-control study. This work was approved by the Mayo Clinic Institutional Review Board.
We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline and checklist for case-control studies. Patients provided written informed consent and were included in the registry after review and confirmation of SCAD on coronary angiogram imaging by at least 2 interventional cardiologists. Patients with coronary dissections associated with iatrogenesis, trauma, or atherosclerosis were not enrolled. Data collection consisted of exhaustive questionnaires, medical history, imaging, and prospective follow-up. From the time of the pilot study in 2010 25 to ongoing, over 1200 participants with confirmed SCAD from throughout the United States (96%) and other countries (4%) have been enrolled.
For the present study, all women who consented into the Mayo Clinic SCAD Registry from August 30, 2011, through April 4, 2019, were reviewed for a history of pregnancy after SCAD. This was conducted by reviewing responses to specific questions about pregnancy after SCAD on the initial study entry questionnaire and 2 follow-up surveys. Additionally, the clinical records of participants who are concurrent patients of the Mayo Clinic SCAD Clinic were reviewed for a post-SCAD pregnancy. Time to follow-up for all patients was determined by date of last contact by survey, phone, email, or clinical evaluation. To test the hypothesis that recurrent SCAD is associated with pregnancy after SCAD, we conducted cohort, case series, and nested case-control analyses (Figure).

Case Series of Women With Post-SCAD Pregnancies
Given the paucity of information regarding women with post-SCAD pregnancies, extensive details of pregnancy outcomes, complications, and current reproductive status were collected by email, phone call, or clinical follow-up. Twenty-three women were identified as having a total of 32 post-SCAD pregnancies. Although 15 have been evaluated in the Mayo Clinic SCAD Clinic, only 2 were seen in clinical follow-up during the course of the present study. The other 21 were contacted by phone or email for additional details and follow-up information, including 8 women who were previously described. 26

Nested Case-Control
To leverage the registry, a nested case-control study was also performed. The demographic characteristics of all women with SCAD in the registry cohort with complete records were reviewed.
Those who were not of childbearing age at the time of initial SCAD were excluded. This was determined by identifying women who marked a reproductive status of hysterectomy, menopause, or postmenopause at time of initial SCAD and women who were older than age 56 years at the time of SCAD. As recurrence is a primary endpoint of interest from both a mechanistic and clinical perspective, cases were identified as patients who had a recurrent SCAD. Recurrent SCAD was defined as an MI or cardiac arrest distinct from the initial SCAD based on detailed physician review of surveys, medical records, and imaging. Because the American Heart Association SCAD consensus statement indicates that SCAD recurrence within 1 month of the initial event could represent continuation of the initial event, 1 SCAD recurrence for the purposes of case identification was limited to those who had recurrence at least 1 month after the initial SCAD. Patients who experienced initial SCAD progression (distinct from recurrence at <1 month), MI from other causes, or other complications, such as in-stent restenosis, were not categorized as having recurrent SCAD. After the cases were identified, controls were matched to each case in an approximate 2:1 ratio. The matched factors were FMD status, age at first SCAD, and year of first SCAD. Exact matching of FMD status was required. Age at first SCAD and year of first SCAD were matched as closely as possible but allowed to vary as much as 8 and 9 years, respectively. FMD status (categories: not imaged or unknown, yes, non-FMD arteriopathy, no, and possible) was included because of concern that this could be a confounder for recurrence. Matching on age was prioritized over year of first SCAD to allow for similar childbearing potential between the groups. The algorithm also required controls to have been followed at least as long as the cases they were matched to, ensuring opportunity for recurrence would be the same within each match. Matching according to year of first SCAD was to account for

Cohort Time to Event
Because of concern regarding the small number of women with pregnancy after SCAD and that some would be excluded after the matching process for the nested case-control study, a cohort time-toevent analysis was also performed with the 636 participants identified as being of childbearing age at time of initial SCAD. The analysis was performed twice using 2 definitions of SCAD recurrence (any time after SCAD vs Ն1 month after SCAD).

Statistical Analysis
Statistical analysis was conducted using JMP, version 8.0 (SAS Institute) and SAS, version 9.2 (SAS Institute). Continuous variable distributions were checked for normality. Where satisfactory, continuous data were summarized as mean (SD); where skewed, median (interquartile range [IQR]) was reported. Discrete variables were expressed as frequencies with percentages. For the primary analysis comparing cases (with recurrence) and controls (without recurrence), conditional logistic regression was used to assess for variable differences while accounting for matching. The Kaplan-Meier curve was used to estimate recurrent SCAD among all women at risk. As a secondary analysis, a Cox proportional hazards model of time to first SCAD recurrence was fit using subsequent (post-SCAD) pregnancy as a time-dependent factor, adjusted for the time-independent covariates of age at first SCAD, year of first SCAD, and FMD status. For all time-to-recurrence analyses, patients were censored at last follow-up or the date that they turned 56 years of age, whichever came first.
Missing data was remediated by chart review, patient contact, or mentioned as a table footnote. A 2-sided P < .05 was considered statistically significant.

Case Series of 23 Women, 32 Pregnancies
Within the overall cohort, 23 women (median     her second child. She then had 3 additional pregnancies, the last of which was a miscarriage. Her 2 recurrent SCADs occurred 12 and 21 years after her final pregnancy.

Nested Case-Control Analysis of Patients With Recurrent SCAD
Ninety-two women with recurrent SCAD were matched to 158 controls (

Discussion
These findings suggest that SCAD is multifactorial with contributory factors beyond pregnancy alone.
SCAD recurrence was uncommon in the case series of women with pregnancy after SCAD. Within the nested case-control analysis, women with SCAD recurrence were less likely to have a history of subsequent pregnancy compared with those without SCAD recurrence. In the cohort analysis, a history of subsequent pregnancy was not associated with SCAD recurrence. This unexpected finding may be in part because of the small number of women who had another pregnancy after SCAD.
Although the small number of women notably limits the power of this analysis, it also reflects the fact that most women do not become pregnant after SCAD, consistent with current recommendations.
However, these data also highlight the complexity of SCAD. It is likely not a single precipitator (eg, pregnancy, stress, exercise) that leads to SCAD onset, but most likely a complex combination of several appreciated and unappreciated factors.
It is reassuring that the majority of women tolerated pregnancy and lactation after SCAD without substantial complications. Given the potential severe consequences of a recurrent SCAD for which there are not yet preventive strategies, our findings should be interpreted with caution. This study does not constitute sufficient evidence to revise current recommendations to avoid pregnancy after SCAD (Box) with preferred contraceptive options being partner sterilization, tubal ligation, or intrauterine devices. 1 The pregnant state represents a cardiovascular "stress test" with physiologic increases in blood volume, heart rate, and cardiac output that may especially affect women with residual cardiac dysfunction, arrhythmias, or those requiring specific medications. Should SCAD recur, pregnancy-associated SCAD has been observed as having a severe presentation. 1  The fundamental desire for biological children can be paramount for some women, and they may proceed with planned or unplanned pregnancy despite these recommendations. Our findings indicate that not all women with pregnancy after a SCAD MI are ultimately destined to have another SCAD. Rather, an unremarkable clinical course was most often observed. If a woman strongly desires pregnancy or continues with an unintended pregnancy after SCAD, counseling is critical with input from a multidisciplinary "pregnancy heart team" comprised of specialists in cardiology, maternal-fetal medicine, and anesthesiology. Recommendations should be guided by current consensus statements and risk stratifications, thereby tailoring advice to the patient's personal cardiac history and medication regimen. 1,2,28 Considerations specific to SCAD include knowing the presence of FMD and other arterial abnormalities such as aneurysms in other arteries, understanding the current cardiac function, and reviewing any ongoing symptomology. An important caveat is that the women in this series who presented with a reduction in left ventricular ejection fraction at the time of SCAD

Limitations
Limitations of this study include the small number of women with pregnancy after SCAD. This study is based on participants of a registry cohort; therefore, selection, referral, and recall bias may confound the findings. Particularly as the success of the Mayo Clinic Registry is in part due to social networking, the younger mean age and higher prevalence of pregnancy-associated SCAD in this cohort as compared with the Canadian cohort 8 may be a reflection of biases inherent to the registry.
Those who had an unknown history or were not screened for FMD had significantly less recurrence in the Cox proportional analysis. This may reflect that those with recurrence may be more likely to be aggressively evaluated for an etiology such as FMD. It is also possible that those who are less likely to seek or report evaluation for FMD may be less likely to seek or report evaluation for symptoms of another SCAD. Finally, all of the women who became pregnant after SCAD had normal or nearnormal cardiac function at the onset of pregnancy, which is not generalizable to all women with history of SCAD.

Conclusions
This study found no association of SCAD recurrence with pregnancy among women with prior SCAD.
Most women had minimal to no complications with pregnancy and lactation after SCAD, which is reassuring and suggests that multiple factors contribute to the onset of SCAD. However, these findings must be interpreted cautiously because of the study limitations. Regardless, because of the rarity of this condition, prospective trials are unlikely, and counseling will be predicated on data such as these despite inherent limitations. Further elucidation of genetic predisposition and underlying mechanisms may eventually allow some degree of recurrence prediction. Until then, optimal care requires considerate counseling and collective decision-making.