Pregnancy outcomes, reproductive history and cardiovascular disease risk in women: What do we know and what is needed?
Year: 2016
Type: editorial
Abstract: Emerging evidence suggests that adverse pregnancy outcomes (APOs) predict cardiovascular disease (CVD) outcomes in women. Heida and colleagues extend this emerging evidence by summarizing the existing data on APOs and reproductive history, including meta-analyses of cohort and case–control studies.1 Specifically, gestational hypertension, pre-eclampsia, preterm delivery, small-for-gestational-age infant, recurrent miscarriage, polycystic ovary syndrome and premature ovarian insufficiency were examined systematically for the purposes of guideline generation. In brief, the review concludes that pre-eclampsia (RR 2.15, 95% confidence interval (CI): 1.76–2.61) qualifies for clinical follow-up, while the other APOs or reproductive conditions (most risk ratios (RRs) > 1.0 but <2.0) do not. The authors are to be commended for this extensive review and analysis on this important topic of relevance to the leading health threat to women – CVD. A number of questions now arise. Is there sufficient evidence to generate guidelines at this time? Guidelines are optimally based on our highest level of evidence (e.g. randomized clinical trials), yet as is acknowledged by the authors, trials do not currently exist in this area. Furthermore, there is acknowledged significant heterogeneity in the data for essentially all of the conditions, yet the authors stipulate clinical follow-up for pre-eclampsia with level B evidence guidelines, but not for any of the other conditions.1 Indeed, prior work demonstrates tremendous inaccuracy in both physician and patient recording and recollection of APOs2 and polycystic ovary syndrome,3 such that the lack of standardized definitions and nomenclature precludes accurate evaluation of the conditions, with subsequent poor estimation of risk. Optimistically, the electronic health record and use of uniform terminology could improve this problem going forward4; the recent US implementation of the new diagnosis codes may improve documentation of APOs in the USA, although providers will need to be educated and reminded to code the APOs and reproductive variables on a routine basis. What is an appropriate elevation of risk ratio that would trigger further action? While the selection of a RR > 2 is somewhat arbitrary, thresholds rather than regression analyses are needed in order to assist healthcare providers and patients as they make decisions in clinical practice. That said, CVD is known to be multi-factorial, and risk prediction scores universally include multiple risk factors.5,6 The comparability of the RRs of the APOs and reproductive variables with the traditional risk factor individual hazard ratios (95% CIs) for CVD in women suggests that a threshold of 2 may be premature (e.g. hypercholesterolemia: 1.06 (0.87–1.30); smoking: 2.39 (1.76–3.26); hypertension: 2.02 (1.54–2.49); pre-hypertension: 1.38 (1.15–1.65); diabetes: 1.94 (1.4–2.67); family history of premature coronary artery disease (CAD): 1.25 (1.03–1.52); and elevated C-reactive protein: 1.45 (1.19–1.77)).7 Further steps are needed in order to add the APOs and reproductive variables to existing risk scores so as to determine the additive value with this sex-specific knowledge. Prior reports have suggested associations with increased calculated 10-year and 30-year CVD risk in women who experience APOs compared to women with uncomplicated pregnancies.8,9 Furthermore, APOs frequently cluster (e.g. pre-eclampsia is often complicated by small birth weight, and preterm delivery can augment future maternal CVD risk).10 It would be prudent to test multiple reproductive variable models in order to develop clinically useful guidelines. Should the APOs and reproductive variables be adjusted for traditional risk factors? This would be optimal in order to establish the independence of a new variable, but would also be pragmatically challenging and possibly not useful. As stated by the authors, pregnancy is considered to be a woman’s first physiological stress test (e.g. unmasking pre-existing conditions or risk, rather than causing the condition or risk). Accordingly, these sex-specific conditions appear to be risk predictors rather than risk factors (e.g. similar to the metabolic syndrome, which evolved as a convenient clustering of risk for ease of recognition by the clinician, rather than a novel risk factor). Accordingly, clinical use of the variables without adjustment should be evaluated for ease of risk identification in clinical care. Is the recommendation that only women with pre-eclampsia should receive follow-up appropriate? Prior work demonstrates that young women’s traditional risk factors are less likely to be identified and treated overall,11 while young women specifically receive less hypertension care in obstetrics–gynecology compared to general medicine clinics.12 Hypertension, as the most prevalent and most easily treated risk factor for reducing future CVD,13 represents a potential opportunity to close the gender gaps that adversely impact younger women. Labetalol, nifedipine and methyldopa are used and are effective in pregnancy, and may be preferred medications should additional pregnancies be anticipated. Investigation should be directed at testing the impact of APO and reproductive variable recognition relative to triggering earlier, more objective risk factor recognition, assessment and, most importantly, appropriate evidence-based guidelines treatment for young women. Given what we now know from this excellent, comprehensive, systematic review, what more is needed? It is important to remember that a lack of evidence is not the same as negative evidence. Specifically, rigorous observational studies utilizing standardized terminology in order to more homogeneously confirm or refute relations between APOs and reproductive variables with CVD in women are not currently available. Heida and colleagues are to be commended for identifying the large knowledge gaps that exist in this area and that impact so many women worldwide. Given the relatively rapid emergence of electronic health records, steps must be taken now to add pregnancy and reproductive history categories that are similar to the standard medical and surgical histories in order to take advantage of this information in the new era of “big data” and to test the veracity of these associations. Consistent, high-quality observational data are needed in order to develop the rationale(s) and, if appropriate, models to be tested in clinical trials so as to inform evidence-based guidelines. We owe this to women everywhere. The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: this work was supported by contracts from the National Heart, Lung and Blood Institutes numbers N01-HV-68161, N01-HV-68162, N01-HV-68163 and N01-HV-68164, grant numbers U0164829, U01 HL649141, U01 HL649241, K23HL105787, F31NR015725, T32HL69751, R01 HL090957, UL1TR000124 and 1R03AG032631 from the National Institute on Aging, GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences grant UL1TR000124 and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, The Women’s Guild of Cedars–Sinai Medical Center, Los Angeles, CA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc., Laurence Harbor, NJ, the Edythe L. Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars–Sinai Medical Center, Los Angeles, California, the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars–Sinai Medical Center, Los Angeles, The Society for Women’s Health Research (SWHR), Washington, D.C., The Linda Joy Pollin Women’s Heart Health Program and the Erika Glazer Women’s Heart Health Project, Cedars–Sinai Medical Center, Los Angeles, California.
Authors: Janet Wei, Margo Minissian, C Noel Bairey Merz
Language: English
Subfield: Obstetrics and Gynecology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1438650436, G2026361351, Behavioral Medicine and Cardiovascular Research Training, EVAL OF ISCHEMIC HEART DISEASE IN WOMEN-CLINICAL CTR, EVAL OF ISCHEMIC HEART DISEASE IN WOMEN-CLINICAL CTR, ISCHEMIC HEART DISEASE IN WOMEN-CLINICAL CENTER, UCLA Clinical and Translational Science Institute, G3751788867, ISCHEMIC HEART DISEASE IN WOMEN--CLINICAL CENTER, G4144345384, G430456586, G461158050, Cardiovascular Events in Women's Ischemia Syndrome Evaluation, Is Spontaneous Preterm Delivery Associated with Inflammation?, Women's Ischemia Syndrome Evaluation (WISE) Coronary Vascular Dysfunction, General Clinical Research Center, Cardiac Autonomic Function in Women, UCLA Clinical and Translational Science Institute
OpenAlex ID: W2508412117