A pinboard by
Amanda Markovitz

I'm a Doctor of Science candidate at Harvard University studying reproductive health & epidemiology


Pregnancy might act like a natural "stress test" to identify women at high risk for heart disease

If your doctor can learn a lot about your heart from having you exercise for 15 minutes during a cardiac stress test, imagine what they could learn from your response to 9 months of massive changes (including a 40-50% increase in blood volume!). This is the idea that pregnancy may act as a naturally occurring “stress test”. Most women will be able to handle these changes and go on to have a normal, healthy pregnancy while for others a pregnancy complication can serve as a signal that the woman may be at greater risk for heart disease later in life.

One of the most studied of these pregnancy complications is preeclampsia, a condition characterized by high blood pressure and protein in the urine, which is associated with 2 times greater risk of heart disease. Preterm delivery, where a baby is born before 37 weeks, and low birth weight (<2,500 grams) are also both associated with about double the heart disease risk. Gestational diabetes, another relatively common complication of pregnancy, is strongly associated with future risk of diabetes but may not be independently associated with heart disease risk.

What our team and other researchers are still trying to understand is whether it would be useful to include these pregnancy complications in predictive models that physicians commonly use to predict how likely it is that someone will get heart disease in the next 10 years. Perhaps they are not useful as predictors above and beyond what is already included in those models, including BMI, blood pressure, blood sugar, lipids, etc. or perhaps pregnancy complications are useful as an independent or early marker of high risk. We also want to identify effective interventions to prevent heart disease in women who experienced a pregnancy complication.


Pregnancy characteristics and women's future cardiovascular health: an underused opportunity to improve women's health?

Abstract: Growing evidence indicates that women with a history of common pregnancy complications, including fetal growth restriction and preterm delivery (often combined as low birth weight), hypertensive disorders of pregnancy, and gestational diabetes, are at increased risk for cardiovascular disease later in life. The purpose of this paper was to review the associations of parity and these 4 pregnancy complications with cardiovascular morbidity and mortality; to review the role of cardiovascular risk factors before, during, and after pregnancy complications in explaining these associations; and to explore the implications of this emerging science for new research and policy. We systematically searched for relevant cohort and case-control studies in Medline through December 2012 and used citation searches for already published reviews to identify new studies. The findings of this review suggest consistent and often strong associations of pregnancy complications with latent and future cardiovascular disease. Many pregnancy complications appear to be preceded by subclinical vascular and metabolic dysfunction, suggesting that the complications may be useful markers of latent high-risk cardiovascular trajectories. With further replication research, these findings would support the utility of these prevalent pregnancy complications in identifying high-risk women for screening, prevention, and treatment of cardiovascular disease, the leading cause of morbidity and mortality among women.

Pub.: 13 Sep '13, Pinned: 28 Jun '17

Associations of pregnancy complications with calculated cardiovascular disease risk and cardiovascular risk factors in middle age: the Avon Longitudinal Study of Parents and Children.

Abstract: The nature and contribution of different pregnancy-related complications to future cardiovascular disease (CVD) and its risk factors and the mechanisms underlying these associations remain unclear.We studied associations of pregnancy diabetes mellitus, hypertensive disorders of pregnancy, preterm delivery, and size for gestational age with calculated 10-year CVD risk (based on the Framingham score) and a wide range of cardiovascular risk factors measured 18 years after pregnancy (mean age at outcome assessment, 48 years) in a prospective cohort of 3416 women. Gestational diabetes mellitus was positively associated with fasting glucose and insulin, even after adjustment for potential confounders, whereas hypertensive disorders of pregnancy were associated with body mass index, waist circumference, blood pressure, lipids, and insulin. Large for gestational age was associated with greater waist circumference and glucose concentrations, whereas small for gestational age and preterm delivery were associated with higher blood pressure. The association with the calculated 10-year CVD risk based on the Framingham prediction score was odds ratio 1.31 (95 confidence interval, 1.11-1.53) for preeclampsia and 1.26 (95 confidence interval, 0.95-1.68) for gestational diabetes mellitus compared with women without preeclampsia and without gestational diabetes mellitus, respectively.Hypertensive disorders of pregnancy and pregnancy diabetes mellitus are independently associated with an increased calculated 10-year CVD risk. Preeclampsia may be the better predictor of future CVD because it was associated with a wider range of cardiovascular risk factors. Our results suggest that pregnancy may be an important opportunity for early identification of women at increased risk of CVD later in life.

Pub.: 22 Feb '12, Pinned: 29 Jun '17

Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births.

Abstract: Individuals who are small at birth are at increased risk of ischaemic heart disease (IHD) in later life. One hypothesis to explain this association is fetal adaptation to a suboptimum intrauterine environment. We investigated whether pregnancy complications associated with low birthweight are related to risk of subsequent IHD in the mother.Routine discharge data were used to identify all singleton first births in Scotland between 1981 and 1985. Linkage to the mothers' subsequent admissions and deaths provided 15--19 years of follow-up. The mothers' risks of death from any cause or from IHD and admission for or death from IHD were related to adverse obstetric outcomes in the first pregnancy. Hazard ratios were adjusted for socioeconomic deprivation, maternal height and age, and essential hypertension.Complete data were available on 129,920 (95.6%) eligible deliveries. Maternal risk of IHD admission or death was associated with delivering a baby in the lowest birthweight quintile for gestational age (adjusted hazard ratio 1.9 [95% CI 1.5--2.4]), preterm delivery (1.8 [1.3--2.5]), and pre-eclampsia (2.0 [1.5--2.5]). The associations were additive; women with all three characteristics had a risk of IHD admission or death seven times (95% CI 3.3--14.5) greater than the reference category.Complications of pregnancy linked to low birthweight are associated with an increased risk of subsequent IHD in the mother. Common genetic risk factors might explain the link between birthweight and risk of IHD in both the individual and the mother.

Pub.: 05 Jul '01, Pinned: 29 Jun '17

Manifestations of chronic disease during pregnancy.

Abstract: Physiologic changes of pregnancy include insulin resistance, thrombophilia, immunosuppression, and hypervolemia. These changes may herald the development of disease in later life.To summarize current evidence on how pregnancy reveals risk of chronic disease.MEDLINE was searched for articles published between 1990 and 2005 relating pregnancy conditions to the development of chronic disease. Bibliographies and the Web sites of the International Society of Obstetric Medicine and International Society for the Study of Hypertension in Pregnancy were also reviewed.Pregnancy exaggerates atherogeniclike responses, including insulin resistance and dyslipidemia, manifesting as preeclampsia or gestational diabetes. These complications herald an increased risk of postpartum cardiovascular disease, with a 2-fold increased risk of coronary artery disease and stroke. Women with gestational diabetes mellitus can progress to type 2 diabetes mellitus. The rate of progression varies from 6% to 92% depending on diagnostic criteria, race/ethnicity, and duration of surveillance (from 6 months to 28 years). Pregnancy increases risk of venous thrombosis by 7- to 10-fold. Heritable thrombophilia is present in at least 15% of Western populations and underlies at least 50% of gestational venous thromboses. Thus, the procoagulant changes during pregnancy can unmask hereditary thrombophilia. An important adaptation leading to immunotolerance of the fetoplacental unit is a switch from helper T-cell (T(H)) 1 dominance to T(H)2 dominance. Patients with a T(H)1-dominant immune disease, such as rheumatoid arthritis or multiple sclerosis, improve during pregnancy. However, rheumatoid arthritis is 5 times more likely to develop after delivery than at any other time. During pregnancy, there is a 50% increase in plasma volume, which can unmask glomerulopathies, peripartum cardiomyopathy, arterial aneurysms, or arteriovenous malformations. Development of intrahepatic cholestasis of pregnancy predicts increased risk of later cholelithiasis.The physiologic changes of pregnancy can reveal risk of chronic diseases. Exaggerated responses reflective of the metabolic syndrome are seen in preeclampsia and gestational diabetes and can herald future cardiovascular and metabolic disease. Pregnancy is therefore an important screening opportunity for cardiovascular and metabolic disease risk factors, with the possibility of early intervention.

Pub.: 08 Dec '05, Pinned: 29 Jun '17

Gestational diabetes and hypertensive disorders of pregnancy as vascular risk signals: an overview and grading of the evidence.

Abstract: The occurrence of common pregnancy-related medical disorders identifies women at high risk of developing future vascular disease. Systematic reviews of cohort studies demonstrate that gestational diabetes confers a 7-fold risk increase for type 2 diabetes, and preeclampsia confers a 1.8-fold risk increase for type 2 diabetes and 3.4-fold risk increase for hypertension. Gestational diabetes and hypertensive disorders of pregnancy (HDP) increase the risk of premature vascular disease, but the 2-fold risk increase associated with preeclampsia is only partially explained by the development of traditional vascular risk factors. Despite the compelling evidence for gestational diabetes and HDP as vascular risk indicators, there are no published Canadian vascular prevention guidelines that recognize these postpartum women. In contrast, the 2011 American Heart Association guidelines on cardiovascular disease in women include gestational diabetes and HDP in their vascular risk assessment. Studies indicate that the importance surveillance of vascular risk factors in these women after pregnancy is underappreciated by the women themselves and their physicians. Although a prudent diet and physically active lifestyle were demonstrated to reduce diabetes risk in women with a gestational diabetes history in the American Diabetes Prevention Program trial, adoption of these health behaviours is low; qualitative studies confirm a need for tailored strategies that address barriers and provide social support. Further research is also needed on approaches to reduce vascular risk in women with a history of gestational diabetes and HDP. Otherwise, an early window of opportunity for chronic disease prevention in young, high-risk women will be missed.

Pub.: 15 Apr '14, Pinned: 29 Jun '17

Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.

Abstract: To quantify the risk of future cardiovascular diseases, cancer, and mortality after pre-eclampsia.Systematic review and meta-analysis.Embase and Medline without language restrictions, including papers published between 1960 and December 2006, and hand searching of reference lists of relevant articles and reviews for additional reports.Prospective and retrospective cohort studies were included, providing a dataset of 3,488,160 women, with 198,252 affected by pre-eclampsia (exposure group) and 29,495 episodes of cardiovascular disease and cancer (study outcomes).After pre-eclampsia women have an increased risk of vascular disease. The relative risks (95% confidence intervals) for hypertension were 3.70 (2.70 to 5.05) after 14.1 years weighted mean follow-up, for ischaemic heart disease 2.16 (1.86 to 2.52) after 11.7 years, for stroke 1.81 (1.45 to 2.27) after 10.4 years, and for venous thromboembolism 1.79 (1.37 to 2.33) after 4.7 years. No increase in risk of any cancer was found (0.96, 0.73 to 1.27), including breast cancer (1.04, 0.78 to 1.39) 17 years after pre-eclampsia. Overall mortality after pre-eclampsia was increased: 1.49 (1.05 to 2.14) after 14.5 years.A history of pre-eclampsia should be considered when evaluating risk of cardiovascular disease in women. This association might reflect a common cause for pre-eclampsia and cardiovascular disease, or an effect of pre-eclampsia on disease development, or both. No association was found between pre-eclampsia and future cancer.

Pub.: 03 Nov '07, Pinned: 29 Jun '17

Cardiovascular disease risk in women with pre-eclampsia: systematic review and meta-analysis.

Abstract: There is increasing evidence that pre-eclampsia, a principal cause of maternal morbidity, may also be a risk factor for future cardiovascular and cerebrovascular events. This review aimed to assess the current evidence and quantify the risks of cardiovascular disease (CVD), cerebrovascular events and hypertension associated with prior diagnosis of pre-eclampsia. Medline and Embase were searched with no language restrictions, as were core journals and reference lists from reviews up until January 2012. Case-control and cohort studies which reported cardiovascular and cerebrovascular diseases or hypertension diagnosed more than 6 weeks postpartum, in women who had a history of pre-eclampsia relative to women who had unaffected pregnancies, were included. Fifty articles were included in the systematic review and 43 in the meta-analysis. Women with a history of pre-eclampsia or eclampsia were at significantly increased odds of fatal or diagnosed CVD [odds ratio (OR) = 2.28, 95% confidence interval (CI): 1.87, 2.78], cerebrovascular disease (OR = 1.76, 95% CI 1.43, 2.21) and hypertension [relative risk (RR) = 3.13, 95% CI 2.51, 3.89]. Among pre-eclamptic women, pre-term delivery was not associated with an increased risk of a future cardiovascular event (RR = 1.32, 95% CI 0.79, 2.22). Women diagnosed with pre-eclampsia are at increased risk of future cardiovascular or cerebrovascular events, with an estimated doubling of odds compared to unaffected women. This has implications for the follow-up of all women who experience pre-eclampsia, not just those who deliver pre-term. This association may reflect shared common risk factors for both pre-eclampsia and cardiovascular and cerebrovascular disease.

Pub.: 12 Feb '13, Pinned: 29 Jun '17

Preeclampsia and future cardiovascular disease in women: How good are the data and how can we manage our patients?

Abstract: Women with a history of preeclampsia have double the risk of future heart disease and stroke, and elevated risks of hypertension and diabetes. The American Heart Association (AHA) and the American College of Obstetrics and Gynecology now include preeclampsia as a risk factor for future cardiovascular disease (CVD) with the recommendation of obtaining a history of preeclampsia and improving lifestyle behaviors for women with such a history. Research has progressed from asking whether preeclampsia is associated with CVD to how preeclampsia is associated with CVD, and the implications for prevention of CVD among women with a history of preeclampsia. A history of preeclampsia "unmasks" future CVD risk; research is inconclusive whether it also causes vascular damage that leads to CVD. For women with prior preeclampsia, the AHA recommends CVD risk reduction actions similar to those for other "at risk" groups: cessation of cigarette smoking, physical activity, weight reduction if overweight or obese and counseling to follow a "DASH" like diet. The efficacy of these lifestyle modifications to lower risk of CVD in women with prior preeclampsia remains to be determined. Barriers exist to implementing lifestyle improvement measures in this population, including lack of awareness of both patients and clinicians of this link between preeclampsia and CVD. We review patient, provider, and systems level barriers and solutions to leverage this information to prevent CVD among women with a history of preeclampsia.

Pub.: 29 Jun '15, Pinned: 29 Jun '17

History of preterm birth and subsequent cardiovascular disease: a systematic review.

Abstract: A history of preterm birth (PTB) may be an important lifetime risk factor for cardiovascular disease (CVD) in women. We identified all peer-reviewed journal articles that met study criteria (English language, human studies, female, and adults ≥19 years old), that were found in the PubMed/MEDLINE databases, and that were published between Jan. 1, 1995, and Sept. 17, 2012. We summarized 10 studies that assessed the association between having a history of PTB and subsequent CVD morbidity or death. Compared with women who had term deliveries, women with any history of PTB had increased risk of CVD morbidity (variously defined; adjusted hazard ratio [aHR] ranged from 1.2-2.9; 2 studies), ischemic heart disease (aHR, 1.3-2.1; 3 studies), stroke (aHR, 1.7; 1 study), and atherosclerosis (aHR, 4.1; 1 study). Four of 5 studies that examined death showed that women with a history of PTB have twice the risk of CVD death compared with women who had term births. Two studies reported statistically significant higher risk of CVD-related morbidity and death outcomes (variously defined) among women with ≥2 pregnancies that ended in PTBs compared with women who had at least 2 births but which ended in only 1 PTB. Future research is needed to understand the potential impact of enhanced monitoring of CVD risk factors in women with a history of PTB on risk of future CVD risk.

Pub.: 24 Sep '13, Pinned: 29 Jun '17

Preterm birth and future risk of maternal cardiovascular disease - is the association independent of smoking during pregnancy?

Abstract: While the association of preterm birth and the risk of maternal cardiovascular disease (CVD) has been well-documented, most studies were limited by the inability to account for smoking during pregnancy - an important risk factor for both preterm birth and CVD. This study aimed to determine whether the increased future risk of maternal cardiovascular disease (CVD) associated with preterm birth is independent of maternal smoking during pregnancy.A population-based record linkage study of 797,056 women who delivered a singleton infant between 1994 and 2011 in New South Wales, Australia was conducted. Birth records were linked to the mothers' subsequent hospitaliation or death from CVD. Preterm births were categorised as late (35-36 weeks), moderate (33-34 weeks), or extreme (≤32 weeks); and as spontaneous or indicated. Cox proportional hazard regression was used to estimate adjusted hazard ratios (AHR) [95 % CI].During the study period, 59,563 women (7.5 %) had at least one preterm birth. After adjustment for CVD risk factors other than smoking, AHR [95 % CI] of CVD among women who ever had a preterm birth was 1.78 [1.61-1.96]. Associations were greater for extreme (AHR = 1.98 [1.63-2.42]) and moderate (AHR = 2.06 [1.69-2.51]) than late preterm birth (AHR = 1.63 [1.44-1.85]), for indicated (AHR = 2.04 [1.75-2.38]) than spontaneous preterm birth (AHR = 1.65 [1.47-1.86]), and for having ≥ two (AHR = 2.29[1.75-2.99]) than having one preterm birth (AHR = 1.73[1.57-1.92]). A further adjustment for maternal smoking attenuated, but did not eliminate, the associations. Smoking during pregnancy was also independently associated with maternal CVD risks, with associations being stronger for mothers who smoked during last pregnancy (AHR = 2.07 [1.93-2.23]) than mothers who smoked during a prior pregnancy (AHR = 1.64 [1.41-1.90]).Associations of preterm birth and maternal CVD risk are independent of maternal smoking during pregnancy. This underscores the importance of smoking cessation in reducing CVD and suggests that a history of preterm delivery (especially if severe, indicated or recurrent) identifies women who could be targeted for CVD screening and preventative therapies.

Pub.: 05 Jul '15, Pinned: 29 Jun '17

Preterm Delivery and Maternal Cardiovascular Disease in Young and Middle-Aged Adult Women.

Abstract: Preterm delivery has been shown to be associated with increased risk of cardiovascular disease (CVD), but it is unknown whether this risk remains after adjustment for prepregnancy lifestyle and CVD risk factors.We examined the association between history of having delivered an infant preterm (<37 weeks) and CVD in 70 182 parous women in the Nurses' Health Study II. Multivariable Cox proportional-hazards models were used to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) for CVD events (myocardial infarction and stroke, n=949); we also adjusted for intermediates to determine the proportion of the association between preterm and CVD accounted for by postpartum development of CVD risk factors.After adjusting for age, race, parental education, and prepregnancy lifestyle and CVD risk factors, preterm delivery in the first pregnancy was associated with an increased risk of CVD (HR, 1.42; 95% CI, 1.16-1.72) in comparison with women with a term delivery (≥37 weeks) in the first pregnancy. When preterm delivery was split into moderate preterm (≥32 to <37 weeks) and very preterm (<32 weeks), the HRs were 1.22 (95% CI, 0.96-1.54) and 2.01 (95% CI, 1.47-2.75), respectively. The increased rate of CVD in the very preterm group persisted even among women whose first pregnancy was not complicated by hypertensive disorders of pregnancy (HR, 2.01; 95% CI, 1.38-2.93). In comparison with women with at least 2 pregnancies, all of which were delivered at term, women with a preterm first birth and at least 1 later preterm birth had a HR of CVD of 1.65 (95% CI, 1.20-2.28). The association between moderate preterm first birth and CVD was accounted for in part by the development of postpartum chronic hypertension, hypercholesterolemia, type 2 diabetes mellitus, and changes in body mass index (proportion accounted for, 14.5%; 95% CI, 4.0-41.1), as was the very-preterm-CVD relationship (13.1%; 95% CI, 9.0-18.7).Preterm delivery is independently predictive of CVD and may be useful for CVD prevention efforts. Because only a modest proportion of the preterm-CVD association was accounted for by development of conventional CVD risk factors, further research may identify additional pathways.

Pub.: 06 Feb '17, Pinned: 28 Jun '17

Offspring birth weight and parental mortality: prospective observational study and meta-analysis.

Abstract: The authors have investigated associations between offspring size at birth and parental cardiovascular disease mortality among 12,086 mothers and 6,936 fathers of participants in the British 1958 birth cohort. Birth weight was inversely associated with all-cause mortality and cardiovascular mortality in both mothers and fathers. The adjusted hazard ratio of cardiovascular disease mortality for a 1-standard deviation increase in offspring birth weight in mothers was 0.87 (95% confidence interval (CI): 0.82, 0.93) and in fathers was 0.94 (95% CI: 0.89, 0.99). The association was not specific for cardiovascular disease. In fathers, similar weak associations with violent and accidental deaths, stomach cancer, and alcohol- and smoking-related outcomes were found. Weak associations for these outcomes were also found for mothers, but the magnitude of the association with cardiovascular disease was greater than with any other outcomes. In a meta-analysis pooling results from this study with six others, the adjusted hazard ratio of cardiovascular disease mortality among mothers was 0.75 (95% CI: 0.67, 0.84) and that among fathers was 0.93 (95% CI: 0.91, 0.95), with evidence that the difference in effect between mothers and fathers was not due to chance (p < 0.001). The weak association of offspring birth weight with cardiovascular disease in fathers may be due to residual confounding by factors such as socioeconomic position and smoking that they share with the offspring's mother and that would therefore be associated with low offspring birth weight as well as adverse outcomes in the father. The stronger association in mothers is consistent with intergenerational effects on intrauterine growth and with the fetal origins hypothesis.

Pub.: 09 May '07, Pinned: 29 Jun '17

Offspring birthweight by gestational age and parental cardiovascular mortality: a population-based cohort study.

Abstract: To estimate risk of parental cardiovascular disease mortality by offspring birthweight.Population-based cohort study.Norwegian mothers and fathers with singleton births during 1967-2002 were followed until 2009 by linkage to the Norwegian cause of death registry.Hazard ratios by offspring absolute birthweight in grams and birthweight adjusted for gestational age (z-score) were calculated using Cox regression and adjusted for parental age at delivery and year of first birth. Stratified analyses on preterm and term births were performed.Maternal and paternal cardiovascular mortality.We followed 711 726 mothers and 700 212 fathers and found a strong link between maternal cardiovascular mortality and offspring birthweight but only slight evidence of associations in fathers. Adjusting birthweight for gestational age (by z-score) uncovered an unexpected strong association of large birthweight (z-score > 2.5) with mothers' cardiovascular mortality (hazard ratio 3.0, 95% CI 2.0-4.6). This risk was apparently restricted to preterm births. In stratified analyses (preterm and term births) hazard ratios for maternal cardiovascular mortality were 1.5 (1.03-2.2) for large preterm babies and 0.9 (0.7-1.2) for large term babies (P-value for interaction = 0.02), using normal weight preterm and term, respectively, as references.Women having large preterm babies are at increased risk of both diabetes and cardiovascular mortality. The birth of a large preterm baby should increase clinical vigilance for onset of diabetes and other cardiovascular disease risk factors.Birth of a large preterm baby should increase vigilance for cardiovascular-disease risk factors.

Pub.: 07 Feb '17, Pinned: 29 Jun '17