Pre-eclampsia (PE) is a pregnancy-specific hypertensive disorder that has been associated with cardiovascular risk factors and vascular changes, such as acute atherosis in placental blood vessels, similar to early-stage atherosclerosis. The objective of this study was to determine whether women with PE have increased atherosclerotic burden, as determined by the carotid intima–media thickness (CIMT), compared with women without PE.
We conducted a systematic review and meta-analysis of studies that reported CIMT, a non-invasive, ultrasound-based measure of subclinical atherosclerosis, in women who did vs those who did not have PE. Studies were eligible if they had been conducted during pregnancy or during the first decade postpartum, and if CIMT was measured in the common carotid artery. Studies published before 7 March 2016 were identified through PubMed, EMBASE and Web of Science. Two reviewers used predefined forms and protocols to evaluate independently the eligibility of studies based on titles and abstracts and to perform full-text screening, data abstraction and quality assessment. Heterogeneity was assessed using the I2 statistic. Standardized mean difference (SMD) was used as a measure of effect size.
Fourteen studies were included in the meta-analysis. Seven studies were carried out during pregnancy complicated by PE, 10 were carried out up to 10 years postpartum and three included measurements obtained at both time periods. Women who had PE had significantly higher CIMT than did those who did not have PE, both at the time of diagnosis (SMD, 1.10 (95% CI, 0.73–1.48); P < 0.001) and in the first decade postpartum (SMD, 0.58 (95% CI, 0.36–0.79); P < 0.001).
La preeclampsia (PE) es un trastorno hipertensivo específico del embarazo que ha sido asociada con factores de riesgo cardiovascular y cambios vasculares, tales como aterosis aguda en los vasos sanguíneos de la placenta, similares a las primeras etapas de la aterosclerosis. El objetivo de este estudio fue determinar si las mujeres con PE han aumentado la carga aterosclerótica, según lo determinado por el espesor del complejo íntima-media de la arteria carótida (CIMT, por sus siglas en inglés), en comparación con las mujeres sin PE.
Se realizó una revisión sistemática y un metaanálisis de estudios que reportaron el CIMT, una medida no invasiva de la aterosclerosis subclínica obtenida mediante ecografía, comparando mujeres con PE y mujeres sin ella. Solo se incluyeron estudios llevados a cabo durante el embarazo o durante la primera década después del parto, y en los que se midió el CIMT en la arteria carótida común. Se usaron las bases de datos de PubMed, EMBASE y Web of Science para identificar estudios publicados antes del 7 marzo de 2016. Dos revisores utilizaron formularios y protocolos preestablecidos para evaluar de forma independiente la elegibilidad de los estudios, a partir de los títulos y los resúmenes, y para realizar un cribado del texto completo, un resumen de los datos y una evaluación de calidad. La heterogeneidad se evaluó mediante el test estadístico I2. Se usó la diferencia de medias estandarizada (SMD, por sus siglas en inglés) como una medida de la magnitud del efecto.
En el metaanálisis se incluyeron catorce estudios. Siete de los estudios se llevaron a cabo durante embarazos complicados por PE, 10 se realizaron hasta 10 años después del parto y tres incluyeron mediciones tomadas en ambos períodos. Las mujeres con PE tuvieron un CIMT significativamente mayor que aquellas que no la tenían, tanto en el momento del diagnóstico (SMD 1,10 (I 95%, 0,73-1,48), P <0,001) como en la primera década después del parto (SMD 0,58 (IC 95%, 0,36-0,79), P <0,001).
La carga aterosclerótica está presente en el momento de la PE y podría ser un mecanismo asociado con esta enfermedad. La medición del CIMT puede ofrecer una oportunidad para la identificación temprana de mujeres premenopáusicas con carga aterosclerótica después de un embarazo con PE.
我们对报道PE患者与无PE患者相比CIMT的研究进行系统综述和meta分析,CIMT为无创性、基于超声的亚临床动脉粥样硬化检测方法。纳入标准为:研究在妊娠期间或产后头10年进行并检测颈总动脉的CIMT。检索PubMed、EMBASE和Web of Science中发表的研究,时间截止至2016年3月7日。由两名人员根据预定的格式和方案,通过题目和摘要独立评估符合纳入标准的研究,并进行全文筛查、数据提取和质量评估。采用I2检验评估异质性。采用标准化均数差(SMD)检测效应量。
Pre-eclampsia (PE) is a pregnancy-specific hypertensive disorder, characterized clinically by hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg) and commonly proteinuria (≥ 300 mg in 24 h), which occur after 20 weeks' gestation. PE remains one of the leading causes of maternal and fetal morbidity and mortality worldwide. The underlying cellular and molecular mechanisms of PE are not well understood and are under active investigation by several research teams. However, there is general agreement that, similar to cardiovascular disease, endothelial dysfunction plays a crucial role in its pathogenesis. On a clinical level, PE and atherosclerotic cardiovascular disease share common risk factors, and most of the severe complications of PE include those that are typically seen with the latter, namely, ischemic heart disease, stroke and heart failure, further supporting the notion that PE is a state of increased atherosclerotic burden. These clinical observations are further reinforced by histological studies of placental vascular changes in PE. Acute atherosis of the placental blood vessels in PE, consisting of subendothelial lipid-filled foam cells, fibrinoid necrosis of the arterial wall and perivascular lymphocytic infiltration, is similar to early-stage atherosclerosis.
The carotid intima–media thickness (CIMT) is increasingly being used as a measure of preclinical atherosclerosis and is evaluated using non-invasive, ultrasound-based measurement of the combined thickness of the intimal and medial arterial wall components. Despite increasing recognition of CIMT as a valuable marker of preclinical atherosclerosis, only a few studies have investigated CIMT at the time of diagnosis of PE. Furthermore, these studies have provided conflicting evidence regarding the association between PE and increases in CIMT. In the current study, we hypothesized that pregnant women will have increased atherosclerotic burden at the time of diagnosis of PE, as defined by CIMT, compared with pregnant women without PE. We conducted a systematic review and meta-analysis of studies that reported CIMT as a measure of subclinical atherosclerosis, both at the time of pregnancy affected by PE and in the first decade postpartum. The latter was evaluated to determine whether subclinical atherosclerosis is present/persists during the premenopausal years after a PE pregnancy.
This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis of Observational Studies in Epidemiology[4, 5], following a standardized protocol that is available from the study authors. A vascular physiologist (T.L.W.) and a biostatistician with expertise in conducting systematic reviews and meta-analyses (N.M.M.) developed the search strategy. Searches of PubMed, EMBASE and Web of Science on 7 March 2016 were performed for studies that compared CIMT among women who had pregnancies complicated by PE and women who had pregnancies that were not complicated by PE. Studies were included if they compared CIMT between these groups before PE, at the time of active disease or if CIMT was measured in non-pregnant women hours to 10 years after delivery. Studies were eligible for inclusion if CIMT was measured in the common carotid artery; studies that measured intima–media thickness in other arteries were excluded.
Studies that were identified based on the above criteria were stratified into the following time periods: (1) before PE: CIMT was measured in pregnant women who were followed until delivery to determine whether they developed PE. No participant had PE at the time of CIMT measurement; (2) at the time of active disease: CIMT was measured after 20 weeks' gestation to compare CIMT in pregnant women with PE vs those without PE; (3) postpartum: CIMT was measured in non-pregnant women, from hours to 10 years after delivery.
There was no restriction on publication language or status. Authors of the relevant abstracts were contacted to identify eligible unpublished datasets and to obtain any missing data, as well as information on the study design and methodology. Studies that combined PE with gestational hypertension and/or chronic hypertension in pregnancy were eligible only if data for the subset of women who developed PE could be obtained. Two reviewers (N.M.M. and T.L.W.) evaluated independently the eligibility of all studies based on the title and abstract and performed full-text screening to select articles for inclusion. Disagreement was resolved by consensus. Two reviewers (T.L.W. and J.M.L.) extracted independently the data and evaluated the quality of selected manuscripts using an adapted version of the Newcastle–Ottawa tool for observational studies (available from the authors upon request). Independent reviewers used standardized forms and protocols when selecting and extracting data. Authors were contacted to clarify and confirm the accuracy of the data. Detailed methodologies for diagnostic criteria, search strategy, article screening and selection, and missing information are provided in Appendix S1.
The primary outcome measured was CIMT, expressed as mean ± SD. Methods for measuring CIMT and the resulting values vary among studies, therefore we used the standardized mean difference (SMD) to examine differences between PE and non-PE groups. A recent study also suggests that SMD may be preferable to mean difference from the standpoint of generalizability. This measure of effect size expresses the difference between group means in units of SD and was estimated by pooling individual trial results using random-effects models via the Der Simonian–Laird method. Heterogeneity was assessed using the chi-square Q and I2 statistic. I2 represents the inconsistency between study results and quantifies the proportion of observed dispersion that is real, i.e. that is due to between-study differences and not to random errors. The categorization of heterogeneity was based on the Cochrane Handbook, which states that I2 < 30%, 30–60% or > 60% corresponds to low, moderate and high heterogeneity, respectively. A separate forest plot was constructed for each analysis showing the SMD (box), 95% CI (lines) and weight (size of box) for each trial. The overall effect size is represented by a diamond. Sensitivity analyses were conducted to examine the effects of: (1) inclusion of studies that presented CIMT as median (interquartile range (IQR)) or median (range); (2) inclusion of measurements performed in less severe vs more severe forms of PE, if pooled measurements were not available; (3) exclusion of studies that included women with chronic hypertension at the time of pregnancy; (4) replacement of the results of a study performed in 2006 with the follow-up results in a subgroup of the same participants who were retested 4 years later; (5) the inclusion of studies for which the exact postpartum time periods are unknown; and (6) the exclusion of studies that were published as abstracts only. P < 0.05 was considered to be statistically significant. Analyses were performed using Review Manager (Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) and in R Language and Environment for Statistical Computing[9, 10].
From the electronic database search, we identified 229 potentially eligible articles; a further five were identified through other sources (Figure 1). Seventy-six full-text articles were reviewed and 22 were selected for inclusion in the systematic review (qualitative synthesis)[11-32]. Fourteen of the studies were included in the meta-analysis (quantitative synthesis) and included studies that measured CIMT at the time of PE (n = 7)[18-24], and up to 10 years postpartum (n = 10)[20, 22, 24-31]. Three studies included CIMT measurements obtained at both the time of PE diagnosis and postpartum[20, 22, 24]. Only two studies examined CIMT prior to the diagnosis of PE[20, 32], therefore this time period was not included in the meta-analysis. Detailed summaries of the 17 full-text publications and five abstracts that were included in the systematic review are provided: Tables S1–S3 summarize the study characteristics; Table S4 shows diagnostic criteria for the studies examining women with more severe and less severe forms of PE; Tables S5–S7 show exclusion criteria; Table S8 shows detailed information about CIMT methodology; Table S9 shows summary statistics used in sensitivity analyses; and Tables S10–S12 show detailed information regarding the quality of the included studies.
CIMT at the time of PE
Seven cross-sectional studies[18-24] reporting CIMT at the time of PE were eligible for inclusion in the meta-analysis and included 143 pregnant women with PE and 357 pregnant women without PE. Two additional studies[11, 14] were included in the qualitative synthesis. CIMT was significantly higher in women with PE at the time of diagnosis (SMD, 1.10 (95% CI, 0.73–1.48); P < 0.001), than in those who did not have PE (Figure 2). The analysis revealed moderate heterogeneity among the results of the respective studies (I2 = 57%, P = 0.030). The presented effect remained significant in the sensitivity analyses that included two studies that reported medians with IQR[11, 14] (SMD, 0.89 (95% CI, 0.50–1.28); P < 0.001), and in a sensitivity analysis that excluded women with chronic hypertension at the time of their pregnancy (SMD, 1.50 (95% CI, 0.73–2.26); P < 0.001)[21, 22, 24]. The results were not different after the inclusion of data from women with less severe vs those from women with more severe forms of PE[14, 19], for which pooled data were not available (SMD, 0.97 (95% CI, 0.55–1.40); P < 0.001). The exclusion of two studies that were published only as abstracts[18, 20] did not alter the estimated effect size (SMD, 1.22 (95% CI, 0.77–1.66); P < 0.001).
Six cross-sectional studies[22, 25, 27-30] and three cohort studies[20, 24, 31] reporting CIMT up to 10 years postpartum, and baseline data from one longitudinal study, were eligible for inclusion in the meta-analysis. These studies included 389 women who had a history of PE and 377 women who did not. Six additional studies (four cross-sectional studies[12, 13, 16, 17] and two cohort studies[11, 15]) were included in the qualitative synthesis. CIMT was significantly higher among women with a history of PE in the studies conducted in the first decade postpartum, with an SMD of 0.58 (95% CI, 0.36–0.79); P < 0.001 (Figure 3). The analysis revealed moderate heterogeneity among the results of the respective studies (I2 = 43%, P = 0.069). This effect remained significant in sensitivity analyses that included three studies that reported medians[11-13] (SMD, 0.40 (95% CI, 0.15–0.64); P = 0.002), and in a sensitivity analysis that excluded women with chronic hypertension at the time of their pregnancy (SMD, 0.53 (95% CI, 0.24–0.81); P < 0.001)[22, 24-27, 29-31]. The results were not different after inclusion of the study for which the exact postpartum time period is unknown (SMD, 0.67 (95% CI, 0.40–0.94); P < 0.001), or after replacement of the results of the study published in 2006 with the follow-up results in a subgroup of the same participants who were retested 4 years later (SMD, 0.57 (95% CI, 0.35–0.79); P < 0.001). Exclusion of three studies that were published only as abstracts[20, 30, 31] did not alter the estimated effect size (SMD, 0.67 (95% CI, 0.39–0.94); P < 0.001).
The aim of this study was to conduct a systematic review and meta-analysis to determine whether CIMT, a sensitive measure for quantifying subclinical atherosclerosis, is elevated in pregnancies affected by PE, both at the time of delivery and up to 10 years thereafter. We found that CIMT was significantly higher among women at the time of their PE diagnosis (SMD, 1.10 (95% CI, 0.73–1.48)), as well as in the first decade postpartum (SMD, 0.58 (95% CI, 0.36–0.79)), than in women who did not have PE. The reported effects remained significant in the sensitivity analyses performed to exclude women with chronic hypertension at the time of pregnancy, to include data obtained from women with less severe vs more severe forms of PE and to include studies for which any approximation of the main outcome or assumption about the study design was used. There were not enough studies to determine whether women who develop PE have higher CIMT values before their PE diagnosis. Our results indicate that there is an increased atherosclerotic burden in women with PE than in women with normotensive pregnancies, both at the time of diagnosis and up to 10 years postpartum, which may contribute to an increased risk for cardiovascular disease in the affected women.
The invasive activity of cytotrophoblast in normal pregnancy leads to important changes in the spiral arteries, causing them to lose muscle and elastic tissue and undergo a transformation into flaccid, large-capacitance uteroplacental arteries[33-35]. The net result of these changes, frequently referred to as ‘physiological change’ or ‘spiral-artery remodeling’, is an increased blood supply that meets the increased metabolic demands of the developing fetus and placenta. In PE, the placental spiral arteries fail to lose their musculoelastic layers, leading ultimately to decreased placental perfusion[35, 36]. These non-transformed arteries are susceptible to acute atherosis, vessel lesions that closely resemble early-stage atherosclerosis.
The pro-atherosclerotic milieu of PE is supported further by studies that report the role of classical cardiovascular risk factors (such as hypertension, diabetes and hyperlipidemia) in the prediction of PE from as early as the first trimester[38, 39]. Clinical corollaries of these observations relate to increased risks for atherosclerotic disease, both at the time of pregnancy and postpartum. One notable example is an increase of 54% in pregnancy-related hospitalizations for stroke from 1994–1995 to 2006–2007 in the USA, with hypertensive disorders as a leading cause. With respect to post-pregnancy outcomes, patients with severe forms of PE are at greater risk for cardiovascular-associated death from as early as the first decade after their affected pregnancy. These studies, taken together, further support the concept of PE as a state of increased atherosclerotic burden that is associated with an increased risk for cardiovascular events, both months postpartum and long term. The overall atherosclerotic burden may be increased further by advanced age at first pregnancy (a trend that is being described increasingly in many countries) and by increased usage of the sophisticated techniques of assisted reproduction, such as in-vitro fertilization, that have made pregnancy possible for women with infertility conditions that are associated with cardiovascular disease risk factors (such as polycystic ovary syndrome)[35, 36]. Despite this convincing evidence of atherosclerotic burden in PE pregnancies, only a small number of studies have investigated CIMT at the time of diagnosis of PE and thereafter.
CIMT is used increasingly as a measure of preclinical atherosclerosis. Nevertheless, current guidelines do not support the routine measurement of CIMT in risk assessment for a first atherosclerotic cardiovascular disease event in the general population. This recommendation is based on the available evidence indicating that the addition of CIMT measurements to the Framingham Risk Score is associated with a small and clinically non-significant improvement in the 10-year prediction of the first atherosclerotic cardiovascular disease event. Recent studies regarding the role of CIMT for risk prediction in highly selected patient subgroups have provided encouraging results. Meta-analyses of the studies that included patients with antiphospholipid syndrome, diabetes mellitus Type 1 and systemic lupus erythematosus have provided evidence that CIMT may serve as a good marker of cardiovascular risk in highly selected patient populations[43-45]. Our current meta-analysis indicates that a greater atherosclerotic burden, as measured by CIMT, is present at the time of PE diagnosis than in women without such a diagnosis, and remains up to 10 years postpartum, when most of the women are still premenopausal. Conceivably, this pro-atherosclerotic milieu could contribute to cardiovascular complications during and after PE pregnancies.
The limitations of our study are those that are inherent to meta-analyses in general. Discrepant data regarding the association between PE and CIMT reported by individual studies may be due to differences in their design, CIMT methodology and patient-recruitment strategies. However, the meta-analysis of published studies clearly indicates that atherosclerotic load is present at the time of PE pregnancy and that it may be one of the mechanisms leading to this disease, which is increasingly viewed as a heterogeneous disorder, with different clinical subtypes possibly reflecting distinct underlying pathological mechanisms. Consistent with this notion are data indicating that statins may decrease endothelial dysfunction in primary human tissues, thus supporting their role as a candidate therapy for PE. As to the impact of PE on future health, CIMT may offer an opportunity for the early recognition of women with an atherosclerotic burden after PE pregnancy, even before menopause, when cardiovascular risk in women tends to increase. Our results support the role of the atherosclerotic process as one of the mechanisms associated with PE and set the stage for longitudinal, adequately powered studies that will use a standardized CIMT technique to validate the role of CIMT for diagnosing vascular disease at the time of pregnancy and for screening for vascular disease thereafter.
This study was supported by National Institute of Health (NIH) P50 AG044170 (V.D.G.). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official view of the NIH.