Cardiovascular complications of obesity during early pregnancy: methodological and practical implications

Obesity (body mass index (BMI) ≥30 kg/m²) poses a major threat to public health currently, affecting approximately 650 million people worldwide. While both men and women are affected by the growing obesity epidemic, women present with higher prevalence rates of both obesity and severe obesity (BMI ≥35 kg/m²) compared to men. Globally, approximately 15% of women are currently considered to be obese and over 5% severely obese (the same figures for men are 10% and 2%, respectively). ¹ Obesity rates are substantially higher during pregnancy, affecting approximately 30% of women. ² Obese women are more likely to manifest long-term conditions including cardiovascular disease (CVD), ³ and do so at younger ages as documented in the study by Dikaiou et al. ⁴ in this issue of the journal. Obesity-related CVD morbidity (e.g. myocardial infarction, stroke) also increases women’s risk of premature mortality. What has been less well characterised is the extent to which obesity during early pregnancy has lasting adverse influences on CVD incidence and mortality.

In this context, Dikaiou et al. present several relevant findings based on a prospective study of 1,495,499 women (mean age 28.3 years and median follow-up of 16.3 years) who gave birth between 1982 and 2014. ⁴ Firstly, the authors reported a two to four times increased relative risk of major CVD events (e.g. myocardial infarction and stroke) and CVD-related mortality among obese women (BMI ≥30 kg/m²) compared to those with a low optimal BMI range (20–22.5 kg/m²). Secondly, the risk of major CVD events and mortality was greater among women with severe obesity relative to obese women. Thirdly, the shape of the association varied across different CVD events and mortality outcomes. These findings strengthen the evidence for the value of obesity screening during early pregnancy stages in order to detect those women at greater risk of future CVD complications.

Considering the findings of Dikaiou et al. ⁴ at face value and assuming that the observed associations are causally associated, what are the possible mechanisms for the observed patterns? The authors proposed several explanatory mechanisms, including haemodynamic changes, metabolic factors, low grade inflammation and oxidative stress. High levels of inflammatory biomarkers (e.g. C-reactive protein (CRP), interleukin-6 (IL-6)) and dyslipidaemia with excess abdominal adiposity are documented pathophysiological pathways leading to increased CVD risk among severely obese women. The vulnerability of obese pregnant women to CVD-related complications may also be directly or indirectly affected by exposure to stressful life events, unhealthy behaviours, genetics, medical comorbidities (e.g. mental health), or air pollution. The study of Diaikou et al. ⁴ offers limited scope to disentangle among the distinctive processes that may drive the link between obesity in early pregnancy with CVD risk. Using causal mediation analysis, our group has established that approximately 40% of the association between depression and atherosclerosis was mediated by way of combined metabolic and inflammation pathways. ⁵ A causal mediation analysis with multiple mediators would offer insights into specific processes linking obesity in early pregnancy with CVD risk. Such knowledge would facilitate the implementation of targeted preventive strategies within at-risk populations.

An important caveat of the study by Daikou et al. ⁴ is that the observed patterns relied on one time point assessment of obesity, yet the CVD implications of obesity in early pregnancy are likely to vary with the duration and age at onset of obesity. Previous studies found that longer obesity duration (≥15 years) was associated with poorer prognosis on a range of cardiac indicators (e.g. endothelial dysfunction) among patients with a similar degree of obesity and tissue adiposity. ⁶ A prospective study using the Framingham Cohort Study documented a 7% increment in CVD-related mortality for every 2 years additionally lived with obesity. ⁷ In a similar fashion, weight gain during early pregnancy has recently been linked with an increased risk of pre-eclampsia, an independent predictor of CVD risk. ⁸ An estimation of the implications of long-term patterns of obesity for CVD-related complications may address methodological concerns around reverse causality. It would also identify how variations in the patterns of obesity in early pregnancy contribute to changes in the burden of CVD risk over time.

The utility of BMI to characterise obesity in relation to CVD risk and premature mortality is, however, questionable. ⁹ This concern is compounded in the study by Dikaiou et al. ⁴ by the use of a self-reported height measure, because individuals tend to overestimate their height. ¹⁰ There is mounting evidence that, among women, abdominal obesity (as assessed by waist circumference) is a more robust indicator of future CVD morbidity relative to just fat mass per se. ¹¹ Abdominal obesity is an independent indicator of the metabolic syndrome, and obesity magnitude directly reflects the CVD prognosis of this condition.^5,12 Recent evidence supports the value of using multiple anthropometric measures to assess more accurately the future risk of CVD within pregnant women. ¹³ Future prospective studies would benefit, thus, from the concurrent measurement of BMI and abdominal obesity (by ultrasound during clinical visits) when assessing the risk of CVD among pregnant women with obesity.

The use of BMI as a marker of adiposity across populations varying in their ethnicity and socioeconomic status may increase the risk of misclassification bias. Women of Asian ethnic minority have, for instance, a higher percentage of body fat per BMI and are more likely to develop abdominal obesity compared to women of white ethnic background. ¹⁴ Women of black ethnic minority, on the other hand, have lower body fat mass per BMI than white women and, thus, might be at lower risk of obesity-related CVD complications. ¹⁵ Research is warranted on the CVD and mortality implications of obesity during early pregnancy among women from ethnic minority backgrounds possibly using different cut-off points for abdominal obesity along the lines suggested by the International Diabetes Federation (IDF). ¹⁶

Early pregnancy obesity offers a window of opportunity for the early detection of women at greater risk of future CVD complications. Regrettably, for many young women, underlying obesity can remain undetected and undiagnosed prior to pregnancy. The identification of obese women early during pregnancy could facilitate the implementation of confirmed effective interventions to prevent or delay the onset of CVD risk. Future investigations are necessary to focus on women from ethnic minorities and low socioeconomic backgrounds, as these groups present the highest risk of CVD morbidity and mortality. These are also the groups less likely to attend regular health checks and follow-up assessments.

Existing clinical interventions found limited support for lifestyle-based interventions in reducing pregnancy weight gain. ¹⁷ These findings imply that additional strategies are needed to prevent the development of CVD complications among obese pregnant women. For instance, the active screening of women prior to conception and educating vulnerable women about the CVD risk associated with obesity in early pregnancy seems a promising avenue. Improved knowledge about direct and indirect pathways leading from obesity in early pregnancy to CVD onset and premature mortality would afford the development of evidence-based preventive strategies.