Introduction
Pre-eclampsia is a pregnancy-specific multisystem disorder that affects 5–8% of pregnancies [
1]. It frequently manifests as new-onset hypertension and proteinuria. It is the most common cause of severe perinatal morbidity and is responsible for more than 50,000 maternal deaths per annum globally [
2]. Pregnancy is known to be a state of physiological insulin resistance and relative glucose intolerance [
3]. Insults to the cardiovascular and renal systems from pre-eclampsia often persist postnatally, with insulin resistance [
4], diffuse vascular endothelial dysfunction [
5] and inflammatory factor activation [
6] reported, although it is unclear whether these are pre-existing conditions prior to the pregnancy or longer-term sequelae of pre-eclampsia. Many of these pathophysiological mechanisms are also linked to the future development of diabetes [
7]. Furthermore, lower insulin sensitivity and higher insulin levels have been found in women with a previous history of pre-eclampsia [
8].
It remains controversial as to whether pre-eclampsia has long-term metabolic sequelae and is an independent risk factor for the future development of diabetes, as it is difficult to separate pre-eclampsia from confounding factors that are associated with future incident diabetes. The existing literature provides conflicting data, with some studies showing significant increases in the risk of future diabetes [
9,
10] and others not observing such a relationship [
11,
12]. Many of the studies that have focussed on the association between pre-eclampsia and future incident diabetes have reported limited clinical details for the cohorts studied, and have not adjusted for BMI [
9], family history of diabetes [
10] or other factors that are known to increase the future risk of incident diabetes, hence raising the potential for unmeasured or unreported confounders contributing to the associations reported. This systematic review and meta-analysis aimed to quantify the risk of diabetes in later life following pre-eclampsia in pregnancy. Here, we provide an overview of the relevant studies and of the association between pre-eclampsia and future incident diabetes.
Discussion
Our systematic review and meta-analysis of 21 studies, including more than 2.8 million women, suggests that there is an association of pre-eclampsia with future incident diabetes. The risk of diabetes in women who had experienced pre-eclampsia was approximately double that of women without a history of pre-eclampsia, and increased to 2.4-fold if type 2 diabetes was considered exclusively. This effect was seen in the first year following delivery and persisted beyond 10 years. Diabetes is a well-known risk factor for pre-eclampsia [
36]. However, pre-eclampsia has not been established as a risk factor for future diabetes. In comparison, gestational diabetes is a well-recognised risk factor for future diabetes. Women with pregnancies complicated by gestational diabetes have previously been reported to have a sevenfold increased risk of developing type 2 diabetes compared with those with normoglycaemic pregnancies [
37]. Our study therefore extends the literature on the association between pre-eclampsia and diabetes.
Current research supports the link between pre-eclampsia and future diabetes, with several national or regional registry studies with large sample sizes and adjustment for confounding factors all showing similar results [
9,
10,
22,
28,
34]. The studies that have not shown an association are mainly those with smaller sample sizes [
11,
12,
18,
19,
21,
23,
25,
26,
29,
30]. There are gaps in the current literature, in particular with respect to the link between pre-eclampsia and type 1 diabetes. Furthermore, it is difficult to know whether the association we report here relates to confounding factors. We were unable to fully evaluate the effects of all confounding factors and undertake further sensitivity analyses due to the absence of such data in the studies included in the current meta-analysis. For example, only two studies adjusted for age and BMI, as well as excluding pre-existing diabetes and hypertension in the study populations [
22,
32]. Moreover, only seven studies either adjusted for or excluded patients with gestational diabetes [
9,
10,
22,
28,
31‐
33], a known risk factor for future diabetes and pre-eclampsia development [
38]. In the few studies where adjustments for age, BMI or gestational diabetes were made (Table
2), the risk of future type 2 diabetes remained increased in women who had pre-eclampsia compared with the control group.
The underlying mechanism for the association between pre-eclampsia and future diabetes is unclear. Pre-eclampsia and diabetes share common risk factors, including age older than 40 years, obesity, hypertension and Afro-Caribbean or South Asian ethnic origin [
39,
40]. It may be that women with pre-eclampsia have an underlying predisposition to insulin resistance and the metabolic syndrome, and present with pre-eclampsia as an early indicator of their adverse metabolic phenotype over the life course.
Risk scores allow a non-invasive method of identifying individuals at high risk of future diabetes. The ADA risk tool takes into account age, BMI, hypertension, history of gestational diabetes, family history of diabetes, sex and levels of physical activity [
41]. The Finnish Diabetes Risk Score (FINDRISC) [
42] is the most commonly used score in Europe, and has been endorsed by the European Society of Cardiology, the EASD [
43] and the Public Health Agency of Canada [
44]. FINDRISC predicts the 10-year risk of developing type 2 diabetes by considering age, BMI, use of antihypertensive medication, history of hyperglycaemia (including gestational diabetes), family history of diabetes, waist circumference, physical activity, and fruit and vegetable intake [
42].
Currently, screening beyond history-taking to identify risk factors for pre-eclampsia during pregnancy is not recommended by the American Congress of Obstetricians and Gynecologists (ACOG). Risk factors recognised by ACOG are: age older than 40 years, obesity, chronic hypertension, diabetes (type 1 or 2), chronic renal disease, previous pre-eclampsia, thrombophilia, systemic lupus erythematosus, primiparity, multiple pregnancy, in vitro fertilisation and a family history of pre-eclampsia [
45]. This overlap of risk factors for developing pre-eclampsia and type 2 diabetes could have contributed to the association of pre-eclampsia and future diabetes we report here. Furthermore, there is likely to be interplay between the cardiovascular and metabolic systems. A history of pre-eclampsia is also related to poor future cardiovascular health, while cardiovascular disease is itself a known risk factor for diabetes [
46]. In the few studies where adjustments for age or BMI were made (Table
2), the risk of future type 2 diabetes remained increased in women who had pre-eclampsia compared with the control group. Nevertheless, as highlighted above, a number of risk factors are known to significantly increase the risk of future diabetes; none of the studies included in this meta-analysis fully adjusted for all of these risk factors, and so we were unable to undertake further sensitivity analyses.
The strength of our study lies in the number of recent studies included and the large sample size; our meta-analysis of 21 studies examined more than 2.8 million women, including more than 72,500 women with pre-eclampsia with 845,834 patient-years of follow-up. The inclusion of more recent studies means that there is a greater likelihood of the study findings being generalisable to current practice. The majority of the studies were designed to examine future diabetes or insulin resistance and the metabolic syndrome as their main outcome (n = 18), with these studies contributing 99% of the women in our meta-analysis.
There are a number of limitations to our analysis. As with any meta-analysis, there is an inherent limitation from publication bias, where studies with positive findings are more likely to be published than those that show neutral outcomes. The majority of women included were from retrospective studies, where there is limited control over the quality of data collected. There may have been inconsistent, incomplete or inaccurate historical data with respect to pre-eclampsia diagnosis, as well as recall bias, which could have caused the incorrect assignment of participants to case and control groups. In addition, five studies used questionnaire data to assess the outcome of diabetes [
11,
25,
26,
29,
31]. Finally, it is likely that significant unmeasured confounders may have contributed to our reported association between pre-eclampsia and future diabetes risk, as none of the studies included in this analysis adequately adjusted for all of the risk factors that form the basis of many of the established diabetes risk prediction scores [
41,
42].
Given the gaps in the current literature, further work is required to examine the association between pre-eclampsia and type 1 diabetes in particular. There is a need for studies that use propensity-matching methods or more comprehensive adjustments for confounding factors, as well as for high-quality studies with long-term follow-up for outcome events. In addition, mechanistic research is required to further our understanding of the association between pre-eclampsia and future diabetes in order to identify risk-reduction strategies.
Our finding of an association between pre-eclampsia and the future development of incident diabetes is clinically important, as it suggests that formal risk assessment for the future development of diabetes using established risk scores may be considered in pregnant women with pre-eclampsia [
41,
42]. Furthermore, clinicians may find it pertinent to enquire about a history of pre-eclampsia as a part of the metabolic and cardiovascular assessment of women or to incorporate into risk-prediction formulas. Since women with pre-eclampsia are already known to be at risk of future cardiovascular disease [
47], our study highlights the importance of lifestyle and risk-factor modification, and regular monitoring of BMI and HbA
1c in these women to further reduce their cardiovascular and metabolic risks. In line with the ACOG recommendation to perform annual fasting glucose testing following severe pre-eclampsia [
45], we recommend a detailed cost–benefit analysis to determine whether and when a screening programme for diabetes in this high-risk population should be initiated.