In this population-based retrospective matched open cohort study, we aimed to explore whether preterm delivery is associated with long-term hypertension or T2DM in women. In the main analysis, unadjusted results suggested that women who delivered preterm were at 42% increased risk of subsequent hypertension events and 67% increased risk of subsequent T2DM events compared with the unexposed group, matched for age and region, who delivered at term. These associations were no longer statistically significant after adjustment for demographical and clinical risk factors, with much of the attenuation and loss of statistical significance appearing to be attributable hypertensive disorders of pregnancy for the hypertension outcome and GDM for the T2DM outcome, which are well-established risk factors for subsequent development of the corresponding outcomes. In subgroup analysis, we attempted to explore the independent associations according to the presence of HDP or GDM. No significant association was found in these subgroup analyses; however, given the relatively small number of outcomes, statistical significance should be interpreted with caution.

We found no significant association between preterm delivery and hypertension or T2DM after adjustment for potential confounders in this study. The findings from our study are inconsistent with results from the Danish,18 19 US20 and Swedish21 studies that found an association between PTD and increased risk of hypertension and T2DM. The effect estimates from previous studies were in the range of 11% to 30% increased risk for future hypertension events and from 17% to 89% increased risk for future diabetes events. In contrast, a prospective cohort study22 of 3416 women in the UK found that preterm delivery showed a weak association with high blood pressure, but not with glucose level.

The Danish studies18 19 showed a relatively higher risk of hypertension (27–30%) and T2DM (61–89%) compared with the other studies; however, these studies included maternal age at first birth, parity, education as confounder and missed out key confounders, including smoking, BMI and comorbidities. The US20 and the Swedish studies21 identified a moderate effect after they adjusted for demographical and clinical factors. They were able to adjust for pregnancy demographical conditions, such as final parity, duration of pre-pregnancy oral contraceptive use and pregnancy duration which it was not possible to include this study. However, they did not include reproductive complications which appeared to act as confounders in this study. This difference in effect size and study results could be explained by differences in the potential confounders adjusted for in the analyses.

Known or possible risk factors for hypertension and T2DM had a consistent and strong impact on effect estimates in this study.43 An association between T2DM and reproductive complications was not observed in the multivariable models (online supplemental table S4) due to a small number of observations. While there was a significantly increased risk of hypertension events in women with health conditions linked to CID (aHR 1.87; 95%CI 1.02 to 3.44) and reproductive tumour (aHR 3.10; 95%CI 1.56 to 6.16), these findings may reflect an increase in risk of hypertension in pre-pregnancy diseases associated with chronic inflammation.44–46 Inflammation has also been implicated to have a causal link with PTD.47 Even though no significant association was observed in this study, these common biological factors imply that PTD may be a sign of subclinical risk of development of hypertension or T2DM in the future, rather than PTD leading to vascular and inflammatory changes. Associations with chronic inflammatory diseases support the view that inflammation may participate in hypertension, providing a pathophysiological link between these reproductive health conditions.11 46 48

Furthermore, hypertensive disorders of pregnancy and gestational diabetes are established risk factors for future risk of corresponding chronic health conditions.22 49 50 The results of this study showed a strong association in the fully adjusted model (online supplemental table S4; HDP with hypertension, aHR 5.05, 95%CI 3.16 to 8.07; GDM with T2DM, aHR 18.80, 95%CI 12.05 to 29.35). These complications frequently coexist with PTD.22 A history of PTD may be an indicator that can enable clinicians to identify women at high risk of cardiometabolic conditions which are accompanied by HDP or GDM.

Regarding perception of implication for public health, the 2021 European Society of Cardiology (ESC) guidance on CVD included PTD in the class IIb risk factors of clinical conditions, meaning that women with a history of PTD may be considered for periodic screening for hypertension and T2DM.51 The usefulness of screening women with a history of PTD is less well established by evidence.51 The findings of this study suggest the association observed in previous studies should be considered more carefully when applying in the UK population, as there was no significant association observed in this study, and previously observed associations could be attributable to confounding conditions. Future investigates of health conditions which accompany with PTD and the causes of PTD and their potential association with development of cardiometabolic condition would help to elucidate the complex interaction between these related conditions.

Overestimating the association may contribute to an economical burden on public health, such as inappropriate use of limited NHS resources. In addition, assessment of lower-risk patients may lead to the potential harms of prescribing unnecessary antihypertensive or diabetic medications and patient anxiety.

Our study used a large primary care database that is generalisable to the UK. CPRD-registered participants represent the UK population regarding demographical characteristics including age, sex and ethnicity.24 According to the Office for National Statistics,3 the average age of mothers in England and Wales remained at 30.7 years in 2020, similar to the mean age in the study population (30.8 years). Another strength of the study is that information on a wide variety of confounders was available. Matching participants by age and region minimised confounding. Female-specific diseases or reproductive complications, such as PCOS, STD, CID and reproductive tumours, were included as potential confounders in analyses. We were also able to follow-up participants over a long period of time.

CPRD has been demonstrated to be reliable, but data is not entered into general practice systems for the purpose of research. Therefore, there were some limitations relating to data availability and data validity. The exposure variable was treated as only a dichotomous variable; differences depending on the gestational age (eg, very preterm, moderately preterm), pregnancy history, multiple pregnancy and recurrent pregnancy event could not be investigated. Also, missing values in the data on smoking, BMI and ethnicity could contribute to bias and impact the results in this study. To mitigate this issue, we conducted multiple imputation as a sensitivity analysis to see the effect of missing values on results.

Patients with undiagnosed hypertension and T2DM could have potentially been included in the unexposed cohort, resulting in misclassification. According to the Health Survey for England 2017,52 one in five people with diabetes is undiagnosed, and this undiagnosed diabetes accounts for 1.5% of adults in the UK. Also, around half of hypertensives are unaware of their condition.53 Although the exposure and outcomes variables were selected through a rigorous process, there are no studies that have validated the recording of PTD, hypertension or T2DM in the CPRD GOLD database. However, under the QOF scheme, reporting of hypertension and diabetes is financially rewarded; consequently, they are well documented in the CPRD. It is possible that a proportion of women in the exposed group may have experienced recurrent PTD in subsequent pregnancies. History of recurrent PTD further augments the risk of long-term maternal cardiometabolic outcomes.19 The possibility of unmeasured confounding still exists, despite the fact that we controlled several known and potential confounders; for example, we were unable to adjust for family history of CVD, physical activity and chlamydia trachomatis infection.

The relatively short follow-up period in a population of young women and the low number of outcome events may have led to type II error in this study; therefore, the lack of statistical significance of the findings should be interpreted with caution. In this study, the overall outcome event rate was 1.7% for hypertension and 0.73% for T2DM, with a median follow-up of 5.11 (IQR 2.15–9.56) years for hypertension outcome and 5.17 (IQR 2.18–9.67) years for T2DM outcome; this was a slightly lower event rate with shorter follow-up period than in the previous national registry-based retrospective cohort study,19 in which overall outcome event rates were 2.4% for hypertension and 0.9% for T2DM with a median follow-up time of 14.6 years (IQR 7.61–21.8) and 12.9 years (IQR 6.86–18.9) for each cohort. Other studies appeared to have followed patients longer. Using a larger dataset such as CPRD Aurum could be considered for further research to increase the number of outcomes and address the issue of statistical power.