Main finding
In this study, we evaluated the association between multiple gestations and the development of HTN after delivery and found that women with multiple gestations had an increased risk of HTN during 7 years follow-up period compared with those with singleton. In addition, as risk ratios for HTN seem to be additive, it was noted that a woman with multiple gestations combined with preeclampsia was at seven-fold increased risk of HTN. It is well-established that the risk of preeclampsia is greater in multiple gestations rather than in singleton pregnancies [
9]. Preeclampsia is thought in part to explain the physiological mechanism by which the association between multiple gestations and the development of HTN is mediated, since women who have had preeclampsia have a high risk of ultimately developing HTN, later in life [
13]. However, in this study, multiple gestations remained significantly associated with the development of HTN later in life when preeclampsia was adjusted in multivariable analysis or participants were divided based on the presence of preeclampsia, suggesting the existence of another mechanism.
Strength and limitation
Our findings should be interpreted with caution due to several limitations. First, we were unable to access information regarding the characteristics of multiple gestations. It has been reported that the rate of severe preeclampsia was significantly increased in triplet pregnancy as compared to twin pregnancy although there was no change in the overall rate of preeclampsia [
14]. In addition, several studies reported that the association of preeclampsia was different by chorionicity [
15,
16] although others were inconclusive [
17]. Thus, it is hypothesized that the association of multiple gestations with the development of HTN may be affected by the number and chorionicity of multiple gestations. Based on the results of the present study, further studies are necessitated to confirm these associations considering these factors. Second, in this study, the subjects were limited to women who had undergone the NHSE before pregnancy to adjust the pre-pregnancy factors for HTN. However, when we analyzed data of all pregnant women who delivered during the study period regardless of pre-pregnancy characteristics (869,822 of singleton and 12,201 of multiple gestations), similar association of multiple gestations with the development of HTN in later life after adjustment for age, primiparity and preeclampsia (HR 1.21, 95% CI 1.19, 1.30) was observed. Third, there were several other confounding factors not adjusted such as fertility treatment which is closely related to maternal old age, multiple gestations, HTN and other obstetric complications. In addition, women who had multiple gestations before 2007 and had subsequent singleton pregnancy were not considered as history of multiple gestation. The KNHI databases does not contain detailed previous obstetric histories and chorionicity in each patient. Last, the results of our study are not generalizable because the enrolled population enrolled was East Asian and our health system might be different from other countries.
Nevertheless, the strength of the present study is that this is the first study to evaluate the association between multiple gestations and the development of HTN later in life after adjustment for the pre-pregnancy factors for HTN with a large population-based long-term follow-up.
Interpretation
Several potential explanations for these associations are possible. First, physiological changes related to multiple gestations during pregnancy may be directly attributed to the development of HTN. In multiple gestations, pronounced hemodynamic changes including greater cardiac output, development of left ventricular mass, fractional shortening and ejection fraction, and lower total vascular resistance develop compared to singleton pregnancy possibly due to the unique physiological changes required to meet the demands of a growing fetus [
18,
19]. Consequently, in uncomplicated twin gestations, significant changes in systolic and diastolic function occur from the first to the third trimester mimicking a diastolic dysfunction as observed in the early stages of chronic cardiac insufficiency [
20]. Moreover, although diastolic parameters normalize after pregnancy, a relative systolic dysfunction seems to persist after delivery [
20]. These findings are similar with those shown at postpartum echocardiography in women who developed a preterm or severe preeclampsia in a singleton pregnancy [
21,
22]. Thus, it is possible that the workload to the heart by the increased circulating volumes in multiple gestations may still affect cardiovascular systems leading to the development of HTN in later life. Moreover, in a twin pregnancy, circulating levels of antiangiogenic substances such as sFlt-1 and sEng [
18], which have a pivotal role in the pathogenesis of the maternal syndrome in preeclampsia [
19], were increased owing to large placental volume. Consequently, it is hypothesized that endothelial dysfunction caused by increased levels of antiangiogenic factors may cause HTN later in life even if preeclampsia did not occur during pregnancy.
Second, this association may be due to the particular characteristics of women with multiple gestations. An accumulating body of research has shown that numerous pregnancy complications appear to be preceded by subclinical vascular and metabolic dysfunction [
23‐
26], suggesting that the complications during pregnancy may be useful markers of latent high-risk CVD [
27]. In the present study, women with multiple gestations had a high incidence of cardiovascular risk such as obesity and DM, which are well-known risk factors for HTN. Thus, the increased risk of HTN later in life may be attributed to common predisposing factors for both multiple gestations and risk of HTN while it remains uncertain whether multiple gestations exacerbates previously unrecognized risk factors of HTN, or if the risk for HTN is the direct result of the manifestation of the disorder itself. Moreover, it has been known that maternal weight gain increases with increasing number of fetuses [
28]. Given that excessive gestational weight gain may increase of the risk for the development of cardiovascular and metabolic disease through long-term maternal abdominal adiposity [
29], women with multiple gestations may have an increased risk for the development of HTN later in life.
Lastly, it is well known that the rate of multiple gestations has increased owing to the expanded use of assisted reproduction [
30,
31]. Previously studies reported the link between fertility treatments with pregnancy complications including preeclampsia [
32‐
35]. Therefore, it is hypothesized that fertility treatments may attribute to the development of HTN in cases of multiple gestations. However, multiple gestations are suggested to be responsible for a large proportion of pregnancy complications associated with fertility [
36]. However, as the data on fertility treatments were not available during the course of the present study, studies with these factors are warranted in the future to confirm our findings.
Guidelines for the management of multiple gestations have previously been published with information about pre-pregnancy and pregnancy management for multiple gestations to minimize the pregnancy complication related to multiple gestations [
36,
37], but there is a lack of established guidelines or consensus regarding long-term follow-up. Based on our results, women with multiple gestations are considered as the high-risk group for the development of HTN later in life.