Hypertensive disorders of pregnancy and subsequent risk of solid cancer—A nationwide cohort study

Abstract

Women with hypertensive disorders of pregnancy (HDP) have higher levels of antiangiogenic growth factors during pregnancy than women with normotensive pregnancies. Since angiogenesis is necessary for solid cancer growth and spread, we hypothesized that women with a history of HDP might have a reduced risk of solid cancers (cancers other than lymphomas, hematologic cancers and nonmelanoma skin cancers) later in life. In a register-based cohort study of 1.08 million women giving birth at least once between 1978 and 2011, we used Cox regression to estimate hazard ratios (HRs) comparing solid cancer rates for women with and without a history of HDP. In this cohort, 68,236 women (6.3%) had 1 pregnancy complicated by HDP and 42,236 women (3.9%) developed solid tumors during follow-up. A history of HDP was not associated with a clinically meaningful reduction in the overall rate of solid cancer (HR 0.96, 95% confidence interval 0.92-1.00), regardless of HDP severity or time since HDP, nor was there a general tendency toward reduced solid cancer rates across organ sites. A history of HDP was only significantly associated with decreased rates of breast and lung cancers and with increased rates of endometrial and urinary tract cancers. Overall, our results do not support the hypothesis that women with a history of HDP have a reduced overall risk of solid cancer due to a persistent post-HDP antiangiogenic state or an innate tendency toward antiangiogenesis. Observed associations with specific cancers may instead be due to other pregnancy-related mechanisms or to residual/unmeasured confounding.Hypertensive disorders of pregnancy (HDP) are a group of disorders that affect up to 10% of pregnancies worldwide; the preeclampsia syndrome alone complicates 2-8% of pregnancies.1,2 While the various disorders classified as HDP share clinical features, their etiology is unclear, and although pathophysiologic pathways may overlap, there is likely etiologic heterogeneity.A balance between proangiogenic factors (e.g., vascular endothelial growth factor [VEGF], placental growth factor [PlGF]) and antiangiogenic factors (e.g., soluble fms-like tyrosine kinase-1 [sFlt1] and soluble endoglin [sEng]) is required to maintain vascular endothelial function. An imbalance toward antiangiogenesis likely contributes to the symptoms of preeclampsia 3 ; antiangiogenic factor levels rise earlier and reach higher levels in preeclamptic pregnancies (particularly in early-onset, severe preeclampsia) than in normal pregnancies. [4][5][6][7][8] However, whether the antiangiogenic imbalance in these women is pregnancyinduced, or women who develop preeclampsia have an innate tendency to antiangiogenesis, is unclear. Angiogenesis is also necessary for the growth and spread of solid cancers 10

Hypertension and the risk of endometrial cancer: a systematic review and meta-analysis of case-control and cohort studies

“…To date relatively few studies have investigated the association between hypertensive disorders of pregnancy and endometrial cancer risk with one study suggesting an increased risk with hypertensive disorders overall64, while another study found no association with preeclampsia overall, although an increased risk was observed with early-onset preeclampsia65. Any further studies could better assess the causality of the observed association between hypertension and endometrial cancer by using genetic risk scores for hypertension6667.…”

The role of pregnancy, perinatal factors and hormones in maternal cancer risk: a review of the evidence

“…Several studies have shown a reduced risk of breast cancer amongst women with a history of preeclampsia, compared with those with normotensive pregnancies . However, the results are not completely consistent and it is unclear whether the anti‐angiogenic imbalance in women who experience preeclampsia is pregnancy‐induced, or if they have an innate tendency towards an anti‐angiogenic response to biological challenge.…”

“…The relationship of other pregnancy characteristics with breast cancer has been studied less often (reviewed in ). To provide some benefit, a full‐term pregnancy appears necessary, as miscarriages do not provide equivalent protection .…”

Cancer and Cardiovascular Risk in Women With Hypertensive Disorders of Pregnancy Carrying a Common IGF1R Variant

“…Results here confirm previously reported associations of HDPs without genotype with increased risk for CVD, lower risk for breast cancer, and no change for nonbreast cancer risk. [1][2][3][4][5][6][7][8][9][10][11] Looking at genotype alone, rs2016347 was only associated with all nonbreast cancers, HR, 0.94; 95% CI, 0.90 to 0.98: P¼.01, and although this decrease in risk was relatively small, it was statistically significant for the recessive model and has not been previously reported. Further studies are needed to validate this finding and facilitate the identification of associations with specific cancer sites, which could have significant clinical relevance.…”

“…However, some studies have reported differences in certain cancer types, with 2 reporting a decreased risk for lung/respiratory cancers and others reporting an increased risk for endometrial cancer, suggesting that the nonbreast cancer impact of HDP may vary by organ or cell type. [10][11][12] Although HDPassociated cancer and CVD risks may be either competing or additive, the hazard ratio (HR) for all-cause mortality in women with HDP is 1.65 compared with women without HDP, 13 reflecting its major impact on future health.…”