Cardiovascular risk factors in women with inheritable thrombophilia a decade after single or recurrent hypertensive disorder of pregnancy

ABSTRACT

Objective: To described cardiovascular risk factors in women with inheritable thrombophilia 8–19 years after early-onset hypertensive disorders of pregnancy (HD) with or without recurrent HD. Methods: Women with recurrent HD were compared with women with single HD, for physical examination and cardiovascular parameters in serum. Results: Systolic blood pressure, diastolic blood pressure, and albumin: creatinine ratio were higher in women with recurrent HD compared with women with single HD (p = 0.046, p = 0.029, and p = 0.008, respectively). In both groups 72.7% had an increased cardiovascular risk. Conclusion: Women with inheritable thrombophilia after single or recurrent HD have a high cardiovascular risk.

KEYWORDS:

• Cardiovascular risk factors
• hypertension
• hypertensive disorders of pregnancy
• inheritable thrombophilia

Introduction

In the Western world, cardiovascular disease (CVD) is the number one cause of death in women (1). It is a commonly accepted theory that pregnancy is a stress test which can identify women who have an elevated risk to develop CVD (2–5). It has not been elucidated yet whether hypertensive disorders of pregnancy (HD) is a disease within the CVD spectrum or that HD itself is a risk factor for CVD later in life, comparable with other risk factors such as hypertension, hypercholesterolemia, and obesity (6,7).

The risk to develop cardiovascular risk factors has been reported to be related to the HD severity (2,8). In retrospective studies, it also is suggested that women with a history of recurrent HD have a higher chance to develop CVD later in life compared with women with a history of single HD (9,10).

It is unknown whether inheritable thrombophilia is an additional risk factor next to HD for CVD (11–13). Whether inheritable thrombophilia is related to HD and therefore indirectly linked to CVD has been debated. Studies, including meta-analyses, taken the severity and time of onset of HD into account, show an association between inheritable thrombophilia and pregnancy complications like early-onset HD (HD < 34 weeks gestation) and small-for-gestational-age (SGA) infants (14–18). Two case–control studies and one cohort study including a meta-analysis conclude that there is no relation between inheritable thrombophilia and pregnancy complications (19–21). Only one of the case–control studies took severity and time of onset of HD into account (20).

One study investigated cardiovascular risk factors in women with thrombophilia more than 5 years after a pregnancy complicated by HD and concluded that thrombophilia might mediate in lowering cardiovascular risk factors compared with women without thrombophilia with a similar obstetric history (22).

We hypothesize that women with a history of recurrent HD develop more cardiovascular risk factors compared with women with a history of single HD.

We have the unique opportunity to investigate cardiovascular risk factors in women with inheritable thrombophilia 8–19 years after early-onset HD with or without recurrent HD, whose pregnancy outcomes were well documented. The specific question of this study is: Is a history of recurrent HD associated with increased incidence of cardiovascular risk factors compared with a history of single HD?

Patients and methods

Participants

This study is a follow-up study of the FRactionated heparin in women with Utero-placental Insufficiency and Thrombophilia (FRUIT-RCT) (23). The FRUIT-RCT included 139 women in the Netherlands (n = 126), Sweden (n = 3), and Australia (n = 10) in the period between January 2000 and December 2009. Inclusion criteria were inheritable thrombophilia and a history of placental insufficiency: HD and/or a SGA infant, and a delivery before 34 weeks gestation. HD was defined as preeclampsia, eclampsia, or HELLP syndrome. Subjects were randomized to receive either both daily low-molecular-weight heparin (LMWH, Dalteparin, weight adjusted) and daily aspirin, or daily aspirin only. For the current follow-up study, we have invited women who lived in the Netherlands with HD during the FRUIT-RCT and matched them with women without HD for age, study arm, and chronic hypertension at start of the FRUIT-RCT. We excluded women with SGA without HD in the FRUIT-RCT index pregnancy. We visited all women in one of the nearest hospitals in the area they lived. The study was approved by the medical ethical committee of the VU University Medical Center in Amsterdam. All women participating in the study provided written informed consent.

Measurements

A validated questionnaire was used which included questions about medical history, current use of medication, and family history including CVD (24).

Physical examination included blood pressure measurements which were measured manually with a validated sphygmomanometer in sitting position at the right upper arm. The mean of two measurements was used in the analyses. Physical examination also included height, weight, and hip and waist circumference measurements.

Venous blood samples were collected after an overnight fast and assayed for glucose, insulin, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, creatinine, ureum, and high-sensitivity c-reactive protein (hs-CRP). Insulin resistance was assessed by the homeostatic model assessment (HOMA): insulin concentration/(22.5 e^–ln glucose concentration). Urine was collected for assessment of microalbuminuria and creatinine, immediately after waking up to calculate the albumin creatinine ratio. After the blood and urine collection, the samples were taken to the laboratory of the VU University Medical Center and analyzed within 5 hours after blood draw.

Definition of clinical diagnoses

Hypertension was defined as a systolic blood pressure ≥140 mmHg, a diastolic blood pressure ≥90 mmHg, or current use of antihypertensive medication. Presence of diabetes mellitus (DM) was defined as fasting glucose ≥7.0 mmol/L or treatment (diet or medication). Hypercholesterolemia was defined as total cholesterol ≥5.0 mmol/L or current use of statins. Increased cardiovascular risk as composite outcome is defined as presence of either hypertension, hypercholesterolemia, BMI > 25, or DM. Metabolic syndrome was defined according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII panel) which means presence of three or more of the following: fasting plasma glucose ≥6.1 mmol/L, serum triglycerides ≥1.69 mmol/L, serum HDL-cholesterol ≤1.29 mmol/L, blood pressure ≥130/≥85 mmHg, or waist circumference ≥88 cm (25).

Statistics

Differences in baseline characteristics of the study population at screening visit were examined using an independent T-test or a Fisher’s exact test when appropriate. Obstetric history in the FRUIT-RCT and cardiovascular risk factors were examined using a Fisher’s exact test, χ² test, independent T-test, or Mann–Whitney U-test when appropriate. Means and standard deviation (SD), numbers and percentages, or median and interquartile range (IQR) were reported. Statistical analyses were performed with IBM SPSS, version 22.0 (SPSS, Inc., Chicago, IL, USA). A two-tailed p-value <0.05 is considered to be significant.

Results

In total, 41 women met the in- and exclusion criteria for this follow-up study and were invited. Out of these 41 women, 2 deceased (1 due to a cerebral lymphoma, the other due to cerebral aneurysm), 5 were lost to follow-up, and 12 refused participation resulting in 22 participants. Of the 22 included women, 11 women developed recurrent HD during the FRUIT-RCT and the other 11 women did not develop recurrent HD during the FRUIT-RCT. The year of index pregnancy (in which all women had early-onset HD) varied from 1996 until 2007; 8–19 years before the current follow-up study.

Characteristics of the women at study visit including items of the questionnaire are presented in Table 1. No differences between groups were demonstrated. Obstetric history of both index and study pregnancy is given in Table 2. Of the 11 women with recurrent HD, 4 women had recurrent early-onset HD. Physical examination showed that women with recurrent HD had a higher systolic and diastolic blood pressure than women with single HD (Table 3a). Out of seven women with chronic hypertension at start of the FRUIT-RCT, five still had hypertension during the follow-up visit. The other two women (both in the recurrent HD group) did not take antihypertensive medication and had a normal blood pressure at follow-up.

Table 1. Characteristics of study population at screening visit.

	Recurrent HD (n = 11)	Single HD (n = 11)		p-Value
Age (years)	44.5 ± 3.6		44.7 ± 4.2	0.91
Non-Caucasian	1 (9.1)		0 (0)	1.00
Years since delivery in FRUIT-RCT	9.1 ± 2.7		10.0 ± 3.3	0.49
Current smoker	0 (0)		2 (18.2)	0.48
Family history of vascular disease^a
First degree family (parents or siblings): arterial	3/10 (30)		3 (27.3)	1.00
First degree family (parents or siblings): venous	2/10 (20.0)		4/10 (40)	0.81
Mother and/or sister HD	6 (54.5)		2 (18.2)	0.18
Thrombophilia disorder^b
Protein S deficiency	1 (9.1)		1 (9.1)	1.00
Protein C deficiency	3 (27.3)		1 (9.1)	0.59
Factor V Leiden	8 (72.7)		5 (45.5)	0.39
Prothrombin gene G20210A mutation	1 (9.1)		4 (36.4)	0.31

Data are depicted as mean ± SD or numbers (%). HD, hypertensive disorders of pregnancy.

^aSome women did not know their family history.

^bSome women were diagnosed with more than one thrombophilia disorder, thrombophilia was diagnosed before inclusion of the FRUIT-RCT and >10 weeks after (index) pregnancy.

Table 2. Obstetric history in women with recurrent and single HD in index and study pregnancy of the FRUIT-RCT.

	Recurrent HD (n = 11)	Single HD (n = 11)	p-Value
Index pregnancy
SGA infant index pregnancy	5 (45.5)	5 (45.5)	1.00
GA delivery index pregnancy (days)	207 [196–219]	205 [197–219]	1.00
Study pregnancy
Chronic hypertension at start of pregnancy	4 (36.4)	3 (27.3)	1.00
Treatment with LMWH and aspirin	7 (63.6)	6 (54.5)	1.00
Treatment with aspirin only	4 (36.4)	5 (45.5)	1.00
SGA infant study pregnancy	2 (18.2)	2 (18.2)	1.00
GA delivery study pregnancy (days)	261 [238–276]	276 [260–281]	0.24

Data are depicted as numbers (%) or median [IQR]. HD, hypertensive disorders of pregnancy; SGA, small-for-gestational-age; GA, gestational age; LMWH, lowmolecular-weight heparin.

Table 3a–c. Cardiovascular risk factors after recurrent and single HD: (a) physical examination, (b) biochemical results, (c) clinical diagnoses.

		Recurrent HD (n = 11)	Single HD (n = 11)	Total group (n = 22)	p-Value	RR (CI)
a: Cardiovascular risk factors at follow-up: physical examination
Body composition
Body mass index (kg/m^2)		27.0 ± 5.1	25.7 ± 4.3	26.3 ± 4.7	0.52	NA
Waist circumference (cm)		84.5 ± 11.5	84.9 ± 11.0	84.7 ± 11.0	0.93	NA
Hip circumference (cm)		107.5 ± 9.8	107.0 ± 8.0	107.2 ± 8.7	0.91	NA
Waist-to-hip ratio		0.78 ± 0.1	0.79 ± 0.1	0.79 ± 0.1	0.79	NA
Blood pressure
Antihypertensive medication use		3 (27.3)	1 (9.1)	4 (18.2)	0.59		1.7 (0.8–3.6)
Systolic blood pressure (mmHg)		133.2 ± 16.5	117.8 ± 17.4	125.5 ± 18.3	0.046	NA
Diastolic blood pressure (mmHg)		87.7 ± 6.1	78.1 ± 11.7	82.9 ± 10.4	0.029	NA
b: Cardiovascular risk factors at follow-up: biochemical results
Lipids
Total cholesterol (mmol/L)		4.81 ± 0.68	5.06 ± 1.22	4.94 ± 0.97	0.55		NA
HDL (mmol/L)		1.48 ± 0.39	1.55 ± 0.38	1.52 ± 0.38	0.67		NA
Triglycerides (mmol/L)		1.25 ± 0.50	1.17 ± 0.80	1.21 ± 0.65	0.80		NA
Glucose metabolism							NA
Fasting blood glucose (mmol/L)		5.36 ± 0.44	5.29 ± 0.43	5.33 ± 0.43	0.70		NA
Insulin (pmol/L)		67.82 ± 24.63	82.27 ± 83.11	75.05 ± 11.92	0.59		NA
HOMA score		16.36 ± 6.75	20.35 ± 22.3	18.35 ± 16.21	0.58		NA
Inflammation							NA
hs-CRP (mg/L)		1.21 [0.51–3.83]	0.95 [0.46–2.03]	0.97 [0.50–2.30]	0.56		NA
Renal function							NA
Creatinine (µmol/L)		75.82 ± 15.73	75.36 ± 7.13	75.59 ± 60.27	0.93		NA
eGFR (mL/min/1.73 m)		88.0 [70.0–90.0]	86.0 [76.0–89.0]	86.5 [75.5–90.0]	0.65		NA
Ureum (mmol/L)		4.91 ± 1.13	5.15 ± 1.19	5.03 ± 1.14	0.64		NA
Albumin:creatinine ratio		1.06 [0.66–4.80]	0.37 [0.27–0.56]	0.58 [0.32–1.13]	0.008		NA
3c: Cardiovascular risk factors at follow-up: clinical diagnoses
Hypertension	7 (63.6)		3 (27.3)	10 (45.5)	0.09		2.1 (0.9–5.2)
Hypercholesterolemia	3 (27.3)		5 (45.5)	8 (36.4)	0.66		0.7 (0.2–1.8)
Body mass index > 25 (kg/m^2)	6 (54.5)		5 (45.5)	11 (50)	0.67		1.2 (0.5–2.8)
Diabetes mellitus	0 (0)		0 (0)	0 (0)	–		NA
Increased cardiovascular risk	8 (72.7)		8 (72.7)	16 (72.7)	1.00		1.0 (0.4–2.6)
Metabolic syndrome	4 (36.4)		3 (27.3)	7 (31.8)	1.00		1.2 (0.5–2.8)

Data are depicted as mean ± SD, numbers (%) or median [IQR]. HD hypertensive disorders of pregnancy; RR, relative risk; CI, confidence interval; NA, not applicable; hs-CRP, high-sensitivity c-reactive protein; eGFR, estimated glomerular filtration rate. Increased cardiovascular risk is defined as presence of either of hypertension, hypercholesterolemia, BMI > 25, or DM.

Biochemical results showed a difference in the albumin creatinine ratio (Table 3b).

The composite outcomes increased cardiovascular risk, as well as metabolic syndrome was found to be equally high in both groups (Table 3c).

Discussion

In this follow-up study, almost three-quarter of women with inheritable thrombophilia and either single or recurrent HD had an increased cardiovascular risk, 8–19 years after early-onset HD. Systolic blood pressure, diastolic blood pressure, and albumin creatinine ratio were higher in women with recurrent HD compared with women with single HD. Overall, nearly half of the women had hypertension, a third metabolic syndrome, and a third hypercholesterolemia.

The high prevalence of hypertension and hypercholesterolemia after HD in these women with inheritable thrombophilia is in line with other studies (8,26). The prevalence of metabolic syndrome after HD is higher in the present study compared with other studies where they describe prevalence between 14% and 25% (8,27). The difference of our study compared with the aforementioned studies is that women who participated in our study all had inheritable thrombophilia, were on average 10 years older at follow-up, and were examined after a longer time interval since pregnancy: the other studies examined women 0.5–2.5 years after pregnancy (8,26,27). Moreover, two of three studies did not include early-onset HD but late-onset HD only (26,27). The other study included women with either early-onset HD, late-onset HD, or pregnancy-induced hypertension (8). These three studies excluded patients with chronic hypertension prior to pregnancy, whereas 31.8% of the population in the present study had chronic hypertension at start of the FRUIT-RCT pregnancy. A fourth study was more comparable to our study, in which they examined women with the same history of early-onset HD as well as 10 years after pregnancy (28). They found the same prevalence of hypertension (43.1%) and hypercholesterolemia (38.6%), however, a lower prevalence of metabolic syndrome (18.0%) compared with our study (45.5%, 36.4%, and 31.8%, respectively). Difference to our study is their age at follow-up; on average about 5 years younger compared with our population (28). Since we found equal prevalence of hypertension and hypercholesterolemia and a higher prevalence of metabolic syndrome compared with women with unknown thrombophilia status (8,26–28), we could not support the finding that thrombophilia might mediate in lowering cardiovascular risk factors compared with women without thrombophilia (22). Moreover, the prevalences in the general Dutch female population in the age range of 40–49 years for hypertension (15%), hypercholesterolemia (17%), and metabolic syndrome (11%) are much lower compared with this study (29).

The differences in systolic blood pressure, diastolic blood pressure, and albumin creatinine ratio in women with recurrent HD are in line with the theory emerging of the results of retrospective studies, suggesting that women with a history of recurrent HD have a higher risk to develop CVD later in life compared with women with a history of single HD (9,10). A systematic review based on the same retrospective studies states that recurrent preeclampsia is associated with a sevenfold increased risk of later hypertension compared with a single episode (2). We could not demonstrate a significant increase in the diagnosis of hypertension in women with recurrent HD compared with women with single HD, but did demonstrate an increased systolic and diastolic blood pressure. Besides a higher albumin creatinine ratio in women with recurrent HD, none of the other parameters differed between both groups. A possible explanation is that women with a history of early-onset HD already have such a high-risk profile that recurrence of the disease does not elicit a further increase. The previously mentioned studies had a retrospective setup, which makes the diagnosis of HD more uncertain compared with our study with a prospective setup (9,10). Second, the endpoint of the study of Wikström et al. (10) was ischemic heart disease, whereas we report on cardiovascular risk factors.

Our results show a high prevalence of hypertension, metabolic syndrome, and hypercholesterolemia in women with inheritable thrombophilia which is comparable with other studies examining women with a history of HD in whom the thrombophilia status is unknown. The results of our study suggest that presence of inheritable thrombophilia does not play a role in a further increase of the development of cardiovascular risk factors. This could be explained by the high risk due to the history of early-onset HD. A next step should be an individualized patient data meta-analysis to examine the influence of thrombophilia on cardiovascular risk factors in women with a history of early-onset HD (8,28).

Strength of this study is that to our knowledge this is the first study which examined cardiovascular risk factors in women with inheritable thrombophilia and a history of either single or recurrent HD in a prospective setting. Limitation of this study is the small study population. Larger prospective studies are needed to examine if women with a history of recurrent HD have more cardiovascular risk factors compared with women with a history of single HD. In the composite outcome, increased cardiovascular risk, the definition of elevated BMI is arbitrarily chosen based on the demonstrated relation between a BMI >25 and CVD mortality (30).

Conclusion

In this follow-up study of the FRUIT-RCT, nearly three quarters of the women had an increased cardiovascular risk, irrespective of single or recurrent HD. Women with recurrent HD did have higher systolic and diastolic blood pressure and albumin creatinine ratio. This is similar to other studies examining cardiovascular risk factors in women with a history of HD without knowledge about their thrombophilia status.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Acknowledgments

We thank all women who participated in this study. We also thank M.G. van Pampus (University Medical Center Groningen, Groningen, the Netherlands), K.M. Sollie-Szarynska (University Medical Center Groningen), J.W. Ganzevoort (Academic Medical Centre, Amsterdam, the Netherlands), J. van Eyck (Isala Hospital, Zwolle, the Netherlands), R. Poeschmann (Medical Spectrum Twente, Enschede, the Netherlands), O. van der Heijden (Radboud University Medical Center, Nijmegen, the Netherlands), A.T. Lely (University Medical Center, Utrecht, the Netherlands), J.M. Middeldorp (Leiden University Medical Center, Leiden, the Netherlands), C. Kolster-Bijdevaate (Leiden University Medical Center), W. Visser (Erasmus Medical Center, Rotterdam, the Netherlands), G. Oei (Maxima Medical Center, Veldhoven, the Netherlands), F. Rosier-van Dunne (Tergooi Hospital, Hilversum, the Netherlands), G. Zeeman (Tjongerschans Hospital, Heerenveen, the Netherlands), J. Bais (Medical Center Alkmaar, Alkmaar, the Netherlands), I.M. Evers (Meander Medical Center, Amersfoort, the Netherlands), M. ten Dam (Canisius Wilhelmina Ziekenhuis, Druten, the Netherlands), B. Doekhie (BovenIJ Hospital, Amsterdam, the Netherlands), and M. Hemelaar (Westfriesgasthuis Hospital, Hoorn, the Netherlands) for their help in recruiting participants and facilitating a room in their hospital where participants could be examined. We thank Prof. Dr. C.J.M. de Groot, gynecologist-perinatologist at the VU University Medical Center, for her feedback on the manuscript. We thank A. Arduç for his help during the visits of all participants in physical examination and blood sample collection.