Prepregnancy cardiometabolic and inflammatory risk factors and subsequent risk of hypertensive disorders of pregnancy




Objective


The purpose of this study was to examine prepregnancy cardiometabolic and inflammatory markers and the subsequent risk of hypertensive disorders of pregnancy.


Study Design


This was a retrospective cohort study of 3380 women who took part in a comprehensive multiphasic health checkup (MHC) examination between 1984 and 1996 and who subsequently delivered at Kaiser Permanente Northern California.


Results


Two hundred five women were diagnosed with a hypertensive disorder of pregnancy. Prepregnancy measurements of overweight/obesity (body mass index, ≥25.0 kg/m 2 ), prehypertension, and inflammation (leukocytes, ≥7.2 10 3 /μL) were associated independently with hypertensive disorder of pregnancy risk (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2–2.3; OR, 2.1; 95% CI, 1.5–2.8; and OR, 1.6; 95% CI, 1.1–2.3, respectively). Being overweight/obese and having prehypertension before pregnancy was associated with a 3.5-fold increased risk of hypertensive disorder of pregnancy compared with women with normal levels of both risk factors.


Conclusion


A prepregnancy cardiometabolic and inflammation risk profile may help clinicians identify high-risk women to target for early intervention or management of hypertensive disorder of pregnancy.


Preeclampsia is a multisystem complication that is characterized by systemic maternal inflammation, endothelial dysfunction, and insulin resistance in pregnancy; it is diagnosed by new-onset hypertension and proteinuria after 20 weeks gestation. Preeclampsia and other hypertensive disorders of pregnancy are the leading contributors to perinatal morbidity and death worldwide. The second half of normal pregnancy is characterized by a progressive state of insulin resistance, hyperinsulinemia, hyperlipidemia, and increasing inflammatory markers, and it has been suggested that these responses may be exaggerated in women who experience hypertensive disorder of pregnancy.


Women with a history of hypertensive disorder of pregnancy (including preeclampsia) appear to have a >2-fold increased risk of cardiovascular and metabolic diseases later in life. Preeclampsia and cardiovascular disease have several common underlying risk factors that include obesity, insulin resistance, dyslipidemia, endothelial dysfunction, and inflammation. However, it is unclear whether women who experience pregnancy-induced hypertension and/or preeclampsia have altered levels of cardiometabolic and inflammatory markers before pregnancy or whether the conditions arise because of disturbances that are induced by the pregnancy itself. A better understanding of prepregnancy predictors of hypertensive disorders in pregnancy may increase our understanding of the underlying cause and enable the identification of women who are at high risk to target for early intervention or prevention strategies.


We examined the association between prepregnancy cardiometabolic and inflammation risk factors (ie, serum glucose, total cholesterol, blood pressure, body mass index [BMI] and leukocytes) alone or in combination, and subsequent risk of hypertensive disorders of pregnancy with a multiethnic cohort of women who took part in a multiphasic health checkup (MHC) examination from 1984-1996 and had a subsequent pregnancy at Kaiser Permanente Northern California (KPNC).


Materials and Methods


Study population


KPNC is an integrated healthcare delivery system that provides medical care for approximately one-third of the commercially insured population in the San Francisco Bay Area. KPNC subscribers are representative of the region.


The source population consisted of female KPNC members who attended a voluntary comprehensive MHC at the Kaiser Permanente Oakland Medical Center from 1984-1996. KPNC members at this facility were invited to participate on enrollment. The MHC consisted of a clinic visit for the completion of questionnaires and clinical measurements of blood pressure, weight, height, and serum random glucose, cholesterol, and leukocytes levels, with the goal of providing health maintenance through early diagnosis. Measurements of serum glucose that was assessed by the hexokinase method and total cholesterol that was assessed with an analyzer (Kodak Ektachem DT60 Chemistry analyzer; Eastman Kodak Co, Rochester, NY) were performed by the regional laboratory of KPNC. This laboratory participates in the College of American Pathologists’ accreditation and monitoring program. BMI was calculated by standard methods from height that was measured with a stadiometer and weight that was measured with a balance beam scale. Information on age, sex, race/ethnicity, education level, cigarette smoking, alcohol consumption, coffee consumption, and the use of medications was collected with self-administered questionnaires, which have been previously described.


Among women of reproductive age (18-45 years old) who participated in the MHC from 1985-1996, we identified all women who subsequently delivered up to 2009 by searching the KPNC Pregnancy Glucose Tolerance Registry. This is an active surveillance registry that annually identifies among KPNC members all pregnancies that result in a livebirth or stillbirth. We selected the first pregnancy and latest serum with complete data for pregravid measurements of interest. When data from >1 MHC visit were available, data from the visit before, but closest to, the index pregnancy were used in the analysis. We excluded women from the study cohort who reported a history of hypertension at the time of the MHC visit (n = 237) and who had a diagnosis of hypertension after the MHC visit but before the index pregnancy (n = 202) and an additional 95 women who had a pregnancy that was complicated by essential hypertension ( International Classification of Diseases , 9th edition [ICD-9] code 642.0), hypertension because of a chronic underlying condition (ICD-9 codes 642.1-642.2), preeclampsia or eclampsia superimposed on preexisting hypertension (ICD-9 code 642.7), and unspecified hypertension of pregnancy (ICD-9 code 642.9).


Ascertainment of pregnancy hypertensive disorders


We identified a total of 205 women with a hypertensive disorder of pregnancy. Of these, 80 women had gestational hypertension according to ICD-9 code 642.3; 106 women had preeclampsia or eclampsia according to ICD-9 codes 642.4-642.7, and 19 women had codes indicative of both. To assess the accuracy of the electronic diagnosis codes, we had medical chart review data on a subset of 171 women from the study cohort. Our chart review included 11 women with a diagnosis code for gestational hypertension (ICD-9 code 642.3) and 16 women with a diagnosis code for preeclampsia (ICD-9 code 642.4 or 642.5); the agreement between the electronic diagnosis and the chart review data was 93.8% for preeclampsia and 90.9% for gestational hypertension. The women who did not meet the criteria for gestational hypertension or preeclampsia had 2 borderline elevated blood pressures with systolic blood pressures of ≥130 mm Hg. Of the 144 women who we identified as not having a hypertensive disorder of pregnancy, we found that 4 women (2.8%) had preeclampsia or gestational hypertension according to medical chart review.


Prepregnancy cardiometabolic and inflammation risk factors


Serum glucose, total cholesterol, leukocyte count, and diastolic and systolic blood pressure were first categorized into tertiles. In addition, each woman’s condition was categorized according to clinically relevant adverse levels of cardiometabolic risk factors: overweight/obesity (a BMI of ≥25 kg/m 2 according to the World Health Organization classification of overweight/obesity ), prehypertension (systolic blood pressure of >120 mm Hg and/or diastolic blood pressure of at least 80 mm Hg for diastolic according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines ), hypercholesterolemia (a serum total cholesterol level of ≥200 mg/dL, which, according to the National Cholesterol Education Program, is above the desirable range), and mild hyperglycemia (a prepregnancy random serum glucose level of ≥100 mg/dL but <200 mg/dL). Fifty-three percent of the women had fasting hyperglycemia (at least a 6-hour fast), and 47% of them had a random glucose test. We used the cutoff of 100 mg/dL that is recommended by the American Diabetes Association to define impaired fasting glucose, given that the 100 mg/dL cut point represented the 95th percentile because of the young age of our study population. We would have had a low prevalence of the risk factor if more stringent criteria were applied. Mild subclinical inflammation was considered to be a leukocyte count in the highest tertile because there is no standard definition based on leukocyte count.


Statistics


Unconditional logistic regression was used to first obtain odds ratios (ORs) as estimates of the relative risk of hypertensive disorder of pregnancy in relation to each individual cardiometabolic and inflammation risk factor separately. We then examined a multivariable model that contained all the clinically relevant cardiometabolic and inflammation risk factors defined earlier to identify independent cardiometabolic predictors of hypertensive disorder of pregnancy. We also looked at associations between an increasing number of prepregnancy risk factors and hypertensive disorder of pregnancy. To assess confounding, we entered covariates into logistic regression models 1 at a time and then compared the adjusted and unadjusted ORs. The final adjusted logistic regression models included covariates that altered unadjusted ORs by at least 10% for at least 1 cardiometabolic or inflammation risk factor. Variables that were evaluated for confounding were race/ethnicity, prepregnancy BMI (kilograms per square meter; except for the model with obesity), parity, maternal education in years, alcohol consumption, cigarette smoking, caffeine consumption and first-degree family history of hypertension. Sensitivity analyses were conducted by restricting analysis to women with preeclampsia to determine whether the association varied by severity of disease. Given that we were unable to control for a history of preeclampsia, we conducted a sensitivity analysis to examine cardiometabolic and inflammation risk factors in relation to hypertensive disorder of pregnancy; we restricted the analysis to nulliparous women to assess whether associations were similar among women without a previous hypertensive disorder of pregnancy.


Heterogeneity in associations by time since MHC examination (<3, 3-5, 6-9, 10-13, and ≥14 years) was assessed by inclusion of appropriate cross-product (interaction) terms in regression models. This study was approved by the human subjects committee of the Kaiser Foundation Research Institute.




Results


On average, the MHC examination that assessed prepregnancy risk factors was performed 4.6 years before delivery (SD, ±3.7; range, 1–20 years). Characteristics of the study cohort by increasing number of cardiometabolic and inflammation risk factors at baseline are presented in Table 1 . Women with more risk factors were slightly older, were less likely to be nulliparous, had fewer years of education, and were more likely to be African American or Hispanic, to be a current smoker, and to have a family history of hypertension. Women with more risk factors also had higher levels of BMI, glucose, cholesterol, and systolic and diastolic blood pressure and leukocyte count.



TABLE 1

Characteristics of the cohort a














































































































































































































































































































































































































































Characteristic Cardiometabolic risk factors b P value Total cohort (n = 3380)
0 (n = 1244) 1 (n = 1266) 2 (n = 647) ≥3 (n = 223)
Age at multiphasic health checkup examination, y c 27.9 ± 5.4 27.7 ± 5.4 28.2 ± 5.4 28.8 ± 5.3 .014 d 27.9 ± 5.4
Age at delivery, y c 32.7 ± 5.4 32.3 ± 5.2 32.5 ± 5.4 32.6 ± 5.5 .33 d 32.5 ± 5.3
<30 y, n (%) 383 (30.8) 420 (33.2) 208 (32.1) 76 (34.1) .27 e 1087 (32.2)
30-34 y, n (%) 413 (33.2) 439 (34.7) 234 (36.2) 73 (32.7) 1159 (34.3)
35-39 y, n (%) 335 (26.9) 319 (25.2) 151 (23.3) 50 (22.4) 855 (25.3)
≥40 y, n (%) 113 (9.1) 88 (7.0) 54 (8.3) 24 (10.8) 279 (8.3)
Time between examination and delivery, y c 4.8 ± 3.8 4.7 ± 3.7 4.2 ± 3.3 3.8 ± 3.1 < .0001 d 4.6 ± 3.7
Education, n (%) < .0001 e
≤12 y 275 (22.1) 349 (27.6) 211 (23.6) 81 (36.3) 916 (27.1)
13-15 y 428 (34.4) 462 (36.5) 245 (37.9) 77 (34.5) 1212 (35.9)
≥16 y 495 (39.8) 416 (32.9) 167 (25.8) 56 (25.1) 1134 (33.6)
Unknown 46 (3.7) 39 (3.1) 24 (3.7) 9 (4.0) 118 (3.5)
Race/ethnicity, n (%) < .0001 e
Non-Hispanic white 477 (38.3) 406 (32.1) 166 (25.7) 68 (30.5) 1117 (33.0)
African American 379 (30.5) 452 (35.7) 265 (41.0) 78 (35.0) 1174 (34.7)
Asian 244 (19.6) 227 (17.9) 100 (15.5) 37 (16.6) 608 (18.0)
Hispanic 108 (8.7) 143 (11.3) 81 (12.5) 33 (14.8) 365 (10.8)
Other 36 (2.9) 38 (3.0) 35 (5.4) 7 (3.1) 116 (3.4)
Hypertension complicating pregnancy, n (%) < .0001 e
Pregnancy-induced hypertension f 25 (2.0) 24 (1.9) 15 (2.3) 16 (7.2) 80 (2.4)
Preeclampsia g or eclampsia h 27 (2.2) 38 (3.0) 30 (4.6) 11 (4.9) 106 (3.1)
Pregnancy-induced hypertension and preeclampsia/eclampsia 5 (0.4) 7 (0.6) 5 (0.8) 2 (0.9) 19 (0.6)
Neither pregnancy-induced hypertension nor preeclampsia/eclampsia 1187 (95.4) 1197 (94.5) 597 (92.3) 194 (87.0) 3175 (93.9)
Parity, n (%) .0003 e
0 525 (42.2) 531 (41.9) 219 (33.8) 90 (40.4) 1365 (40.4)
1 199 (16.0) 218 (17.2) 129 (19.9) 43 (19.3) 589 (17.4)
≥2 125 (10.0) 133 (10.5) 102 (15.8) 33 (14.8) 393 (11.7)
Unknown 395 (31.8) 384 (30.3) 197 (30.4) 57 (25.6) 1033 (30.6)
Alcohol use, n (%) .54 e
None 245 (19.7) 235 (18.6) 116 (17.9) 50 (22.4) 646 (19.1)
Occasional or more drinks/d 765 (61.5) 806 (63.7) 414 (64.0) 127 (56.9) 2112 (62.4)
Unknown 234 (18.8) 225 (17.8) 117 (18.1) 46 (20.6) 622 (18.4)
Smoking, n (%) .0005 e
Never 715 (57.5) 686 (54.2) 330 (51.0) 108 (48.4) 1839 (54.4)
Former 183 (14.7) 197 (15.6) 89 (13.8) 27 (12.1) 496 (14.7)
Current 132 (10.6) 174 (13.7) 114 (17.6) 43 (19.3) 463 (13.7)
Unknown 214 (17.2) 209 (16.5) 114 (17.6) 45 (20.2) 582 (17.2)
Coffee consumption, n (%) .89 e
None 254 (20.4) 236 (18.6) 116 (17.9) 43 (19.3) 649 (19.2)
Occasional 343 (27.6) 383 (30.3) 199 (30.8) 68 (30.5) 993 (29.4)
≥1 cup/d 381 (30.6) 381 (30.1) 193 (29.8) 68 (30.5) 1023 (30.3)
Unknown 266 (21.4) 266 (21.0) 139 (21.5) 44 (19.7) 715 (21.2)
Family history of 1st-degree hypertension, n (%) .006 e
Yes 367 (29.5) 407 (32.1) 231 (35.7) 91 (40.8) 1096 (32.4)
No 517 (41.6) 473 (37.4) 236 (36.5) 77 (34.5) 1303 (38.6)
Unknown 360 (28.9) 386 (30.5) 180 (27.8) 55 (24.7) 981 (29.0)
Body mass index, kg/m 2 c 21.1 ± 2.0 23.3 ± 4.1 26.5 ± 5.6 29.9 ± 5.9 < .0001 d 23.6 ± 4.8
Serum glucose, mg/dL c 83.4 ± 7.3 84.1 ± 8.5 86.4 ± 14 93.1 ± 22.2 < .0001 d 84.9 ± 11.1
Serum cholesterol, mg/dL c 162.2 ± 21.4 175.5 ± 32.9 194.4 ± 36.4 213 ± 38.7 < .0001 d 176.7 ± 33.9
Systolic blood pressure, mm Hg c 108.7 ± 10.7 112.8 ± 12.8 118.6 ± 14.2 126.4 ± 15.3 < .0001 d 113.3 ± 13.5
Diastolic blood pressure, mm Hg c 65.4 ± 7.5 67.3 ± 8.5 70.3 ± 9.3 74 ± 10.9 < .0001 d 67.6 ± 8.8
White blood cell count, 10 3 /mm 3 c 5.5 ± 1.0 6.9 ± 2 7.6 ± 1.9 8.4 ± 1.7 < .0001 d 6.6 ± 1.9

Hedderson. Cardiometabolic and inflammatory risk factors and hypertensive disorder of pregnancy. Am J Obstet Gynecol 2012.

a Anyone with past medical history of hypertension at time of serum collection was excluded;


b Cardiometabolic risk factors include (1) serum glucose ≥100 mg/dL; (2) serum cholesterol ≥200 mg/dL; (3) systolic blood pressure ≥135 mm Hg or diastolic blood pressure ≥85 mm Hg; (4) body mass index ≥25 kg/m 2 ; (5) white blood cell count ≥7.2 × 10 3 per mm 3 (highest tertile for cohort);


c Data are given as mean ± SD;


d F-test from analysis of variance;


e χ 2 test;


f Pregnancy-induced hypertension (ICD-9 codes 643.3x);


g Preeclampsia (ICD-9 codes 642.4x, 642.5x);


h Eclampsia (ICD-9 code 642.6x).



Table 2 presents data from separate logistic regression models for each individual prepregnancy cardiometabolic and inflammation risk factor. After adjustment for year of serum, age at delivery, years between serum collection and pregnancy, race/ethnicity, BMI, maternal education, family history of hypertension, parity, smoking status, and alcohol and coffee intake during the year before the examination (compared with women in the first tertile), women in the third tertile had a risk of hypertensive disorder of pregnancy that was 2.6-fold higher for diastolic blood pressure and 2.7-fold higher for systolic blood pressure (OR, 2.6; 95% confidence interval [CI], 1.8–12.6 and OR, 2.7; 95% CI, 1.7–4.0, respectively). Women in the highest tertile of prepregnancy leukocyte count were 50% more likely to experience a hypertensive disorder in pregnancy after multivariable adjustment (OR, 1.5; 95% CI, 1.0–2.3). Compared with women who were normal weight at the baseline examination, women who were overweight or obese were approximately 2 times as likely to experience a hypertensive disorder during pregnancy (OR, 1.8; 95% CI, 1.3–2.6 and OR, 2.2; 95% CI, 1.4–3.4, respectively). Prepregnancy glucose and cholesterol levels were not associated with subsequent risk of hypertensive disorders of pregnancy.



TABLE 2

Pregravid cardiometabolic risk factors and hypertensive disorders of pregnancy








































































































































































































































































Pregravid risk factor Cases, n (%) a Comparison group, n (%) b Odds ratio (95% CI)
Minimally adjusted c Multivariable adjusted d
Separate logistic regression models
Random glucose, mg/dL
<81 71 (34.6) 982 (30.9) 1.0 1.0
81-86 63 (30.7) 1000 (31.5) 1.0 (0.7–1.4) 1.0 (0.7–1.4)
≥87 71 (34.6) 1193 (37.6) 1.0 (0.7–1.4) 0.9 (0.6–1.3)
Total cholesterol, mg/dL
<160 60 (29.3) 1040 (32.8) 1.0 1.0
160-187 78 (38.0) 1064 (33.5) 1.3 (0.9–1.9) 1.2 (0.8–1.7)
≥188 67 (32.7) 1071 (33.7) 1.1 (0.8–1.7) 1.0 (0.7–1.5)
Diastolic blood pressure, mm Hg
<63 40 (19.5) 1011 (31.8) 1.0 1.0
63-70 55 (26.8) 1118 (35.2) 1.3 (0.9–2.0) 1.3 (0.8–2.0)
≥71 110 (53.7) 1046 (32.9) 2.9 (2.0–4.3) 2.6 (1.8–3.9)
Systolic blood pressure, mm Hg
<107 38 (18.5) 1071 (33.7) 1.0 1.0
107-117 65 (31.7) 1039 (32.7) 1.9 (1.2–2.8) 1.7 (1.1–2.6)
≥118 102 (49.8) 1065 (33.5) 3.2 (2.1–4.8) 2.7 (1.7–4.0)
BMI, kg/m 2
<25.0 124 (60.5) 2348 (74.0) 1.0 1.0
25.0-29.9 50 (24.4) 536 (16.9) 1.8 (1.3–2.6) 1.8 (1.3–2.6)
≥30.0 31 (15.1) 291 (9.2) 2.1 (1.3–3.3) 2.2 (1.4–3.4)
White blood cell count, 10 3 /μL
<5.6 49 (23.9) 983 (31.0) 1.0 1.0
5.6-7.1 70 (34.1) 1127 (35.5) 1.2 (0.8–1.8) 1.2 (0.8–1.7)
≥7.2 86 (42.0) 1065 (33.5) 1.7 (1.2–2.4) 1.5 (1.0–2.3)
Single multivariate model
Hyperglycemia: random glucose, mg/dL
<100 193 (94.1) 3306 (95.6) 1.0 1.0
≥100 12 (5.9) 139 (4.4) 1.3 (0.7–2.4) 1.3 (0.7–2.4)
Hypercholesterolemia (total cholesterol mg/dL)
<200 159 (77.6) 2459 (77.4) 1.0 1.0
≥ 200 46 (22.4) 716 (22.6) 0.9 (0.6–1.3) 0.9 (0.6–1.3)
Blood pressure
Normal e 98 (47.8) 2123 (66.9) 1.0 1.0
Pre-/hypertension f 107 (52.2) 1052 (33.1) 2.1 (1.6–2.9) 2.1 (1.5–2.8)
Overweight/obese: BMI, kg/m 2
<25 124 (60.5) 2348 (74.0) 1.0 1.0
≥25 81 (39.5) 827 (26.0) 1.6 (1.2–2.2) 1.6 (1.2–2.3)
Mild inflammation: tertile of white blood cell count, 10 3 /μL
<5.6 49 (23.9) 983 (31.0) 1.0 1.0
5.6-7.1 70 (34.1) 1127 (35.5) 1.2 (0.8–1.8) 1.2 (0.8–1.8)
≥7.2 86 (42.0) 1065 (33.5) 1.5 (1.0–2.2) 1.6 (1.1–2.3)

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May 15, 2017 | Posted by in GYNECOLOGY | Comments Off on Prepregnancy cardiometabolic and inflammatory risk factors and subsequent risk of hypertensive disorders of pregnancy

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