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Association of antepartum blood pressure levels and angiogenic profile among women with chronic hypertension
Pregnancy Hypertension 14 (2018) 110–114
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Association of antepartum blood pressure levels and angiogenic profile among women with chronic hypertension
T
Ruby Minhasa, Danielle Younga, Rabab Naseema, Ariel Muellera,b, Sireesha Chinthalaa, Joana Lopes Perdigaoa, Kiang-Teck J. Yeoc, Siaw Li Chanc, Avery Tungd, Julia Bregand Whitea, ⁎ Sajid Shahuld, Sarosh Ranaa, a
Section of Maternal Fetal Medicine/Department of Obstetrics & Gynecology, University of Chicago, Chicago, IL, USA Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA c Department of Pathology, University of Chicago, Chicago, IL, USA d Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA b
A B S T R A C T
Background: Angiogenic factors have been implicated in the pathogenesis of preeclampsia. This pilot study explored the association between antenatal blood pressure levels and angiogenic biomarkers (sFlt1 and PlGF) among women with chronic hypertension (cHTN). Methods: Blood samples were collected from women with cHTN (with/without superimposed preeclampsia) within 96 h prior to delivery. Subjects were stratified by mean outpatient BP as controlled (cBP < 140/90) or uncontrolled (uBP ≥ 140/90). Descriptive statistics were generated and assessed as appropriate. Logistic regression was employed to assess for adverse pregnancy outcomes between groups. Results: Data from seventy-eight women were analyzed, of which 58 (74.4%) were African American. Fifty-six (71.8%) had cBP and 22 (28.2%) had uBP. Use of antepartum outpatient antihypertensive medications was more frequent in patients with uBP (46.4% vs. 13.6%, p = 0.01). Compared to women with cBP, women with uBP had higher levels of pre-delivery sFlt1 and sFlt1/PlGF ratio (sFlt: 4218.5 vs. 3056.0 pg/ml, p = 0.046; sFlt/PlGF: 62.5 vs. 25.0, p = 0.04). Additionally, more uBP patients had superimposed preeclampsia with severe features (54.6% vs. 25.0%; p = 0.01) and preterm delivery (defined as a gestational age < 35 weeks (40.9% vs. 10.7%; p = 0.002)) than cBP patients. In the multivariable model, women with uBP had greater odds of preterm delivery (OR 6.78; p = 0.01), superimposed preeclampsia (OR 3.20; p = 0.03) and preeclampsia with severe features (OR 3.27; p = 0.04) than women with cBP. Conclusion: In women with cHTN, elevated antepartum BP is associated with worsened outcomes and may be associated with abnormal angiogenic profile at delivery. Larger studies are needed to confirm these findings.
1. Introduction During pregnancy, chronic hypertension (cHTN) is defined as having been present and observable prior to pregnancy or diagnosed before the twentieth week of gestation [1]. The prevalence of cHTN is 5% in all pregnant women with a higher prevalence among high risk groups such as obese and African American women [2]. cHTN is associated with higher maternal and fetal morbidity and mortality, including superimposed preeclampsia, abruption placentae, and intrauterine growth restriction [3]. The management of hypertension during pregnancy remains controversial. The 2015 CHIPs trial found no effect of tight control of blood pressure on the risk of pregnancy loss, high-level neonatal care, or overall maternal complications, although less-tight control was associated with a higher frequency of severe maternal hypertension [4]. In addition, the American College of Obstetrics and Gynecology (ACOG) recommends antihypertensive therapy only for women with severe, persistent chronic
⁎
hypertension (systolic blood pressure [BP] ≥160 mmHg or diastolic BP > 105 mmHg) [5]. However, a large 2017 retrospective study observed that blood pressures ≥140/90 mm Hg were associated with a greater risk of maternal complications and adverse fetal outcomes regardless of the number of medications used to control the blood pressures. This study concluded that blood pressure control, rather than the number of agents used to achieve that control, was most associated with pregnancy outcomes [6]. A randomized trial evaluating the benefits and harms of pharmacologic treatment of mild cHTN in pregnancy is currently underway in the United States (NCT02299414). Angiogenic factors have been implicated in the pathogenesis of preeclampsia and its associated outcomes [7–11]. Existing data find abnormalities in angiogenic factors among women with cHTN that develop preeclampsia [12–14]. However, few studies have evaluated the association of blood pressure control during pregnancy on levels of angiogenic factors at the time of delivery.
Corresponding author. E-mail address: [email protected] (S. Rana).
https://doi.org/10.1016/j.preghy.2018.09.003 Received 7 April 2018; Received in revised form 25 July 2018; Accepted 4 September 2018 Available online 05 September 2018 2210-7789/ © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
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2.3. Automated assays
We hypothesized that women with uncontrolled blood pressures would have elevated anti-angiogenic factor levels and be more likely to have poor maternal and fetal outcomes. To test our hypothesis, we measured the relationship between antepartum blood pressures during prenancy and angiogenic factor levels at the time of delivery in pregnant women with cHTN. We also wanted to confirm the relationship between blood pressure control and adverse outcome that has been previously reported.
All consenting patients had a blood sample collected within 96 h prior to delivery. Blood samples were centrifuged at 3000 RPM for 10 min at 4 degrees Celsius, and then plasma was aliquoted and frozen at -800 degrees until the time of analysis. All de-identified samples were thawed once for analysis. Assays for sFlt1 and PlGF were performed on BRAHMS KRYPTOR Compact Plus (ThermoFisher Scientific) automated immunoassay platform using automated kits as previously described, at the clinical chemistry laboratory at the University of Chicago. The detectable ranges for sFlt1 and PlGF are 90 to 69,080 and 11 to 7000 pg/ mL, respectively [15]. The coefficient of variation for both assays were < 5%. All measurements were performed once in batches after delivery on all patients so none of the treating physicians were aware of the assay results. The technician performing the analysis was blinded to the final patient diagnosis.
2. Methods 2.1. Patient population We performed a retrospective cohort analysis among subjects who consented to participate in a prospective ongoing observational study, Angiogenic Dysfunction Of Pregnancy and Transthoracic echocardiogram (ADOPTe). Institutional Review Board approval was obtained from the University of Chicago Biological Sciences Division (IRB# 140977). Subjects in ADOPTe are enrolled upon admission for delivery to the University of Chicago Family Birth Center. This study involved a subset of patients with chronic hypertension (cHTN) who received prenatal care and delivered at the University of Chicago between January 2015 and March 2017. The primary exposure was blood pressure during pregnancy. The criterion for outpatient treatment was per individual physicians based on their practice and American College of Obstetricians and Gynecologists (ACOG) recommendations [5] and varied by provider preference and experience. All blood pressures documented in a patient's chart for each prenatal visit were abstracted from the medical record for analysis. The average of all of these outpatient blood pressure values was then calculated. The diagnosis of cHTN was abstracted by the research staff and confirmed by two authors (JLP and SR). All measurements of BP's were part of routine clinical care. Members of the study team abstracted maternal data from the medical record from electronic medical records and entered into a database for further analysis. Baseline data collection included demographic data (age, pre-pregnancy height and weight, race/ethnicity, parity, history of preterm birth or pre-eclampsia and maternal comorbidities). All systolic and diastolic blood pressure readings during pregnancy were obtained at each outpatient prenatal visit. Outcome data included mode of delivery, gestational age at delivery, indication for delivery, highest blood pressures during admission, diagnosis of a hypertensive disorder and maternal complications. Neonatal outcome data included birth weight and neonatal intensive care unit (NICU) admission and was abstracted from both the maternal and fetal chart to ensure concordance.
2.4. Statistical analysis Based on prior studies stratifying antepartum blood pressures [6] we did a priori stratified analyses by the average antepartum blood pressure of < 140/90 mmHg (controlled) or ≥140/90 mm Hg (uncontrolled). Uncontrolled BPs occurred either in patients not taking blood pressure medications or those with BP's exceeding the 140/90 threshold despite treatment with oral antihypertensive medications. All blood pressures from all of the prenatal visits were abstracted from the medical record. The average of all recorded blood pressures was used in the analysis. The primary maternal outcome was difference in levels of angiogenic factors at delivery. Other outcomes included superimposed preeclampsia, preeclampsia with severe features, preterm delivery (< 35 weeks), cesarean delivery, antepartum hospitalizations to rule out superimposed preeclampsia and small for gestational age. Trained members of the study team abstracted maternal data from the medical record. All data is first collected on a standardized data form before being entered into an electronic database (REDCap) for further analysis. Descriptive statistics were generated and reported as mean ± standard deviation, median (interquartile range) or frequencies and proportions, depending on type and distribution. Normality was assessed with the Shapiro-Wilk test. Differences between groups were assessed with a t-test, Wilcoxon rank sum, chi-square, or Fisher’s Exact test, as appropriate. Logistic regression was used to assess differences in outcome after controlling for pre-pregnancy body mass index, age and race. Odds ratios (OR) and 95% confidence intervals (CI) are presented. All two-sided p-values < 0.05 were considered significant. SAS 9.4 (SAS Institute Inc., Cary, NC) was used for all analyses. 3. Results 3.1. Clinical demographics
2.2. Diagnosis of preeclampsia Data from 78 patients with chronic hypertension was included in this analysis. The majority of our study population identified as African American (74.4%). A total of 719 outpatient blood pressures were recorded for all patients, of which only 3.2% were documented within seven days of delivery and exceeded a blood pressure of 140/90. Averaging these values resulted in fifty-six (71.8%) patients having an average prenatal blood pressures < 140/90 (cBP) and 22 (28.2%) had average prenatal blood pressures ≥140/90 (uBP). Hypertensive agent use was more frequent in patients with uBP (46.4% vs. 13.6%, p = 0.01) and more patients in the uBP were using multiple agents (uBP 31.8% vs. cBP 12.5%; p = 0.01). Race, ethnicity, mean age, median pre-pregnancy body mass index, smoking status, substance abuse history, obstetric history, and aspirin use was not statistically different between groups (Table 1). As expected, when compared to women with cHTN alone, women with superimposed preeclampsia had higher sFlt1
Chronic hypertension was defined using the ACOG definition of elevated blood pressures (≥ 140 SBP or 90 DBP) prior to 20 weeks gestation. Superimposed preeclampsia was defined by the new onset of proteinuria (urine protein creatinine ratio of ≥0.3 or a 24 h urine protein of ≥ 300 mg) or significant end-organ dysfunction including, 1) rise in liver enzyme activity to twice the upper limit of normal, aspartate aminotransferase (AST) ≥74 U/L or alanine transaminase (ALT) ≥70 U/L), 2) acute renal insufficiency (creatinine ≥ 1.1 mg/dL), 3) right upper quadrant pain, severe headaches, pulmonary congestion or edema, 4) a decrease in platelet levels (< 100,000 /mm3) after 20 weeks of gestation in a woman with chronic/preexisting hypertension. Preeclampsia with severe features was defined as ACOG [1] All diagnoses were assigned by the study coordinator based on the above standard definition and confirmed by two authors (JP and SR).
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Table 1 Clinical Characteristics of Patients. Controlled BP < 140/90 N = 56
Uncontrolled BP ≥ 140/90 N = 22
P-Value
Demographics Race White/Caucasian Black/African American Other Ethnicity Hispanic Non-Hispanic Unknown Age (years) Pre-pregnancy Body Mass Index Number of prenatal visits
12 (21.43) 40 (71.43) 4 (7.14)
4 (18.18) 18 (81.82) 0 (0)
2 (3.57) 53 (94.64) 1 (1.79) 32.02 ± 5.75 31.09 (27.29, 41.60) 11.0 (7.0, 12.0)
0 (0) 21 (95.45) 1 (4.55) 32.05 ± 4.41 35.51 (29.19, 41.10) 8.5 (3.0, 11.0)
0.98 0.24 0.07
Risk Factors Never Smoked Substance abuse
41 (73.21) 1 (1.79)
18 (85.71) 1 (4.55)
0.34 0.49
Obstetric History Nulliparous Previous preeclampsia diagnosis
22 (39.29) 12 (21.43)
8 (36.36) 7 (31.82)
0.81 0.34
26 (46.43) 23 (41.07) 7 (12.50)
3 (13.64) 12 (54.55) 7 (31.82)
25 (44.64) 6 (10.71) 0 (0) 4 (7.14) 4 (7.14)
14 (63.64) 7 (31.82) 1 (4.55) 4 (18.18) 3 (13.64)
0.13 0.04 0.28 0.21 0.40
19 (33.93) 9 (16.07)
8 (36.36) 3 (13.64)
0.84 1.00
Hypertension Medication Hypertensive Agents No agent Single agent Multiple agent Anti-hypertensive used Labetalol Nifedipine Hydralazine Methyldopa Other Other Medications Aspirin use after 12 weeks EGA Aspirin use before 12 weeks EGA
0.54
0.74
0.01
Data is presented as mean ± standard deviation or n (%) depending on variable type. BP: blood pressure; EGA: estimated gestational age.
did not vary by control of blood pressure group; however there was a trend for higher rates of abruption, NICU admission and higher rates of postpartum admission among women with uBP compared to cBP (Table 3). In both the univariate and multivariable model (adjusted for age, pre-pregnancy body mass index and race), uBP was associated with increased odds for preterm delivery < 35 weeks, superimposed preeclampsia and superimposed preeclampsia with severe features (Table 4).
(6158 vs 2712; p = 0.002) and lower PlGF (63 vs 138; p = 0.003) levels, and a higher sFlt1/PlGF ratio (77 vs 21; p = 0.001). 3.2. Postpartum blood pressure After delivery the median (IQR) systolic blood pressure was 165.5 (154.0, 179.0) for patients with antepartum uBP as compared to 153.0 (140.0, 165.0) for patients with cBP (p = 0.003). Similarly, proportion of patients with severe Postpartum HTN (PP SBP ≥ 160 or DBP ≥ 110) were higher among patients with uBP vs cBP (68.2% vs 38.3%, P = 0.02). Postpartum diastolic blood pressure also appeared higher for participants with uncontrolled blood pressure in the antepartum period, however this was not statistically significant (median 99.0 [94.0, 108] vs 94.0 [88.0, 105.0]; p = 0.05).
4. Discussion In this study of pregnant women with chronic hypertension we found that higher blood pressure during pregnancy is associated with elevated plasma sFlt1 levels at the time of delivery. We also found that uncontrolled blood pressures were associated with adverse maternal outcomes and preterm delivery related to preeclampsia. Consistent with previous studies we found that women with superimposed preeclampsia have an abnormal angiogenic profile compared to patients with uncomplicated chronic hypertension [16]. These findings add to the growing evidence that lower blood pressures during pregnancy may be associated with improved pregnancy outcomes. If validated in other studies, our data suggest that the mechanism for such an outcome benefit may be modulation of angiogenic profile at the time of delivery. Randomized trials aimed at controlling BP's during pregnancy will clarify whether control of BP's is associated with favorable angiogenic profiles. Data from our lab [7,17] and others [18,19], suggest that
3.3. Levels of blood pressure control, angiogenic profile and clinical outcomes Women with uBP had higher levels of sFlt1, and higher sFlt/PlGF ratio compared to those with cBP (both P < 0.05; Table 2). When compared to women with cBP, more women with uBP were diagnosed with superimposed preeclampsia with severe features (54.6% vs 25.0%; p = 0.01) and women with cBP were more likely to remain with diagnosis of cHTN (36.4% vs 67.9%; p = 0.01). Preterm delivery < 35 weeks was more common in women with uBP compared to cBP (40.9% vs. 10.7%; p = 0.002). Women with uBP were admitted to rule out preeclampsia more often than those without cBP (77.3% vs 30.4%; p = 0.0002). Mode of delivery and small for gestational age neonate 112
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Table 2 Maternal and Fetal Outcomes.
*
Controlled BP < 140/90 (N = 56)
Uncontrolled BP ≥ 140/90 (N = 22)
P-Value
Hypertensive diagnosis at delivery cHTN only Superimposed PE without severe features Superimposed PE with severe features Hypertensive indication for preterm delivery* Admission to rule out preeclampsia
38 (67.86) 4 (7.14) 14 (25.00) 6 (10.71) 17 (30.36)
8 (36.36) 2 (9.09) 12 (54.55) 9 (40.91) 17 (77.27)
0.01 1.00 0.01 0.002 0.0002
Mode of delivery Vaginal Cesarean section Small for gestational age (BW < 10th percentile) Abruption NICU admission Postpartum admission within six weeks
26 (46.43) 30 (53.57) 14 (25.00) 0 (0) 24 (42.86) 2 (3.57)
9 (40.91) 13 (59.09) 6 (27.27) 1 (4.55) 14 (63.64) 3 (13.64)
0.66 0.84 0.28 0.10 0.13
Defined as < 35 weeks; BP: blood pressure; cHTN: chronic hypertension; PE: preeclampsia; BW: birthweight; NICU: neonatal intensive care unit.
with chronic hypertension that the incidence of superimposed preeclampsia, severe preeclampsia, preterm delivery (< 35 weeks) and preeclampsia-related hospital admissions were higher with blood pressures above 140/90. (6) We note that although our patients all had chronic hypertension, many were not taking antihypertensive medications, implying that they had a mild disease. Our sample size was too limited for subgroup analysis. In addition, because of the small sample size we are unable to confirm our findings that sFlt1 is elevated in a multivariable model because of overfitting. Larger, randomized trials can provide more insight into the effects of anti-hypertensive therapy on levels of angiogenic factors among women with cHTN. Our study has several limitations. Due to the retrospective nature of the study and small sample size, we are unable to determine whether antihypertensive treatment reduces sFlt1 levels, whether the timing of anti-hypertensive initiation affects sFlt1 levels, and whether the relationship we observe for angiogenic factors such as sFlt1 persists after adjusting for potential confounders. Another limitation is that outpatient data were collected retrospectively and the approach to blood pressure control was not standardized, although all patients were treated according to ACOG guidelines. Our study population was also predominantly African America, which makes our results less generalizable to other patient populations. A considerable strength of our study is that the relationship between level of antepartum blood pressure and plasma angiogenic profiles has not been evaluated before. Although data of blood pressures during pregnancy was collected retrospectively, we only included patients who received prenatal care at the University of Chicago and sFlt1 levels and outcomes were available on all patients. Furthermore, analysis of angiogenic factors was done on an automated platform which is reproducible and accurate.[15] In conclusion, we found a relationship between higher blood pressures during pregnancy and increased plasma levels of antiangiogenic factor sFlt1 at the time of delivery. Given the small sample size and inability to control for potential confounders, this result should be interpreted with caution. Despite this, our data raise the possibility that blood pressure control may limit sFlt1 levels in pregnant women at risk for hypertensive diseases of pregnancy and potentially improve preeclampsia related outcomes. Additional studies should confirm this finding in a larger cohort. Future areas of study need to verify whether the intensity of blood pressure control can modify the angiogenic profile [28], reduce adverse outcomes due to hypertension and whether interventions that may restore angiogenic balance could improve pregnancy outcomes related to preeclampsia.
Table 3 Angiogenic Profile.
sFlt1 (pg/mL) PlGF (pg/mL) sFlt1/PIGF
Controlled BP < 140/90( N = 56)
Uncontrolled BP ≥ 140/90 (N = 22)
P-value
3056.0 (1566.0, 5437.0) 111.0 (60.0, 314.0) 25.0 (6.0, 80.0)
4218.5 (2712.0, 9762.0) 82.0 (47.0, 147.0) 62.5 (21.0, 215.0)
0.046 0.11 0.04
BP: blood pressure; sFlt: Soluble fms-like tyrosine kinase-1; PIGF: placental growth factor.
Table 4 Multivariate Analysis. Uncontrolled BP ≥ 140/90 Odds Ratio (95% Confidence Interval)
P-Value
Univariate Model Preterm delivery (< 35 weeks) 5.77 (1.74, 19.15) Superimposed PE 3.69 (1.31, 10.39) Superimposed PE with severe features 3.60 (1.28, 10.13)
0.004 0.01 0.02
Multivariable Model* Preterm delivery (< 35 weeks) 6.78 (1.72, 26.71) Superimposed PE 3.20 (1.10, 9.34) Superimposed PE with severe features 3.27 (1.09, 9.88)
0.01 0.03 0.04
*
Adjusted for age, race and pre-pregnancy BMI. PE: preeclampsia.
preeclampsia is caused by an angiogenic imbalance and that the antiangiogenic factor sFlt1 plays an important role. Therapeutic interventions currently being investigated for inhibition of sFlt1 include statins [20], small molecules such as ouabain [21], and ligands that bind to sFlt1, such as vascular endothelial growth factor (VEGF) and PlGF [22,23]. Although the etiology of preeclampsia is incompletely understood, the placenta is thought to play an important role. However, some recent evidence suggests that preeclampsia may be a primary cardiovascular disorder [24]. We have recently observed that abnormal cardiac function during second trimester may predate the development of superimposed preeclampsia in pregnant patients with cHTN [25]. In vitro administration of antihypertensive drugs to placental explants do not affect sFlt1 level [26,27], suggesting that the relationship between antihypertensive treatment and sFlt1 levels in preeclampsia may be due to a systemic effect of the drugs on maternal blood pressure and circulation rather than an effect of these drugs on placental biosynthesis and/or sFlt1 secretion. In this study we only measured sFlt1 in the plasma, so we cannot determine whether lower blood pressures leads to reduction of sFlt1 production from placenta or other sources. Our findings are consistent with a 2017 study finding in parturients
Acknowledgements Measurements of sFlt1 and PlGF were done on the BRAHMS KRYPTOR Compact Plus (ThermoFisher Scientific) automated 113
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immunoassay platform using automated kits that were provided in kind by ThermoFisher Scientific. Thermofisher played no part in study design, analysis or manuscript preparation.
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Funding Department of Obstetrics and Gynecology at the University of Chicago. Conflicts of interest S. Rana reports serving as consultant to Roche Diagnostics and Thermo Fisher Scientific. S. Rana also has funding from Roche diagnostics and Siemens for other studies related to use of angiogenic factors in pregnancy. All other authors report no conflict of interest. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.preghy.2018.09.003. References [1] American College of O, Gynecologists, Task Force on Hypertension in P. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy, Obstet. Gynecol. 122 (5) (2013) 1122–1131. [2] U. Magriples, M.H. Boynton, T.S. Kershaw, K.O. Duffany, S.S. Rising, J.R. Ickovics, Blood pressure changes during pregnancy: impact of race, body mass index, and weight gain, Am. J. Perinatol. 30 (5) (2013) 415–424. [3] B.M. Sibai, Chronic hypertension in pregnancy, Obstet. Gynecol. 100 (2) (2002) 369–377. [4] L.A. Magee, P. von Dadelszen, E. Rey, S. Ross, E. Asztalos, K.E. Murphy, et al., Lesstight versus tight control of hypertension in pregnancy, N. Engl. J. Med. 372 (5) (2015) 407–417. [5] S.P. Committee, SMFM Statement: benefit of antihypertensive therapy for mild-tomoderate chronic hypertension during pregnancy remains uncertain, Am. J. Obstet. Gynecol. 213 (1) (2015) 3–4. [6] S.E. Allen, A. Tita, S. Anderson, J.R. Biggio, D.L. Harper, Is use of multiple antihypertensive agents to achieve blood pressure control associated with adverse pregnancy outcomes? J. Perinatol. 37 (4) (2017) 340–344. [7] S.E. Maynard, J.Y. Min, J. Merchan, K.H. Lim, J. Li, S. Mondal, et al., Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia, J. Clin. Invest. 111 (5) (2003) 649–658. [8] R.J. Levine, S.E. Maynard, C. Qian, K.H. Lim, L.J. England, K.F. Yu, et al., Circulating angiogenic factors and the risk of preeclampsia, N. Engl. J. Med. 350 (7) (2004) 672–683. [9] T. Chaiworapongsa, R. Romero, Y.M. Kim, G.J. Kim, M.R. Kim, J. Espinoza, et al., Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia, J. Matern. Fetal Neonatal Med. 17 (1) (2005) 3–18. [10] T. Engels, J. Pape, K. Schoofs, W. Henrich, S. Verlohren, Automated measurement of sFlt1, PlGF and sFlt1/PlGF ratio in differential diagnosis of hypertensive
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Association of antepartum blood pressure levels and angiogenic profile among women with chronic hypertension
T
Ruby Minhasa, Danielle Younga, Rabab Naseema, Ariel Muellera,b, Sireesha Chinthalaa, Joana Lopes Perdigaoa, Kiang-Teck J. Yeoc, Siaw Li Chanc, Avery Tungd, Julia Bregand Whitea, ⁎ Sajid Shahuld, Sarosh Ranaa, a
Section of Maternal Fetal Medicine/Department of Obstetrics & Gynecology, University of Chicago, Chicago, IL, USA Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA c Department of Pathology, University of Chicago, Chicago, IL, USA d Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA b
A B S T R A C T
Background: Angiogenic factors have been implicated in the pathogenesis of preeclampsia. This pilot study explored the association between antenatal blood pressure levels and angiogenic biomarkers (sFlt1 and PlGF) among women with chronic hypertension (cHTN). Methods: Blood samples were collected from women with cHTN (with/without superimposed preeclampsia) within 96 h prior to delivery. Subjects were stratified by mean outpatient BP as controlled (cBP < 140/90) or uncontrolled (uBP ≥ 140/90). Descriptive statistics were generated and assessed as appropriate. Logistic regression was employed to assess for adverse pregnancy outcomes between groups. Results: Data from seventy-eight women were analyzed, of which 58 (74.4%) were African American. Fifty-six (71.8%) had cBP and 22 (28.2%) had uBP. Use of antepartum outpatient antihypertensive medications was more frequent in patients with uBP (46.4% vs. 13.6%, p = 0.01). Compared to women with cBP, women with uBP had higher levels of pre-delivery sFlt1 and sFlt1/PlGF ratio (sFlt: 4218.5 vs. 3056.0 pg/ml, p = 0.046; sFlt/PlGF: 62.5 vs. 25.0, p = 0.04). Additionally, more uBP patients had superimposed preeclampsia with severe features (54.6% vs. 25.0%; p = 0.01) and preterm delivery (defined as a gestational age < 35 weeks (40.9% vs. 10.7%; p = 0.002)) than cBP patients. In the multivariable model, women with uBP had greater odds of preterm delivery (OR 6.78; p = 0.01), superimposed preeclampsia (OR 3.20; p = 0.03) and preeclampsia with severe features (OR 3.27; p = 0.04) than women with cBP. Conclusion: In women with cHTN, elevated antepartum BP is associated with worsened outcomes and may be associated with abnormal angiogenic profile at delivery. Larger studies are needed to confirm these findings.
1. Introduction During pregnancy, chronic hypertension (cHTN) is defined as having been present and observable prior to pregnancy or diagnosed before the twentieth week of gestation [1]. The prevalence of cHTN is 5% in all pregnant women with a higher prevalence among high risk groups such as obese and African American women [2]. cHTN is associated with higher maternal and fetal morbidity and mortality, including superimposed preeclampsia, abruption placentae, and intrauterine growth restriction [3]. The management of hypertension during pregnancy remains controversial. The 2015 CHIPs trial found no effect of tight control of blood pressure on the risk of pregnancy loss, high-level neonatal care, or overall maternal complications, although less-tight control was associated with a higher frequency of severe maternal hypertension [4]. In addition, the American College of Obstetrics and Gynecology (ACOG) recommends antihypertensive therapy only for women with severe, persistent chronic
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hypertension (systolic blood pressure [BP] ≥160 mmHg or diastolic BP > 105 mmHg) [5]. However, a large 2017 retrospective study observed that blood pressures ≥140/90 mm Hg were associated with a greater risk of maternal complications and adverse fetal outcomes regardless of the number of medications used to control the blood pressures. This study concluded that blood pressure control, rather than the number of agents used to achieve that control, was most associated with pregnancy outcomes [6]. A randomized trial evaluating the benefits and harms of pharmacologic treatment of mild cHTN in pregnancy is currently underway in the United States (NCT02299414). Angiogenic factors have been implicated in the pathogenesis of preeclampsia and its associated outcomes [7–11]. Existing data find abnormalities in angiogenic factors among women with cHTN that develop preeclampsia [12–14]. However, few studies have evaluated the association of blood pressure control during pregnancy on levels of angiogenic factors at the time of delivery.
Corresponding author. E-mail address: [email protected] (S. Rana).
https://doi.org/10.1016/j.preghy.2018.09.003 Received 7 April 2018; Received in revised form 25 July 2018; Accepted 4 September 2018 Available online 05 September 2018 2210-7789/ © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
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2.3. Automated assays
We hypothesized that women with uncontrolled blood pressures would have elevated anti-angiogenic factor levels and be more likely to have poor maternal and fetal outcomes. To test our hypothesis, we measured the relationship between antepartum blood pressures during prenancy and angiogenic factor levels at the time of delivery in pregnant women with cHTN. We also wanted to confirm the relationship between blood pressure control and adverse outcome that has been previously reported.
All consenting patients had a blood sample collected within 96 h prior to delivery. Blood samples were centrifuged at 3000 RPM for 10 min at 4 degrees Celsius, and then plasma was aliquoted and frozen at -800 degrees until the time of analysis. All de-identified samples were thawed once for analysis. Assays for sFlt1 and PlGF were performed on BRAHMS KRYPTOR Compact Plus (ThermoFisher Scientific) automated immunoassay platform using automated kits as previously described, at the clinical chemistry laboratory at the University of Chicago. The detectable ranges for sFlt1 and PlGF are 90 to 69,080 and 11 to 7000 pg/ mL, respectively [15]. The coefficient of variation for both assays were < 5%. All measurements were performed once in batches after delivery on all patients so none of the treating physicians were aware of the assay results. The technician performing the analysis was blinded to the final patient diagnosis.
2. Methods 2.1. Patient population We performed a retrospective cohort analysis among subjects who consented to participate in a prospective ongoing observational study, Angiogenic Dysfunction Of Pregnancy and Transthoracic echocardiogram (ADOPTe). Institutional Review Board approval was obtained from the University of Chicago Biological Sciences Division (IRB# 140977). Subjects in ADOPTe are enrolled upon admission for delivery to the University of Chicago Family Birth Center. This study involved a subset of patients with chronic hypertension (cHTN) who received prenatal care and delivered at the University of Chicago between January 2015 and March 2017. The primary exposure was blood pressure during pregnancy. The criterion for outpatient treatment was per individual physicians based on their practice and American College of Obstetricians and Gynecologists (ACOG) recommendations [5] and varied by provider preference and experience. All blood pressures documented in a patient's chart for each prenatal visit were abstracted from the medical record for analysis. The average of all of these outpatient blood pressure values was then calculated. The diagnosis of cHTN was abstracted by the research staff and confirmed by two authors (JLP and SR). All measurements of BP's were part of routine clinical care. Members of the study team abstracted maternal data from the medical record from electronic medical records and entered into a database for further analysis. Baseline data collection included demographic data (age, pre-pregnancy height and weight, race/ethnicity, parity, history of preterm birth or pre-eclampsia and maternal comorbidities). All systolic and diastolic blood pressure readings during pregnancy were obtained at each outpatient prenatal visit. Outcome data included mode of delivery, gestational age at delivery, indication for delivery, highest blood pressures during admission, diagnosis of a hypertensive disorder and maternal complications. Neonatal outcome data included birth weight and neonatal intensive care unit (NICU) admission and was abstracted from both the maternal and fetal chart to ensure concordance.
2.4. Statistical analysis Based on prior studies stratifying antepartum blood pressures [6] we did a priori stratified analyses by the average antepartum blood pressure of < 140/90 mmHg (controlled) or ≥140/90 mm Hg (uncontrolled). Uncontrolled BPs occurred either in patients not taking blood pressure medications or those with BP's exceeding the 140/90 threshold despite treatment with oral antihypertensive medications. All blood pressures from all of the prenatal visits were abstracted from the medical record. The average of all recorded blood pressures was used in the analysis. The primary maternal outcome was difference in levels of angiogenic factors at delivery. Other outcomes included superimposed preeclampsia, preeclampsia with severe features, preterm delivery (< 35 weeks), cesarean delivery, antepartum hospitalizations to rule out superimposed preeclampsia and small for gestational age. Trained members of the study team abstracted maternal data from the medical record. All data is first collected on a standardized data form before being entered into an electronic database (REDCap) for further analysis. Descriptive statistics were generated and reported as mean ± standard deviation, median (interquartile range) or frequencies and proportions, depending on type and distribution. Normality was assessed with the Shapiro-Wilk test. Differences between groups were assessed with a t-test, Wilcoxon rank sum, chi-square, or Fisher’s Exact test, as appropriate. Logistic regression was used to assess differences in outcome after controlling for pre-pregnancy body mass index, age and race. Odds ratios (OR) and 95% confidence intervals (CI) are presented. All two-sided p-values < 0.05 were considered significant. SAS 9.4 (SAS Institute Inc., Cary, NC) was used for all analyses. 3. Results 3.1. Clinical demographics
2.2. Diagnosis of preeclampsia Data from 78 patients with chronic hypertension was included in this analysis. The majority of our study population identified as African American (74.4%). A total of 719 outpatient blood pressures were recorded for all patients, of which only 3.2% were documented within seven days of delivery and exceeded a blood pressure of 140/90. Averaging these values resulted in fifty-six (71.8%) patients having an average prenatal blood pressures < 140/90 (cBP) and 22 (28.2%) had average prenatal blood pressures ≥140/90 (uBP). Hypertensive agent use was more frequent in patients with uBP (46.4% vs. 13.6%, p = 0.01) and more patients in the uBP were using multiple agents (uBP 31.8% vs. cBP 12.5%; p = 0.01). Race, ethnicity, mean age, median pre-pregnancy body mass index, smoking status, substance abuse history, obstetric history, and aspirin use was not statistically different between groups (Table 1). As expected, when compared to women with cHTN alone, women with superimposed preeclampsia had higher sFlt1
Chronic hypertension was defined using the ACOG definition of elevated blood pressures (≥ 140 SBP or 90 DBP) prior to 20 weeks gestation. Superimposed preeclampsia was defined by the new onset of proteinuria (urine protein creatinine ratio of ≥0.3 or a 24 h urine protein of ≥ 300 mg) or significant end-organ dysfunction including, 1) rise in liver enzyme activity to twice the upper limit of normal, aspartate aminotransferase (AST) ≥74 U/L or alanine transaminase (ALT) ≥70 U/L), 2) acute renal insufficiency (creatinine ≥ 1.1 mg/dL), 3) right upper quadrant pain, severe headaches, pulmonary congestion or edema, 4) a decrease in platelet levels (< 100,000 /mm3) after 20 weeks of gestation in a woman with chronic/preexisting hypertension. Preeclampsia with severe features was defined as ACOG [1] All diagnoses were assigned by the study coordinator based on the above standard definition and confirmed by two authors (JP and SR).
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Table 1 Clinical Characteristics of Patients. Controlled BP < 140/90 N = 56
Uncontrolled BP ≥ 140/90 N = 22
P-Value
Demographics Race White/Caucasian Black/African American Other Ethnicity Hispanic Non-Hispanic Unknown Age (years) Pre-pregnancy Body Mass Index Number of prenatal visits
12 (21.43) 40 (71.43) 4 (7.14)
4 (18.18) 18 (81.82) 0 (0)
2 (3.57) 53 (94.64) 1 (1.79) 32.02 ± 5.75 31.09 (27.29, 41.60) 11.0 (7.0, 12.0)
0 (0) 21 (95.45) 1 (4.55) 32.05 ± 4.41 35.51 (29.19, 41.10) 8.5 (3.0, 11.0)
0.98 0.24 0.07
Risk Factors Never Smoked Substance abuse
41 (73.21) 1 (1.79)
18 (85.71) 1 (4.55)
0.34 0.49
Obstetric History Nulliparous Previous preeclampsia diagnosis
22 (39.29) 12 (21.43)
8 (36.36) 7 (31.82)
0.81 0.34
26 (46.43) 23 (41.07) 7 (12.50)
3 (13.64) 12 (54.55) 7 (31.82)
25 (44.64) 6 (10.71) 0 (0) 4 (7.14) 4 (7.14)
14 (63.64) 7 (31.82) 1 (4.55) 4 (18.18) 3 (13.64)
0.13 0.04 0.28 0.21 0.40
19 (33.93) 9 (16.07)
8 (36.36) 3 (13.64)
0.84 1.00
Hypertension Medication Hypertensive Agents No agent Single agent Multiple agent Anti-hypertensive used Labetalol Nifedipine Hydralazine Methyldopa Other Other Medications Aspirin use after 12 weeks EGA Aspirin use before 12 weeks EGA
0.54
0.74
0.01
Data is presented as mean ± standard deviation or n (%) depending on variable type. BP: blood pressure; EGA: estimated gestational age.
did not vary by control of blood pressure group; however there was a trend for higher rates of abruption, NICU admission and higher rates of postpartum admission among women with uBP compared to cBP (Table 3). In both the univariate and multivariable model (adjusted for age, pre-pregnancy body mass index and race), uBP was associated with increased odds for preterm delivery < 35 weeks, superimposed preeclampsia and superimposed preeclampsia with severe features (Table 4).
(6158 vs 2712; p = 0.002) and lower PlGF (63 vs 138; p = 0.003) levels, and a higher sFlt1/PlGF ratio (77 vs 21; p = 0.001). 3.2. Postpartum blood pressure After delivery the median (IQR) systolic blood pressure was 165.5 (154.0, 179.0) for patients with antepartum uBP as compared to 153.0 (140.0, 165.0) for patients with cBP (p = 0.003). Similarly, proportion of patients with severe Postpartum HTN (PP SBP ≥ 160 or DBP ≥ 110) were higher among patients with uBP vs cBP (68.2% vs 38.3%, P = 0.02). Postpartum diastolic blood pressure also appeared higher for participants with uncontrolled blood pressure in the antepartum period, however this was not statistically significant (median 99.0 [94.0, 108] vs 94.0 [88.0, 105.0]; p = 0.05).
4. Discussion In this study of pregnant women with chronic hypertension we found that higher blood pressure during pregnancy is associated with elevated plasma sFlt1 levels at the time of delivery. We also found that uncontrolled blood pressures were associated with adverse maternal outcomes and preterm delivery related to preeclampsia. Consistent with previous studies we found that women with superimposed preeclampsia have an abnormal angiogenic profile compared to patients with uncomplicated chronic hypertension [16]. These findings add to the growing evidence that lower blood pressures during pregnancy may be associated with improved pregnancy outcomes. If validated in other studies, our data suggest that the mechanism for such an outcome benefit may be modulation of angiogenic profile at the time of delivery. Randomized trials aimed at controlling BP's during pregnancy will clarify whether control of BP's is associated with favorable angiogenic profiles. Data from our lab [7,17] and others [18,19], suggest that
3.3. Levels of blood pressure control, angiogenic profile and clinical outcomes Women with uBP had higher levels of sFlt1, and higher sFlt/PlGF ratio compared to those with cBP (both P < 0.05; Table 2). When compared to women with cBP, more women with uBP were diagnosed with superimposed preeclampsia with severe features (54.6% vs 25.0%; p = 0.01) and women with cBP were more likely to remain with diagnosis of cHTN (36.4% vs 67.9%; p = 0.01). Preterm delivery < 35 weeks was more common in women with uBP compared to cBP (40.9% vs. 10.7%; p = 0.002). Women with uBP were admitted to rule out preeclampsia more often than those without cBP (77.3% vs 30.4%; p = 0.0002). Mode of delivery and small for gestational age neonate 112
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Table 2 Maternal and Fetal Outcomes.
*
Controlled BP < 140/90 (N = 56)
Uncontrolled BP ≥ 140/90 (N = 22)
P-Value
Hypertensive diagnosis at delivery cHTN only Superimposed PE without severe features Superimposed PE with severe features Hypertensive indication for preterm delivery* Admission to rule out preeclampsia
38 (67.86) 4 (7.14) 14 (25.00) 6 (10.71) 17 (30.36)
8 (36.36) 2 (9.09) 12 (54.55) 9 (40.91) 17 (77.27)
0.01 1.00 0.01 0.002 0.0002
Mode of delivery Vaginal Cesarean section Small for gestational age (BW < 10th percentile) Abruption NICU admission Postpartum admission within six weeks
26 (46.43) 30 (53.57) 14 (25.00) 0 (0) 24 (42.86) 2 (3.57)
9 (40.91) 13 (59.09) 6 (27.27) 1 (4.55) 14 (63.64) 3 (13.64)
0.66 0.84 0.28 0.10 0.13
Defined as < 35 weeks; BP: blood pressure; cHTN: chronic hypertension; PE: preeclampsia; BW: birthweight; NICU: neonatal intensive care unit.
with chronic hypertension that the incidence of superimposed preeclampsia, severe preeclampsia, preterm delivery (< 35 weeks) and preeclampsia-related hospital admissions were higher with blood pressures above 140/90. (6) We note that although our patients all had chronic hypertension, many were not taking antihypertensive medications, implying that they had a mild disease. Our sample size was too limited for subgroup analysis. In addition, because of the small sample size we are unable to confirm our findings that sFlt1 is elevated in a multivariable model because of overfitting. Larger, randomized trials can provide more insight into the effects of anti-hypertensive therapy on levels of angiogenic factors among women with cHTN. Our study has several limitations. Due to the retrospective nature of the study and small sample size, we are unable to determine whether antihypertensive treatment reduces sFlt1 levels, whether the timing of anti-hypertensive initiation affects sFlt1 levels, and whether the relationship we observe for angiogenic factors such as sFlt1 persists after adjusting for potential confounders. Another limitation is that outpatient data were collected retrospectively and the approach to blood pressure control was not standardized, although all patients were treated according to ACOG guidelines. Our study population was also predominantly African America, which makes our results less generalizable to other patient populations. A considerable strength of our study is that the relationship between level of antepartum blood pressure and plasma angiogenic profiles has not been evaluated before. Although data of blood pressures during pregnancy was collected retrospectively, we only included patients who received prenatal care at the University of Chicago and sFlt1 levels and outcomes were available on all patients. Furthermore, analysis of angiogenic factors was done on an automated platform which is reproducible and accurate.[15] In conclusion, we found a relationship between higher blood pressures during pregnancy and increased plasma levels of antiangiogenic factor sFlt1 at the time of delivery. Given the small sample size and inability to control for potential confounders, this result should be interpreted with caution. Despite this, our data raise the possibility that blood pressure control may limit sFlt1 levels in pregnant women at risk for hypertensive diseases of pregnancy and potentially improve preeclampsia related outcomes. Additional studies should confirm this finding in a larger cohort. Future areas of study need to verify whether the intensity of blood pressure control can modify the angiogenic profile [28], reduce adverse outcomes due to hypertension and whether interventions that may restore angiogenic balance could improve pregnancy outcomes related to preeclampsia.
Table 3 Angiogenic Profile.
sFlt1 (pg/mL) PlGF (pg/mL) sFlt1/PIGF
Controlled BP < 140/90( N = 56)
Uncontrolled BP ≥ 140/90 (N = 22)
P-value
3056.0 (1566.0, 5437.0) 111.0 (60.0, 314.0) 25.0 (6.0, 80.0)
4218.5 (2712.0, 9762.0) 82.0 (47.0, 147.0) 62.5 (21.0, 215.0)
0.046 0.11 0.04
BP: blood pressure; sFlt: Soluble fms-like tyrosine kinase-1; PIGF: placental growth factor.
Table 4 Multivariate Analysis. Uncontrolled BP ≥ 140/90 Odds Ratio (95% Confidence Interval)
P-Value
Univariate Model Preterm delivery (< 35 weeks) 5.77 (1.74, 19.15) Superimposed PE 3.69 (1.31, 10.39) Superimposed PE with severe features 3.60 (1.28, 10.13)
0.004 0.01 0.02
Multivariable Model* Preterm delivery (< 35 weeks) 6.78 (1.72, 26.71) Superimposed PE 3.20 (1.10, 9.34) Superimposed PE with severe features 3.27 (1.09, 9.88)
0.01 0.03 0.04
*
Adjusted for age, race and pre-pregnancy BMI. PE: preeclampsia.
preeclampsia is caused by an angiogenic imbalance and that the antiangiogenic factor sFlt1 plays an important role. Therapeutic interventions currently being investigated for inhibition of sFlt1 include statins [20], small molecules such as ouabain [21], and ligands that bind to sFlt1, such as vascular endothelial growth factor (VEGF) and PlGF [22,23]. Although the etiology of preeclampsia is incompletely understood, the placenta is thought to play an important role. However, some recent evidence suggests that preeclampsia may be a primary cardiovascular disorder [24]. We have recently observed that abnormal cardiac function during second trimester may predate the development of superimposed preeclampsia in pregnant patients with cHTN [25]. In vitro administration of antihypertensive drugs to placental explants do not affect sFlt1 level [26,27], suggesting that the relationship between antihypertensive treatment and sFlt1 levels in preeclampsia may be due to a systemic effect of the drugs on maternal blood pressure and circulation rather than an effect of these drugs on placental biosynthesis and/or sFlt1 secretion. In this study we only measured sFlt1 in the plasma, so we cannot determine whether lower blood pressures leads to reduction of sFlt1 production from placenta or other sources. Our findings are consistent with a 2017 study finding in parturients
Acknowledgements Measurements of sFlt1 and PlGF were done on the BRAHMS KRYPTOR Compact Plus (ThermoFisher Scientific) automated 113
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immunoassay platform using automated kits that were provided in kind by ThermoFisher Scientific. Thermofisher played no part in study design, analysis or manuscript preparation.
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Funding Department of Obstetrics and Gynecology at the University of Chicago. Conflicts of interest S. Rana reports serving as consultant to Roche Diagnostics and Thermo Fisher Scientific. S. Rana also has funding from Roche diagnostics and Siemens for other studies related to use of angiogenic factors in pregnancy. All other authors report no conflict of interest. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.preghy.2018.09.003. References [1] American College of O, Gynecologists, Task Force on Hypertension in P. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy, Obstet. Gynecol. 122 (5) (2013) 1122–1131. [2] U. Magriples, M.H. Boynton, T.S. Kershaw, K.O. Duffany, S.S. Rising, J.R. Ickovics, Blood pressure changes during pregnancy: impact of race, body mass index, and weight gain, Am. J. Perinatol. 30 (5) (2013) 415–424. [3] B.M. Sibai, Chronic hypertension in pregnancy, Obstet. Gynecol. 100 (2) (2002) 369–377. [4] L.A. Magee, P. von Dadelszen, E. Rey, S. Ross, E. Asztalos, K.E. Murphy, et al., Lesstight versus tight control of hypertension in pregnancy, N. Engl. J. Med. 372 (5) (2015) 407–417. [5] S.P. Committee, SMFM Statement: benefit of antihypertensive therapy for mild-tomoderate chronic hypertension during pregnancy remains uncertain, Am. J. Obstet. Gynecol. 213 (1) (2015) 3–4. [6] S.E. Allen, A. Tita, S. Anderson, J.R. Biggio, D.L. Harper, Is use of multiple antihypertensive agents to achieve blood pressure control associated with adverse pregnancy outcomes? J. Perinatol. 37 (4) (2017) 340–344. [7] S.E. Maynard, J.Y. Min, J. Merchan, K.H. Lim, J. Li, S. Mondal, et al., Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia, J. Clin. Invest. 111 (5) (2003) 649–658. [8] R.J. Levine, S.E. Maynard, C. Qian, K.H. Lim, L.J. England, K.F. Yu, et al., Circulating angiogenic factors and the risk of preeclampsia, N. Engl. J. Med. 350 (7) (2004) 672–683. [9] T. Chaiworapongsa, R. Romero, Y.M. Kim, G.J. Kim, M.R. Kim, J. Espinoza, et al., Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia, J. Matern. Fetal Neonatal Med. 17 (1) (2005) 3–18. [10] T. Engels, J. Pape, K. Schoofs, W. Henrich, S. Verlohren, Automated measurement of sFlt1, PlGF and sFlt1/PlGF ratio in differential diagnosis of hypertensive
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