Abstract
Background
The pathophysiology of hypertension in the immediate postpartum period is unclear.
Methods and Results
We studied 988 consecutive women admitted to a tertiary medical center for cesarean section of a singleton pregnancy. Angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF), both biomarkers associated with preeclampsia, were measured on antepartum blood samples. We then performed multivariable analyses to determine factors associated with the risk of developing postpartum hypertension. Of the 988 women, 184 women (18.6%) developed postpartum hypertension. 77 out of 184 women developed de novo hypertension in the postpartum period and the remainder had a hypertensive disorder of pregnancy in the antepartum period. A higher body mass index and history of diabetes mellitus were associated with development of postpartum hypertension. The antepartum sFlt1/PlGF ratio positively correlated with blood pressures in the postpartum period [highest postpartum systolic (r=0.29; P<0.001) and diastolic (r=0.28, P<0.001)]. Moreover, the highest tertile of the antepartum sFlt1/PlGF ratio was independently associated with postpartum hypertension [OR: 2.25 (1.19, 4.25), P=0.01 in the de novo hypertensive group and 2.61 (1.12, 6.05) in the persistent hypertensive group; P=0.02] in multivariable analysis. Women developing postpartum hypertension had longer hospitalization than those who remained normotensive (6.5 ± 3.5 versus 5.7 ± 3.4 days; P<0.001).
Conclusions
Hypertension in the postpartum period is relatively common and is associated with prolonged hospitalization. Women with postpartum hypertension share similar clinical risk factors as well as a similar antepartum plasma angiogenic profile found in women with preeclampsia. These data suggest that postpartum hypertension may represent a group of women with subclinical or unresolved preeclampsia.
Keywords: angiogenic factors, de novo postpartum hypertension, persistent postpartum hypertension, preeclampsia
Introduction
The hypertensive disorders of pregnancy (HDP) are a well-recognized cause of maternal morbidity and mortality worldwide. The World Health Organization, in a systematic review of global data, recently identified HDP as a dominant cause of maternal death in developing countries--accounting for approximately 18% of all maternal deaths worldwide.1 Even among western countries, characterized by very low rates of maternal death in the peri- and postpartum periods, HDP remain significantly associated with the future development of maternal hypertension (HTN), ischemic heart disease, and stroke.2
Development of de novo hypertension in the immediate postpartum period (postpartum hypertension; PPHTN) is an infrequently studied clinical syndrome, that is usually defined as hypertension appearing post-delivery through 6 weeks postpartum.3 Postpartum hypertension (PPHTN) can present either as a de novo condition following a normotensive pregnancy or as persistent hypertension following a pregnancy complicated by severe preeclampsia.4 PPHTN following a normotensive pregnancy may herald the development of seizures (postpartum eclampsia), which is associated with significant morbidity. A recent large retrospective study indeed found that 63% of patients readmitted with delayed postpartum preeclampsia had no antecedent diagnosis of a HDP.5 Furthermore, PPHTN increases the risk of intracerebral hemorrhage,6 which is compounded by generally decreased medical surveillance in the postpartum period after hospital discharge.
Despite the potential danger that PPHTN poses to women, only limited data exist in the literature describing its incidence and risk factors.7 This is again partly due to infrequent medical visits for most women during the immediate postpartum period, often not first occurring until 6 weeks after delivery. Furthermore, the often asymptomatic nature of PPHTN limits capture of these patients for study. Most data in the literature are retrospective in nature and usually represent only the most severe cases, such as patients readmitted with hypertensive crisis or seizures/eclampsia.8 Even less is known regarding the possible underlying pathobiology of PPHTN. While iatrogenic causes such as excess intravenous fluid administration and certain medications (eg. non-steroidal anti-inflammatory drugs, ergot alkaloids, etc.) have been associated with PPHTN,4, 9 very little is known about the pathophysiology of PPHTN. 10, 11
We therefore studied women with singleton pregnancies for antepartum risk factors that may lead to the development of PPHTN in the immediate postpartum period. In addition to collecting detailed antepartum demographic, clinical, and laboratory data, we measured the antepartum circulating levels of angiogenic factors--the antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and the proangiogenic placental growth factor (PlGF)--that have been linked to the pathogenesis of preeclampsia.12-17
Methods
Study Design and Oversight
This retrospective clinical study was performed at Beth Israel Deaconess Medical Center (Boston, MA) in accordance with all institutional policies and with approval of the institutional review board. Because discarded blood samples were used for analysis, informed patient consent was not required for this study; the institutional review board waived the need for written informed consent from the participants for both the use of discarded blood samples and review of medical records.
Study Participants and Clinical Data
We retrospectively studied 988 women admitted for cesarean section (C-section) of a singleton pregnancy during the period from October, 2012 through March, 2014. We focused only on the subjects who underwent C-section, as they had routine blood draws prior to delivery. We recorded a number of antepartum characteristics such as maternal age, body mass index (BMI; kg/m2) upon admission, gestational age on admission, gestational age at delivery, parity, smoking status, race, history of any hypertensive disorder and/or diabetes in a previous pregnancy, highest systolic and diastolic blood pressures during the antepartum period, and laboratory values such as alanine aminotransferase (ALT) level, serum creatinine and uric acid levels, and platelet count. Each patient's clinical course was recorded, with collection of additional clinical data such as infant birth weight, maternal estimated blood loss (EBL) during delivery, sequential postpartum systolic and diastolic blood pressures, and intraoperative plus postpartum intravenous fluid therapy. The length of hospital admission, number of patients requiring readmission, and number of patients requiring antihypertensive medication were also recorded for all participants. PPHTN was defined as any systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg, at least 48 hours after delivery and up to 6 weeks postpartum. Blood pressures were also recorded from the outpatient office visits, when available, up to 6 weeks postpartum.
Measurement of Antepartum Circulating Angiogenic Proteins
Discarded venous EDTA blood samples collected prior to C-section (between 12 to 96 hours before C-section), were collected from the hospital laboratory, plasma aliquoted, and stored at -70° C. Blood samples were missing in 7 subjects. A single operator performed quantitative sandwich enzyme-linked immunosorbent assay (ELISA) for both sFlt1 and PlGF biomarkers on these discarded plasma samples from the remaining subjects (N=981) in duplicate using commercially available ELISA kits (R&D Systems, Inc., Minneapolis, MN) as described elsewhere.13 The interassay coefficient for sFlt1 and PlGF were 7% and 11%, respectively. The operator was blinded to the clinical information. The clinicians treating the patients did not have any knowledge of the biomarker levels as the assays were in done in one batch after the outcomes had occurred.
Patient Cohort Classification
All subjects in our study were first classified into two groups: (1) normotensive pregnancy (NL: systolic blood pressure (SBP) less than 140 mmHg and diastolic blood pressure (DBP) less than 90 mmHg prior to delivery; n=774 patients) and (2) hypertensive pregnancy (HTN: SBP greater than or equal to 140 mmHg and/or DBP greater than or equal to 90 mmHg once prior to delivery; n=214 patients.) These two groups were then further categorized as either remaining/becoming normotensive (as defined above) or as developing postpartum hypertension (PPHTN: SBP greater than or equal to 140 mmHg and/or DBP greater than or equal to 90 mmHg) 48 hours or more after C-section. The resultant four subgroups into which all subjects were categorized, therefore, were: NL/NL, NL/PPHTN, HTN/NL, and HTN/PPHTN.
Statistical Analysis
Antepartum, delivery, and postpartum characteristics of normotensive and hypertensive patients are presented overall and by postpartum hypertensive status as means ± standard deviations, medians (25th percentile, 75th percentile), or numbers and percentages. Characteristics were compared between postpartum groups using independent samples t-tests or chi-square tests, as appropriate. Angiogenic factors were natural log transformed to meet the assumptions of parametric testing. Pearson's correlation coefficients were used to determine the associations between natural log-transformed antepartum angiogenic factors and highest recorded antepartum and postpartum systolic blood pressure (SBP) and diastolic blood pressure (DBP). Separate univariate and multivariable logistic regression models were utilized to predict risk of PPHTN by the overall tertile of each angiogenic factor among normotensive and hypertensive patients. Adjustment was made for variables significant in univariate models as well as clinically known confounders: (1) gestational age, (2) body mass index, (3) nulliparous, (4) race, (5) history of chronic hypertension, and (6) history of diabetes. Odds ratios and 95% confidence intervals were used to summarize the results of logistic regression models. The average days of hospitalization were compared between normotensive and hypertensive groups using independent samples t-tests (natural log transformed average days of hospitalization) and chi-square tests. Statistical analyses were conducted with the use of SAS software, version 9.4 (SAS Institute). Two-tailed P values of less than 0.05 were considered to indicate statistical significance.
Results
Patient Characteristics Associated with PPHTN
Among 774 normotensive pregnancies, 9.9% (n=77) of these women went on to develop de novo PPHTN (Table 1). African-American women (20.8% vs. 7.0%), women with a higher BMI at delivery (mean ± SD: 34.1 ± 7.3 vs. 30.0 ± 5.2 kg/m2), and women with a history of diabetes mellitus (13.0% vs. 3.9%) demonstrated increased risk of developing de novo PPHTN as compared to normotensive women who remained normotensive (all P<0.001). The highest recorded antepartum SBP and DBP, while still in the normotensive range, were significantly higher in those women developing de novo PPHTN (SBP 127 ± 8 versus 119 ± 11; DBP 78 ± 7 versus 74 ± 8 [all P<0.001]; Table 1).
Table 1. Clinical and Laboratory Characteristics of Initially Normotensive Group.
| Characteristic | All NL (N=774) |
NL/NL (N=697) |
NL/PPHTN (N=77) |
P-value |
|---|---|---|---|---|
| All prior to delivery | ||||
| Gestational Age (weeks) | 39 ± 2 | 39 ± 2 | 39 ± 3 | 0.70 |
| Age (years) | 33 ± 5 | 33 ± 5 | 32 ± 6 | 0.12 |
| Body Mass Index (kg/m2) | 30.4 ± 5.6 | 30.0 ± 5.2 | 34.1 ± 7.3 | <0.001* |
| Nulliparous | 337 (43.5) | 303 (43.5) | 34 (44.2) | 0.91 |
| Smoker | 14 (1.8) | 12 (1.7) | 2 (2.6) | 0.57 |
| Race | <0.001* | |||
| White/Caucasian | 426 (55.0) | 383 (55.0) | 43 (55.8) | |
| Black/African American | 65 (8.4) | 49 (7.0) | 16 (20.8) | |
| Asian | 119 (15.4) | 113 (16.2) | 6 (7.8) | |
| Other/Unknown | 164 (21.2) | 152 (21.8) | 12 (15.6) | |
| History of Hypertension | 13 (1.7) | 11 (1.6) | 2 (2.6) | 0.51 |
| History of Diabetes | 37 (4.8) | 27 (3.9) | 10 (13.0) | <0.001* |
| IVF this Gestation | 36 (4.7) | 31 (4.5) | 5 (6.5) | 0.42 |
| Antepartum Characteristics | ||||
| Highest SBP (mmHg) | 120 ± 11 | 119 ± 11 | 127 ± 8 | <0.001* |
| Highest DBP (mmHg) | 74 ± 8 | 74 ± 8 | 78 ± 7 | <0.001* |
| ALT (U/L)† | 18.9 ± 15.1 | 21.2 ± 18.3 | 15.0 ± 5.7 | 0.15 |
| Creatinine (mg/dL)† | 0.6 ± 0.1 | 0.6 ± 0.1 | 0.6 ± 0.1 | 0.97 |
| Uric Acid (mg/dL)† | 4.6 ± 0.9 | 4.8 ± 0.9 | 4.5 ± 0.8 | 0.31 |
| Platelet Count (K/uL) | 218 ± 57 | 218 ± 56 | 224 ± 64 | 0.33 |
| sFlt1 (pg/ml)ǂ | 7895 (5117, 12619) |
7721 (5088, 12199) |
10189 (5655, 16650) |
0.004* |
| PlGF (pg/ml)ǂ | 243 (159, 399) |
249 (162, 409) |
214 (139, 295) |
0.06 |
| sFlt1/PIGF Ratioǂ | 34.2 (15.0, 68.0) |
33.1 (14.1, 65.9) |
52.1 (22.0, 84.6) |
0.002* |
| Delivery Characteristics | ||||
| Birthweight (g) | 3355 ± 659 | 3348 ± 642 | 3416 ± 793 | 0.48 |
| Postpartum Characteristics | ||||
| Estimated Blood Loss (ml) | 787 ± 215 | 787 ± 217 | 788 ± 188 | 0.99 |
| Total IV Fluids‡ | 2027 ± 674 | 2036 ± 681 | 1942 ± 610 | 0.25 |
Table shows mean± SD, median (25th %ile, 75th %ile) or n (%)
NL=normal, PPHTN=postpartum hypertension, NL/NL= Systolic blood pressure (SBP) <140 and diastolic blood pressure (DBP) <90 prior to delivery and SBP<140 and DBP<90 at 48 hours-6 weeks postpartum after C-section, NL/PPHTN= SBP<140 and DBP<90 prior to delivery and SBP≥140 and/or DBP≥90 at 48 hours-6 weeks postpartum after C-section, IVF=in vitro fertilization, ALT=alanine transaminase, sFlt1=soluble fms-like tyrosine kinase1, PIGF=placenta growth factor, IV=intravenous
ALT = 35 subjects, creatinine= 40 subjects, uric acid = 28 subjects; ǂN = 769 subjects for sFlt1, PlGF and sFlt1/PlGF assays
Intraoperative and postpartum day 1;
Significant at P<0.05
Among 214 hypertensive pregnancies of any cause, 50.0% (n=107) remained hypertensive in the postpartum period. Similar to patients with de novo PPHTN, patients with persistent hypertension had higher BMI at delivery (mean ± SD: 35.1 ± 7.3 vs. 32.3 ± 5.3 kg/m2), history of hypertension (29.9% vs. 3.7%) and diabetes mellitus (21.5% vs. 5.6%) compared to women who were normotensive postpartum, (all P<0.01). The highest recorded antepartum SBP and DBP were significantly higher in those women developing persistent PPHTN [SBP 155 ± 15 vs. 141 ± 9 mm Hg; DBP 94 ± 9 vs. 89 ± 7 mm Hg (all P<0.001)] than among initially hypertensive women who became normotensive in the postpartum period Table 2.
Table 2. Clinical and Laboratory Characteristics of Initially Hypertensive Group.
| Characteristic | All HTN (N=214) |
HTN/NL (N=107) |
HTN/PPHTN (N=107) |
P-value |
|---|---|---|---|---|
| All prior to delivery | ||||
| Gestational Age (weeks) | 38 ± 3 | 39 ± 2 | 37 ± 3 | <0.001* |
| Age (years) | 33 ± 5 | 32 ± 5 | 34 ± 5 | 0.03* |
| Body Mass Index (kg/m2) | 33.7 ± 6.5 | 32.3 ± 5.3 | 35.1 ± 7.3 | 0.002* |
| Nulliparous | 140 (65.4) | 70 (65.4) | 70 (65.4) | 1.00 |
| Smoker | 3 (1.4) | 1 (0.9) | 2 (1.9) | 0.57 |
| Race | 0.82 | |||
| White/Caucasian | 123 (57.5) | 61 (57.0) | 62 (57.9) | |
| Black/African American | 29 (13.6) | 15 (14.0) | 14 (13.1) | |
| Asian | 13 (6.1) | 5 (4.7) | 8 (7.5) | |
| Other | 49 (22.9) | 26 (24.3) | 23 (21.5) | |
| History of Hypertension | 36 (16.8) | 4 (3.7) | 32 (29.9) | <0.001* |
| History of Diabetes | 29 (13.6) | 6 (5.6) | 23 (21.5) | <0.001* |
| IVF this Gestation | 15 (7.0) | 8 (7.5) | 7 (6.5) | 0.79 |
| Antepartum Characteristics | ||||
| Highest SBP (mmHg) | 148 ± 14 | 141 ± 9 | 155 ± 15 | <0.001* |
| Highest DBP (mmHg) | 91 ± 9 | 89 ± 7 | 94 ± 9 | <0.001* |
| ALT (U/L)† | 29.3 ± 55.3 | 25.4 ± 41.1 | 30.9 ± 60.2 | 0.57 |
| Creatinine (mg/dL)† | 0.6 ± 0.2 | 0.6 ± 0.2 | 0.6 ± 0.2 | 0.59 |
| Uric Acid (mg/dL)† | 5.3 ± 1.1 | 5.2 ± 1.3 | 5.3 ± 1.1 | 0.70 |
| Platelet Count (K/uL) | 219 ± 64 | 219 ± 59 | 219 ± 69 | 0.96 |
| sFlt1 (pg/ml)ǂ | 12421 (8023, 18036) |
11708 (7429, 16417) |
13067 (8660, 22816) |
0.02* |
| PlGF (pg/ml)ǂ | 174 (111, 279) |
213 (131, 319) |
148 (98, 222) |
0.002* |
| sFlt1/PIGF Ratioǂ | 73.9<br (32.2, 163.3) | 57.2 (26.0, 128.8) |
93.9 (47.3, 199.3) |
<0.001* |
| Diagnosis | ||||
| Preeclampsia | 49 (22.9) | 7 (6.5) | 42 (39.3) | <0.001* |
| Gestational Hypertension | 20 (9.4) | 5 (4.7) | 15 (14.0) | 0.02* |
| Chronic Hypertension | 16 (7.5) | 3 (2.8) | 13 (12.1) | 0.009* |
| Transient Hypertension | 129 (60.3) | 92 (86.0) | 37 (34.6) | <0.001* |
| Delivery Characteristics | ||||
| Birthweight (g) | 3260 ± 824 | 3393 ± 715 | 3129 ± 903 | 0.02* |
| Postpartum Characteristics | ||||
| Estimated Blood Loss (ml) | 842 ± 260 | 872 ± 305 | 811 ± 204 | 0.08 |
| Total IV Fluids‡ | 1865 ± 680 | 1920 ± 723 | 1809 ± 632 | 0.23 |
Table shows mean± SD, median (25th %ile, 75th %ile) or n (%)
HTN=hypertension, NL=normal, PPHTN=postpartum hypertension, HTN/NL= Patients initially hypertensive and normotensive postpartum, HTN/PPHTN=patients with persistent hypertension, IVF=in vitro fertilization, ALT=alanine transaminase, sFlt1=soluble fms-like tyrosine kinase-1, PIGF=placenta growth factor, HELLP=hemolysis-elevated liver enzymes-low platelets counts
Diagnosis of Preeclampsia, Gestational Hypertension and Chronic Hypertension per ICD9 code. Subjects who had any antepartum blood pressure ≥140/90 but without ICD9 diagnosis had transient hypertension.
ALT = 119 subjects, creatinine= 121 subjects, uric acid = 114 subjects;
N = 212 subjects for sFlt1, PlGF and sFlt1/PlGF assays.
Intraoperative and postpartum day 1;
Significant at P<0.05
There was no difference in intraoperative and postoperative intravenous fluid volumes administered between women with PPHTN and those without. More than 90% of all patients received a nonsteroidal medication, and there was no difference in doses between these two groups. The majority of patients (62.0%) developed PPHTN between 48-72 hours following delivery, while another 27.2% developed the disorder on day 4 and 5.4% on day 5. The remaining patients developed PPHTN after the first week. Out of 184 patients with PPHTN, 39 patients had severe hypertension (defined as SBP ≥160 or DBP ≥110 mm Hg).
Angiogenic Factors and PPHTN
Women who developed de novo PPHTN had significantly higher antepartum sFlt1 levels as compared to women who remained normotensive postpartum (median [25th-75th %ile]: 10189 pg/ml [5655-16650] versus 7721 pg/ml [5088-12199]) and a higher sFlt1/ PlGF ratio (52.1 [22.0, 84.6] versus 33.1 [14.1, 65.9]) (all P<0.05; Table 1). Similar results were seen in women with persistent PPHTN compared to subjects who were normotensive postpartum among the initially hypertensive group (sFlt1/PlGF ratio 93.9 (47.3, 199.3) versus 57.2 (26.0, 128.8); P<0.001; Table 2).
Those in the highest tertile of antepartum circulating sFlt1 concentration [OR: 1.89 (1.07, 3.31); P=0.03], lowest PlGF concentration [OR: 2.38 (1.26, 4.49); P=0.008], and highest tertile of sFlt1/PlGF ratio [OR: 2.23 (1.24, 4.04); P=0.008] were at a significantly increased risk of developing de novo PPHTN in univariate analyses, and these effects persisted after multivariable adjustment: sFlt1: [OR: 2.29 (1.22, 4.33); P=0.01]; PlGF: [OR: 2.15 (1.10, 4.20); P=0.02]; and sFlt1/PlGF ratio: [OR: 2.25 (1.19, 4.25); P=0.01] (Table 3). Similar results were seen among the initially hypertensive group. Multivariable analysis for the highest tertile of sFlt1/PlGF ratio revealed a significantly increased odds ratio favoring the persistence of hypertension postpartum [2.61 (1.12, 6.05); p=0.02], (Table 4). Of the 988 patients, 263 patients had labor prior to the C-section. Excluding patients with labor prior to C-section did not change the results (data not shown).
Table 3. Increasing Risk of Postpartum Hypertension with Increasing Level of sFlt1/PIGF Ratio among Women who were Initially Normotensive.
| Tertile 1 | Tertile 2 | Tertile 3 | |||||||
|---|---|---|---|---|---|---|---|---|---|
| PPHTN N (%) |
Odds Ratio (95% CI) |
P-value | PPHTN N (%) |
Odds Ratio (95% CI) |
P-value | PPHTN N (%) |
Odds Ratio (95% CI) |
P-value | |
| Univariate | |||||||||
|
| |||||||||
| sFlt1 | 21 (8.2) | 1.0 | Ref | 19 (7.4) | 0.89 (0.47, 1.71) | 0.73 | 37 (14.5) | 1.89 (1.07, 3.31) | 0.03* |
|
| |||||||||
| PlGF‡ | 15 (5.8) | 1.0 | Ref | 29 (11.4) | 2.07 (1.08, 3.96) | 0.03* | 33 (12.8) | 2.38 (1.26, 4.49) | 0.008* |
|
| |||||||||
| sFlt1/PIGF Ratio | 18 (7.0) | 1.0 | Ref | 22 (8.6) | 1.24 (0.65, 2.37) | 0.52 | 37 (14.5) | 2.23 (1.24, 4.04) | 0.008* |
|
| |||||||||
| Multivariable† | |||||||||
|
| |||||||||
| sFlt1 | 21 (8.2) | 1.0 | Ref | 19 (7.4) | 1.09 (0.55, 2.18) | 0.80 | 37 (14.5) | 2.29 (1.22, 4.33) | 0.01* |
|
| |||||||||
| PlGF‡ | 15 (5.8) | 1.0 | Ref | 29 (11.4) | 2.15 (1.10, 4.22) | 0.03* | 33 (12.8) | 2.15 (1.10, 4.20) | 0.02* |
|
| |||||||||
| sFlt1/PIGF Ratio | 18 (7.0) | 1.0 | Ref | 22 (8.6) | 1.34 (0.68, 2.67) | 0.40 | 37 (14.5) | 2.25 (1.19, 4.25) | 0.01* |
PPHTN=postpartum hypertension, CI=confidence interval, sFlt1=soluble fms-like tyrosine kinase-1, PIGF=placenta growth factor
Significant at P<0.05
Adjusted for gestational age, age, body mass index, nulliparous, race, history of chronic hypertension, and history of diabetes. sFlt1, PIGF, and sFlt1/PIGF ratio were analyzed in separate models.
Lowest tertile is highest PlGF level
Table 4. Increasing Risk of Postpartum Hypertension with Increasing Level of sFlt1/PIGF Ratio among Women who were Initially Hypertensive.
| Tertile 1 | Tertile 2 | Tertile 3 | |||||||
|---|---|---|---|---|---|---|---|---|---|
| PPHTN N (%) | Odds Ratio (95% CI) | P-value | PPHTN N (%) | Odds Ratio (95% CI) | P-value | PPHTN N (%) | Odds Ratio (95% CI) | P-value | |
| Univariate | |||||||||
|
| |||||||||
| sFlt1 | 31 (44.3) | 1.0 | Ref | 33 (46.5) | 1.09 (0.56 2.12) | 0.79 | 41 (57.8) | 1.72 (0.88, 3.35) | 0.11 |
|
| |||||||||
| PlGF‡ | 26 (36.6) | 1.0 | Ref | 36 (50.0) | 1.73 (0.89, 3.38) | 0.11 | 43 (62.3) | 2.86 (1.44, 5.68) | 0.003* |
|
| |||||||||
| sFlt1/PIGF Ratio | 25 (35.7) | 1.0 | Ref | 38 (53.5) | 2.07 (1.06, 4.07) | 0.03* | 42 (59.2) | 2.61 (1.32, 5.15) | 0.006* |
|
| |||||||||
| Multivariable† | |||||||||
|
| |||||||||
| sFlt1 | 31 (44.3) | 1.0 | Ref | 33 (46.5) | 1.51 (0.68, 3.35) | 0.31 | 41 (57.8) | 1.70 (0.76, 3.79) | 0.19 |
|
| |||||||||
| PlGF‡ | 26 (36.6) | 1.0 | Ref | 36 (50.0) | 1.85 (0.85, 4.06) | 0.12 | 43 (62.3) | 2.39 (1.02, 5.60) | 0.046* |
|
| |||||||||
| sFlt1/PIGF Ratio | 25 (35.7) | 1.0 | Ref | 38 (53.5) | 2.12 (0.94, 4.77) | 0.07 | 42 (59.2) | 2.61 (1.12, 6.05) | 0.02* |
PPHTN=postpartum hypertension, CI=confidence interval, sFlt1=soluble fms-like tyrosine kinase-1, PIGF=placenta growth factor
Significant at P<0.05
Adjusted for gestational age, age, body mass index, nulliparous, race, history of chronic hypertension, and history of diabetes. sFlt1, PIGF, and sFlt1/PIGF ratio were analyzed in separate models.
Lowest tertile is highest PlGF level
The antepartum log transformed ln (sFlt1) positively correlated with highest postpartum systolic (r=0.26; P<0.001) and diastolic (r=0.26; P<0.001) blood pressures, the ln (PlGF) negatively correlated with highest post-partum systolic (r=-0.23; P<0.001) and diastolic (r=-0.22; P<0.001) blood pressures, and the ln (sFlt1/PlGF ratio) positively correlated with highest post-partum systolic (r=0.29; P<0.001) and diastolic (r=0.28; P<0.001) blood pressures. The predictive risk of PPHTN increased with rising levels of antepartum sFlt1/PlGF ratio among all women (Figure 1).
Figure 1. sFlt1/PlGF Ratio and Predictive Risk of Postpartum Hypertension.
The cumulative predicted risk of postpartum hypertension at different levels of natural log transformed sFlt1/PIGF ratio. The sample sizes shown below the figure represent the number of patients at risk for each 2-unit increment of ln sFlt1/PIGF ratio.
Women developing PPHTN also experienced a significantly longer hospitalization than those who did not (days admitted: 6.5 ± 3.5 versus 5.7 ± 3.4 days) and had higher proportion of patients treated by antihypertensive medications (22.8% versus 0.5%), both P<0.001 (Table 5A). sFlt1/PlGF ratio was also elevated among women who were treated with antihypertensive medications compared to those who were not [89.5 (37.5, 165.6) versus 38.5 (17.1, 80.4); P<0.001] (Table 5B).
Table 5A. Length of Hospitalization and Number Treated with Antihypertensive Medication Across All Subgroups.
| Characteristic | PPNL (N=804) |
PPHTN (N=184) |
P-value |
|---|---|---|---|
| Days Admitted (Mean ± SD) | 5.7 ± 3.4 | 6.5 ± 3.5 | <0.001* |
| Number of Patients on Antihypertensive Medication (%) | 4 (0.5) | 42 (22.8) | <0.001* |
PPNL=normal postpartum (NL/NL + HTN/NL), PPHTN=postpartum hypertension (NL/PPHTN + HTN/PPHTN)
Significant at P<0.05.
Table 5B. Angiogenic Factors by Hypertensive Medication Use.
| No HTN Meds† (N=942) |
HTN Medsǂ (N=46) |
P-value | |
|---|---|---|---|
| sFlt1 | 8627 (5474, 13834) | 12657 (7973, 18484) | <0.001* |
| PlGF | 233 (149, 381) | 146 (89, 297) | 0.001* |
| sFlt1/PlGF Ratio | 38.5 (17.1, 80.4) | 89.5 (37.5, 165.6) | <0.001* |
HTN= hypertension, sFlt1=soluble fms-like tyrosine kinase-1, PIGF=placenta growth factor
Data presented as median (25th -75th). *Significant at P<0.05.
N = 936 subjects for sFlt1, PlGF and sFlt1/PlGF assays
N = 45 subjects for sFlt1, PlGF and sFlt1/PlGF assays
Discussion
In this large observational clinical study at a single tertiary care hospital, we have demonstrated that the development of de novo PPHTN following normotensive pregnancies was common (9.9%) and that ∼ 50% of women with hypertensive pregnancies demonstrated persistence of hypertension in the postpartum period. The clinical risk factors for the eventual appearance of de novo PPHTN strongly resembled those for preeclampsia. Moreover, the antepartum angiogenic factor levels central to the pathogenesis of preeclampsia - the antiangiogenic sFlt1 and the proangiogenic PlGF - followed the same pattern (higher sFlt1, lower PlGF, and higher sFlt1/PlGF ratio) and independently predicted the development of de novo and persistent postpartum hypertension. Among all affected patients in our study, the highest tertile of the sFlt1/PlGF ratio increased the odds of developing PPHTN (both de novo and persistent) in univariate and multivariate analyses. Finally, women developing PPHTN had longer hospital stay than those who were normotensive after delivery and required more antihypertensive medications.
Limited data describing the overall incidence and risk factors for PPHTN exist in the literature.7, 18, 19 Most studies have been retrospective20, have not focused on PPHTN per se,5, 21 or have been of small cohort size. 22 To our knowledge, this current work represents one of the largest clinical studies designed to specifically study PPHTN within the literature. Our finding that the development of PPHTN was common--with an incidence of nearly 18% in our cohort--was quite notable. Considering the associated maternal morbidity (and potential mortality) of unrecognized (and therefore untreated) PPHTN, this higher-than-anticipated frequency suggests that the initial postpartum medical visit may need to occur sooner than is typically performed, particularly for those women with risk factors. From our data, these high-risk features appear to be identical to many of those of preeclampsia: elevated BMI, history of diabetes mellitus, and antepartum blood pressure elevation. Taken together with prior observations, our data suggest that de novo or persistent hypertension can occur even after the placenta has been delivered. Therefore, health care providers should alert women to and continue to be vigilant for signs and symptoms of this disorder and manage them promptly to avoid serious complications such as pulmonary edema or eclampsia in the postpartum period.
Indeed, evaluation of antepartum circulating angiogenic factors revealed an identical pattern to that observed in preeclampsia, in these women. These data therefore suggest that development of de novo PPHTN may actually represent a group of women with subclinical preeclampsia that manifests as hypertension postpartum. Similarly, patients with persistent PPHTN had higher antepartum sFlt1/PlGF ratios than those who were normotensive in the postpartum period suggesting that persistent PPHTN may represent a subgroup of patients who may have unresolved preeclampsia either due to delayed clearance of anti-angiogenic factor or may have a severe form of preeclampsia. Our findings also extend the biology of these factors - sFlt1 and PlGF - beyond preeclampsia and into another hypertensive disorder of pregnancy. Antepartum measurement of these angiogenic factors, in combination with a woman's other clinical risk factors for PPHTN, may better enable clinicians in the future to determine which patients require closer surveillance after delivery, and closer follow up after hospital discharge.
Some limitations of our study require mention. First, our cohort was limited to women undergoing C-section only, which may introduce bias and limit the generalizability of our findings. However, this study design was chosen to increase the time period over which we were able to collect data on postpartum blood pressure measurements, since women undergoing C-section are typically hospitalized longer than those delivering vaginally. Also, all consecutive singleton pregnancies undergoing C-section were included in our study--regardless of the indication for C-section--to minimize this potential bias. Furthermore, we would have preferred to have access to longitudinal blood pressure measurements beyond one week post-delivery in all women, in order to determine the duration of postpartum hypertension among the affected women in our cohort. However, ambulatory blood pressure monitoring is not routinely used to monitor for postpartum preeclampsia, and hence this data was not available. Furthermore, data were not available for all patients at 6 weeks follow-up in the outpatient clinic, as only a fraction of our cohort delivering at our center had their postpartum care there also. Another limitation of our study is that not all subjects had routine preeclampsia labs drawn during the antepartum period. This may have led to lack of statistical significance for some of the routine clinical laboratory tests such as uric acid or serum creatinine. Finally, in our study we did not find significant overall morbidity other than a modest increase in the duration of hospitalization. Future studies should determine if the antepartum angiogenic profile among high risk patients correlates with postpartum morbidity, such as postpartum eclampsia or postpartum HELLP syndrome. It would also be important to evaluate whether women with PPHTN are at risk for the development of cardiovascular disease in the long term.
In conclusion, we prospectively identified the major clinical risk factors for the development of PPHTN--and for the first time, implicated antepartum plasma levels of the angiogenic factors sFlt1 and PlGF in the pathogenesis of this disorder. Moreover, our description of the striking clinical similarities between the factors predicting the development of de novo PPHTN and those predicting preeclampsia, coupled with the similarity of the angiogenic profile which precedes de novo PPHTN and also accompanies preeclampsia, suggest that the development of de novo PPHTN may in fact represent subclinical preeclampsia.
Acknowledgments
Funding: R.T. is supported by K24 award from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); S. A. K is an investigator of the Howard Hughes Medical Institute; S. R. is supported by KO8 award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. E.W.S is supported by R56 award from National Heart Lung and Blood Institute.
Footnotes
Conflict of Interest Disclosures: R. T. and S. A. K are co-inventors on patents related to preeclampsia biomarkers that are held at Massachusetts General Hospital and Beth Israel Deaconess Medical Center. R.T and S.A.K. have financial interest in Aggamin LLC. R.T. S.A.K. and S.R report serving as a consultant to Roche Diagnostics. S.A.K reports serving as a consultant to Siemens Diagnostics and has received research funding from Thermofisher. All other authors report no conflict.
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