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One-third of patients with eclampsia at term do not have an abnormal angiogenic profile

  • Tinnakorn Chaiworapongsa EMAIL logo , Roberto Romero EMAIL logo , Francesca Gotsch , Nardhy Gomez-Lopez , Manaphat Suksai , Dahiana M. Gallo , Eunjung Jung , Dustyn Levenson and Adi L. Tarca
Published/Copyright: December 27, 2022
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Journal of Perinatal Medicine
From the journal Journal of Perinatal Medicine Volume 51 Issue 5

Abstract

Objectives

An abnormal angiogenic profile is present in about one-half of women with preeclampsia at term. Few studies examined the roles of angiogenic biomarkers in eclampsia. The aims of this study were to determine (1) whether the degree of an anti-angiogenic state, reflected by a low placental growth factor (PlGF) to soluble fms-like tyrosine kinase-1 (sFlt-1) ratio, in women with eclampsia differed from that of women with severe preeclampsia; and (2) the prevalence of women who had an abnormal angiogenic profile at the diagnoses of preterm and term eclampsia.

Methods

A cross-sectional study was conducted to include women in the following groups: (1) uncomplicated pregnancy (n=40); (2) severe preeclampsia (n=50); and (3) eclampsia (n=35). Maternal serum concentrations of PlGF and sFlt-1 were determined by immunoassays.

Results

Women with preterm, but not term, eclampsia had a more severe anti-angiogenic state than those with severe preeclampsia (lower PlGF and PlGF/sFlt-1 ratio, each p<0.05). However, the difference diminished in magnitude with increasing gestational age (interaction, p=0.005). An abnormal angiogenic profile was present in 95% (19/20) of women with preterm eclampsia but in only 67% (10/15) of women with eclampsia at term.

Conclusions

Angiogenic biomarkers can be used for risk assessment of preterm eclampsia. By contrast, a normal profile of angiogenic biomarkers cannot reliably exclude patients at risk for eclampsia at term. This observation has major clinical implications given that angiogenic biomarkers are frequently used in the triage area as a test to rule out preeclampsia.

Keywords: anti-angiogenic factors; hypertensive disease; placental growth factor (PlGF); preeclampsia; soluble fms-like tyrosine kinase-1 (sFlt-1)

Introduction

Eclampsia is a life-threatening condition, complicating 1.6–10 per 10,000 deliveries in industrialized countries, and the number is much higher in developing countries [1], [2], [3], [4], [5], [6]. This severe complication of pregnancy is commonly diagnosed in the presence of convulsions in a pregnant woman with preexisting gestational hypertension or preeclampsia [7]. The causes of eclampsia are unknown; however, there is a generally accepted link between this condition and preeclampsia. Currently, preeclampsia/eclampsia is a leading cause of maternal and perinatal death worldwide [1, 3, 8]. Understanding of the pathophysiology and discovery of biomarkers to identify women at high risk of developing this syndrome may allow lifesaving interventions as an onset of seizure is not always clinically predictable.

Accumulating evidence shows that an anti-angiogenic state is central to the pathogenesis of preeclampsia [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. Abnormalities in circulating angiogenic and anti-angiogenic factors have been observed in most cases of women with preterm preeclampsia [24], [25], [26]. These changes occur before the clinical diagnosis [10, 14, 27, 28], correlate with the disease severity [9], [10], [11], [12, 29], and identify women who will develop maternal and perinatal complications [18, 26, 30], [31], [32], [33], [34], [35], [36], [37], [38], [39]. Preeclampsia, however, is a heterogeneous condition [40], [41], [42], [43], [44], [45], [46], which may explain why angiogenic biomarkers have a better predictive value of preterm preeclampsia than of preeclampsia at term [26, 30, 31, 33, 47], [48], [49], [50], [51]. Recently, we reported that the majority of women diagnosed with preterm preeclampsia have an abnormal angiogenic profile, defined as the ratio between placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) multiple of the median (MoM) below the 10th percentile for gestational age [52]. Yet, such abnormalities are detectable in about one-half of women with preeclampsia at term [52]. Therefore, it is possible that eclampsia is a heterogeneous condition as well. So far, only a few studies have examined the role of circulating angiogenic and anti-angiogenic factors in women with eclampsia [7, 53, 54].

The two studies that compared the serum concentrations of angiogenic and antiangiogenic factors between women with eclampsia and those with severe preeclampsia reported conflicting results [7, 53]. Indeed, the observation of higher serum sFlt-1 concentrations in eclampsia than in severe preeclampsia [53] has not been replicated in another study [7].

The objectives of this study were to determine (1) whether the degree of an anti-angiogenic state, as reflected by the serum concentrations of PlGF/sFlt-1, in women with eclampsia (preterm and term) differed from those with severe preeclampsia and an uncomplicated pregnancy; and (2) the prevalence of women with an abnormal angiogenic profile at the diagnosis of preterm and term eclampsia.

Materials and methods

Study design and participants

This cross-sectional study included 125 pregnant women allocated into the following groups: (1) uncomplicated pregnancy (n=40); (2) severe preeclampsia (n=50); and (3) eclampsia (n=35) matched within two weeks of gestational age at venipuncture. Women with severe preeclampsia and those with eclampsia were stratified into preterm (<37 weeks of gestation) and term according to the gestational age at diagnosis. Exclusion criteria comprised hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, postpartum eclampsia, multiple pregnancy, or a fetus with chromosomal or congenital anomalies.

Patients were enrolled at Hutzel Women’s Hospital, Detroit, Michigan, and all provided written informed consent prior to the collection of samples. The use of clinical data and biological specimens for research purposes was approved by the Institutional Review Boards of the Wayne State University and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services. Many of the maternal serum samples analyzed in this study have also been used to investigate the role of angiogenic/anti-angiogenic factors in normal pregnancies and in pregnancies with complications [7].

Clinical definitions

Preeclampsia was defined as new-onset hypertension and proteinuria that developed after 20 weeks of gestation [55]. Hypertension was diagnosed when the systolic blood pressure was ≥140 mm Hg or the diastolic blood pressure ≥90 mm Hg on at least two occasions, 4 h to 1 week apart [56]. Proteinuria was defined as a urine protein ≥300 mg in a 24 h urine collection or in the presence of two random urine specimens, obtained 4 h to 1 week apart, showing ≥1+ protein by dipstick or one dipstick demonstrating ≥2+ protein [56]. Severe preeclampsia was defined as systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥110 mm Hg, or proteinuria >5 g in a 24 h urine collection, or ≥3+ protein on a dipstick, or in the presence of multi-organ involvement [55]. HELLP syndrome was diagnosed in the presence of hemolysis (serum lactate dehydrogenase ≥600 IU/L; bilirubin ≥1.2 mg/dL; the presence of schistocytes in peripheral blood), elevated liver enzymes (serum aminotransferase or aspartate aminotransferase ≥70 IU/L), and thrombocytopenia (platelet count <100,000/mm3) [57]. Eclampsia was defined as convulsions in pregnant women with preexisting gestational hypertension or preeclampsia, or as new-onset convulsions in women without a previously known hypertensive or seizure disorder but in whom hypertension was a part of the clinical presentation [7]. Women with an uncomplicated pregnancy were defined as those without major medical, obstetrical, or surgical complications at the time of enrollment and who subsequently delivered an appropriate weight for the gestational age of a neonate at term [7].

Sample collection and multiplex immunoassays

Maternal blood samples were obtained from women with severe preeclampsia or eclampsia at the time of diagnosis and from those with an uncomplicated pregnancy during an antenatal clinic visit or before scheduled cesarean delivery. Samples were centrifuged at 1,300 g for 10 min at 4 °C and stored at −70 °C until assayed. Concentrations of PlGF and sFlt-1 in maternal serum were determined with specific and sensitive quantitative immunoassays [human vascular endothelial growth factor receptor or VEGFR-1/Flt-1 (Catalog #DVR100B) and Human PlGF, Quantikine ELISA; R&D Systems, Minneapolis, MN, USA]. The calculated inter- and intra-assay coefficients of variation for PlGF immunoassays were 5.7 and 4.4%, respectively, and for sFlt-1, they were 6.2 and 2.2%, respectively. The detection limit for PlGF and sFlt-1 were 9.2 and 16.8 pg/mL, respectively.

Statistical analysis

Demographics and clinical characteristics as well as concentrations of PlGF, sFlt-1, and their ratio were compared among study groups, stratified according to gestational age at diagnosis into preterm and term subgroups. Demographic categorical data were summarized as proportions, whereas continuous variables were summarized by medians and interquartile ranges. Differences were examined by using a chi-square or a Fisher’s exact test and the Kruskal-Wallis test with the post-hoc Mann–Whitney U test.

Generalized linear models were used to assess differences in biomarkers while adjusting for potential confounders and considering gestational age as a continuous variables. Data were log(base 2) transformed prior to analysis. The models included an interaction term between gestational age at sample collection and the clinical group, while covariates were parity and sample storage duration. Therefore, these models allowed comparing the difference in means between groups at the earliest gestational age when data was available, and also the difference in the rate of concentration change (slopes) with gestational age.

In addition to the analysis above that compared the concentrations of biomarkers or their ratios directly, data was also expressed into Multiples of the median (MoM) values by dividing the observed value for each study participant by the previously described median value [52]. An abnormal angiogenic profile was defined as a plasma PlGF/sFlt-1 ratio MoM below the 10th percentile for gestational age in normal pregnancy using previously described cut-offs [52]. Since the established reference range of PlGF/sFlt-1 ratio was based on analyte concentrations measured in plasma samples, each serum concentration of PlGF and sFlt-1 in the current study was converted into plasma concentration according to the study by Ogge et al. [58]. The plasma concentration of sFlt-1 was lower than the serum concentration by 6.5%. By contrast, the plasma concentration of PlGF was lower than the serum concentration by 14.6%. Statistical analyses were performed using the R statistical language version 4.1.2 and IBM SPSS version 19.0 (IBM Corporation, Armonk, NY).

Results

Demographics and clinical characteristics

Demographics, clinical characteristics, and obstetrical outcomes of women in the study population are displayed in Table 1 (for patients <37 weeks of gestation) and Table 2 (for patients ≥37 weeks of gestation). Among the three groups, there were no significant differences in maternal age, pre-pregnancy body mass index, and gestational age at venipuncture.

Table 1:

Demographics and clinical characteristics of women in preterm gestation (< 37 weeks of gestation).

Uncomplicated pregnancy pα Severe preeclampsia pβ Eclampsia pγ
(n=13) (n=27) (n=20)
Maternal age, years 22 (19–26.5) 0.9 23 (17–27) 0.7 21 (18–26) 0.7
Nulliparity 12 (92%) 0.03d 15 (56%) 0.7 11/18 (61%) 0.09
Pre-pregnancy BMI, kg/m2 23.2 (19.9–32.4)a 0.8 23.9 (20.6–30.1)b 0.2 26.9 (24.7–30.1)c 0.3
Maximum systolic BP, mmHg 110 (100–111) <0.001d 174 (158–180) 0.4 174 (161–191) <0.001d
Maximum diastolic BP, mmHg 70 (60–76) <0.001d 102 (90–113) 0.2 108 (95–120) <0.001d
GA at diagnosis, weeks 32.9 (31.3–34.7) 0.1 34 (32.1–36.0) 0.1 32.6 (30.1–35.9) 0.9
GA at delivery, weeks 39.7 (38.9–40.6) <0.001d 34.5 (32.4–36.1) 0.07 32.6 (30.7–36.0) <0.001d
Birthweight, g 3,232 (2,905–3,580) <0.001d 1960 (1,679–2,640) 0.01d 1,609 (1,226–2,211) <0.001d
Sample storage time, years 13.1 (12.3–13.5) 0.1 11.9 (3.7–13.3) 0.048d 7.1 (3.2–12.5) 0.001d
sFlt-1, pg/mL 2,802 (2,433–5,210) <0.001d 17,600 (13,588–34485) 0.2 29,342 (16,350–53197) <0.001d
PlGF, pg/mL 477 (339–1,149) <0.001d 94 (62–151) 0.008d 46 (28–81) <0.001d
sFlt-1/PlGF ratio 4.40 (2.73–12.23) <0.001d 219 (116–513) 0.018d 645 (272–1,157) <0.001d
PlGF/sFlt-1 ratio 0.2272 (0.0860–0.3841) <0.001d 0.0046 (0.0019–0.0086) 0.018d 0.0016 (0.0008–0.0039) <0.001d
Abnormal angiogenic profile (serum) 27 (100%) 0.4 19 (95%)
Abnormal angiogenic profile (converted to plasma) 27 (100%) 0.4 19 (95%)

  1. pα: compared between uncomplicated pregnancy and severe preeclampsia; pβ: compared between severe preeclampsia and eclampsia; pγ: compared between uncomplicated pregnancy and eclampsia. an=5. bn=10. cn=12. dp=<0.05. BMI, body mass index; BP, blood pressure; GA, gestational age; kg, kilogram; m, meter; PlGF, placental growth factor; sFlt-1; soluble fms-like tyrosine kinase-1.

Table 2:

Demographics and clinical characteristics of women at term (≥ 37 weeks of gestation).

Uncomplicated pregnancy pα Severe preeclampsia pβ Eclampsia pγ
(n=27) (n=23) (n=15)
Maternal age, years 19 (18–22) 0.1 21 (19–25) 0.2 23 (19–33) 0.8
Nulliparity 23 (85%) 0.2 16 (70%) 0.3 13 (87%) 1.0
Pre-pregnancy BMI, kg/m2 26.6 (22.7–28.1)a 0.9 25.4 (20.8–36.6)b 0.8 24.9 (22.6–34.8)c 0.9
Maximum systolic BP, mmHg 123 (120–137) <0.001d 170 (161–188) 0.1 165 (150–174) <0.001d
Maximum diastolic BP, mmHg 67 (61–71) <0.001d 100 (94–107) 0.3 96 (86–105) <0.001d
GA at venipuncture, weeks 39.1 (38.6–401.1) 0.5 39 (37.9–39.9) 0.8 39 (38.4–40.0) 0.9
GA at delivery, weeks 39.9 39.0–40.4) 0.04 39 (38–39.9) 0.8 39.1 (38.4–39.9) 0.2
Birthweight, grams 3,500 (3,140–3,760) 0.02d 2,955 (2,635–3,650) 0.7 3,175 (2,800–3,350) 0.03d
Sample storage time, years 12.5 (11.1–13.2) 0.005d 11.4 (3.8–12.2) 0.4 9.7 (4.6–11.6) <0.001d
sFlt-1, pg/mL 7,527 (4,734–8,756) <0.001d 17,378 (9,736–32676) 0.6 18,917 (3,754–25156) 0.03d
PlGF, pg/mL 264 (187–566) <0.001d 123 (80–170) 0.8 131 (79–204) 0.002d
sFlt-1/PlGF ratio 25.89 (10–51) <0.001d 159 (55–275) 0.6 132 (37–241) 0.002d
PlGF/sFlt-1 ratio 0.0386 (0.0194–0.0986) <0.001d 0.0063 (0.0036–0.0183) 0.6 0.0076 (0.0041–0.0270) 0.002d
Abnormal angiogenic profile (serum) 19 (83%) 0.4 10 (67%)
Abnormal angiogenic profile (converted to plasma) 19 (83%) 0.4 10 (67%)

  1. pα: compared between uncomplicated pregnancy and severe preeclampsia; pβ: compared between severe preeclampsia and eclampsia; pγ: compared between uncomplicated pregnancy and eclampsia. an=15. bn=13. cn=11. dp=<0.05. BMI, body mass index; BP, blood pressure; GA, gestational age; kg, kilogram; m, meter; PlGF, placental growth factor. sFlt-1, soluble fms-like tyrosine kinase-1.

Angiogenic and anti-angiogenic biomarkers in women with preterm and term eclampsia

Women with eclampsia and those with severe preeclampsia, regardless of their gestational age, had a lower median serum concentration of PlGF, a lower median PlGF/sFlt-1 ratio, and a higher median sFlt-1 concentration than women with an uncomplicated pregnancy (all, p<0.001, Tables 1 and 2), suggesting an imbalance toward an anti-angiogenic state.

Comparing the women with eclampsia to those with severe preeclampsia, the median serum concentrations of PlGF and the PlGF/sFlt-1 ratio were significantly lower, and that of the sFlt-1/PlGF ratio was significantly higher in women with preterm eclampsia than in those with severe preeclampsia (p=0.008, 0.02, and 0.02 respectively; Table 1, Figure 1). By contrast, there were no differences in serum concentrations of sFlt-1, PlGF, and their ratio between women with eclampsia at term and those with severe preeclampsia (p>0.5 for all; Table 2, Figure 2).

Figure 1: Angiogenic and anti-angiogenic factors in preterm gestations. Serum concentrations of (A) placental growth factor (PlGF), (B) soluble fms-like tyrosine kinase (sFlt)-1, (C) PlGF/sFlt-1 ratio, and (D) sFlt-1/PlGF ratio in uncomplicated pregnancies, in women with severe preeclampsia, and in those with preterm eclampsia (<37 weeks of gestation).
Figure 1:

Angiogenic and anti-angiogenic factors in preterm gestations. Serum concentrations of (A) placental growth factor (PlGF), (B) soluble fms-like tyrosine kinase (sFlt)-1, (C) PlGF/sFlt-1 ratio, and (D) sFlt-1/PlGF ratio in uncomplicated pregnancies, in women with severe preeclampsia, and in those with preterm eclampsia (<37 weeks of gestation).

Figure 2: Angiogenic and anti-angiogenic factors in term gestations. Serum concentrations of (A) placental growth factor (PlGF), (B) soluble FMS-like tyrosine kinase (sFlt)-1, (C) PlGF/sFlt-1 ratio, and (D) sFlt-1/PlGF ratio in uncomplicated pregnancies, in women with severe preeclampsia, and in those with eclampsia at term (≥37 weeks of gestation).
Figure 2:

Angiogenic and anti-angiogenic factors in term gestations. Serum concentrations of (A) placental growth factor (PlGF), (B) soluble FMS-like tyrosine kinase (sFlt)-1, (C) PlGF/sFlt-1 ratio, and (D) sFlt-1/PlGF ratio in uncomplicated pregnancies, in women with severe preeclampsia, and in those with eclampsia at term (≥37 weeks of gestation).

Further analysis was performed considering gestational age at diagnosis as a continuous variable and assessing differences between groups as a function of gestational age while taking into account parity and sample storage duration. The serum concentrations of PlGF and PlGF/sFlt-1 ratio were significantly lower, and that of sFlt-1 was significantly higher in preterm eclampsia than in severe preeclampsia (Figure 3). For example, at 31 weeks of gestation, the PlGF/sFlt-1 ratio was 4.2-fold lower in eclampsia than in severe preeclampsia (p=0.007). The difference diminished in magnitude with advancing gestation (interaction, p=0.005; Figure 3). Collectively, in preterm gestations, women with eclampsia had a more severe degree of an anti-angiogenic state than those with severe preeclampsia. By contrast, in term gestations, no significant differences in the serum concentrations of angiogenic biomarkers (sFlt-1, PlGF, and their ratio) between women with eclampsia and those with severe preeclampsia were observed.

Figure 3: Serum (A) placental growth factor (PlGF) concentrations, (B) soluble FMS-like tyrosine kinase (sFlt)-1 concentrations, and (C) PlGF/sFlt-1 ratio as a function of gestational age at diagnosis in eclampsia (red) and in severe preeclampsia (black). The regression lines represent the quadratic model that fits the log2-transformed data. The serum concentrations of PlGF and the PlGF/sFlt-1 ratio were significantly lower and that of sFlt-1 was significantly higher in preterm eclampsia than in severe preeclampsia, taking into account parity, sample storage duration, and gestational age at diagnosis. For example, at 31 weeks of gestation, the differences in biomarker concentrations between eclampsia and severe preeclampsia were as follows: PlGF: 2.1-fold lower, p=0.02; PlGF/sFlt-1: 4.2-fold lower, p=0.007; and sFlt-1: 1.9-fold higher, p=0.03. These differences diminished in magnitude with advancing gestation (interaction, p=0.02, p=0.005, and p=0.02, respectively). The differences remained significant in the following gestational age intervals: PlGF between 31 and 33 weeks of gestation; PlGF/sFlt-1 between 31 and 34 weeks of gestation; and sFlt-1 between 31 and 32 weeks of gestation (all, p<0.05).
Figure 3:

Serum (A) placental growth factor (PlGF) concentrations, (B) soluble FMS-like tyrosine kinase (sFlt)-1 concentrations, and (C) PlGF/sFlt-1 ratio as a function of gestational age at diagnosis in eclampsia (red) and in severe preeclampsia (black). The regression lines represent the quadratic model that fits the log2-transformed data. The serum concentrations of PlGF and the PlGF/sFlt-1 ratio were significantly lower and that of sFlt-1 was significantly higher in preterm eclampsia than in severe preeclampsia, taking into account parity, sample storage duration, and gestational age at diagnosis. For example, at 31 weeks of gestation, the differences in biomarker concentrations between eclampsia and severe preeclampsia were as follows: PlGF: 2.1-fold lower, p=0.02; PlGF/sFlt-1: 4.2-fold lower, p=0.007; and sFlt-1: 1.9-fold higher, p=0.03. These differences diminished in magnitude with advancing gestation (interaction, p=0.02, p=0.005, and p=0.02, respectively). The differences remained significant in the following gestational age intervals: PlGF between 31 and 33 weeks of gestation; PlGF/sFlt-1 between 31 and 34 weeks of gestation; and sFlt-1 between 31 and 32 weeks of gestation (all, p<0.05).

Prevalence of an abnormal angiogenic profile in eclampsia

An abnormal serum PlGF/sFlt-1 ratio was present in almost all patients (95%, 19/20) with preterm eclampsia (Table 1) and in only 67% (10/15) of women with eclampsia at term (Table 2). The results remained similar after plasma PlGF and sFlt-1 concentrations were estimated based on their serum concentrations.

Table 3 describes the clinical characteristics and laboratory results of women diagnosed with eclampsia without an abnormal angiogenic profile at term (numbers 1–5) and preterm (number 6) gestations. The single patient diagnosed with preterm eclampsia and a normal angiogenic profile presented at 36+4 weeks of gestation with a plasma PlGF/sFlt-1 ratio of 1.92 MoM.

Table 3:

Demographics, clinical characteristics, and outcomes of women with eclampsia and a normal angiogenic profile in term (#1–5) and preterm (#6) gestations.

Clinical presentation Highest BP

systolic; diastolic, mmHg		 Urine protein

dipstick or 24 h, mg/day		 Others Clinical course Delivery PlGF/sFlt-1 MoM (converted to plasma)
1 19 y/o G1P0 at 41w2d

Pre-pregnancy BMI 34 kg/m2		 170; 107 3+

814		 AST 30, ALT 20, Plt 209, sCr 0.7, LDH 188 Seizure x 2 in her car and the emergency room

History of headaches for the past 2 days		 Induction of labor due to eclampsia; vaginal delivery; birthweight 2,870 g

MRI brain—posterior reversible encephalopathy syndrome		 0.67
2 23 y/o G4P1A2 at 39w6d

Pre-pregnancy BMI 35.8 kg/m2

History of previous preeclampsia		 166; 101 2+ AST 24, ALT 15, Plt 177, sCr 0.6, LDH 133 Presented with headache and high blood pressure

Seizure in the operating room during cesarean section		 Repeat cesarean section; birthweight 3,175 g

MRI brain—unremarkable		 0.25
3 36 y/o G9P5A3 at 41w Pre-pregnancy BMI 25.5 kg/m2 156; 82 trace AST 8, Plt 231 Seizure upon delivery Induction of labor due to postdate; vaginal delivery; birthweight 3,170 g

CT brain—unremarkable		 0.26
4 25 y/o G1P0 at 39w1d 150; 86 negative AST 36, ALT 46, Plt 235, sCr 0.8 Antepartum seizure Vaginal delivery; birthweight 3,140 g 0.25
5 16 y/o G1P0 at 38w5d 160; 90 trace AST 18, ALT 18, Plt 232, sCr 0.5 Antepartum seizure Vaginal delivery; birthweight 2,715 g 2.62
6 25 y/o G4P2A1 at 36w4d

Pre-pregnancy BMI 24.4 kg/m2		 168; 98 441 AST 26, ALT 24, Plt 205, sCr 0.5 Previous classical cesarean section in labor

Seizure before surgery started		 Repeat cesarean section; birthweight 2,540 g 1.92

  1. A, abortion; ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; d, days; BP, blood pressure; CT, computerized tomography; G:gravida; kg, kilogram; m, meter; MoM, multiple of the median; MRI, magnetic resonance imaging; N/A, not available; P, parity; PlGF, placental growth factor; Plt, platelet counts; sCr, serum creatinine; sFlt-1; soluble fms-like tyrosine kinase-1; w, weeks; y/o=years old.

Discussion

Principal findings of the study

(1) Women with preterm eclampsia, but not eclampsia at term, had a more severe degree of an anti-angiogenic state than those with severe preeclampsia, as reflected by a lower PlGF/sFlt-1 ratio; and (2) an abnormal angiogenic profile was present in almost all women with preterm eclampsia and in only two-thirds of the women with eclampsia at term.

Significance of eclampsia at term

The incidence of eclampsia decreased with advancing gestational age. Yet, the number of eclampsia cases was substantially higher at term compared to preterm [59]. Thus, the burden of eclampsia is associated with term eclampsia, for which the predictive performance of angiogenic biomarkers for preeclampsia is modest. Despite the progress in the prediction and prevention of early preeclampsia [60], [61], [62], preeclampsia at term, which accounts for the majority of all preeclamptic cases [63], remains a clinical challenge [54]. There is an urgent need to understand the role of angiogenic and anti-angiogenic factors in preeclampsia/eclampsia in late gestation [54] and to develop effective predictive biomarkers as well as therapeutic strategies for this life-threatening disease.

Women with preterm eclampsia had a more severe degree of an anti-angiogenic state than those with severe preeclampsia

The finding that women with preterm eclampsia had a lower PlGF/sFlt-1 ratio than those with severe preeclampsia indicates a more severe degree of an anti-angiogenic state in women with preterm eclampsia. Indeed, abnormalities of angiogenic biomarkers correlated well with the severity of preeclampsia as determined by the level of blood pressure [10, 11, 53, 64], gestational age at diagnosis [10, 11], abnormality in uterine and umbilical artery Doppler velocimetry [29], platelet counts [11, 53], liver enzymes [53, 64], uric acid concentration [53], duration from diagnosis of preeclampsia to delivery [30], [31], [32, 36], neonatal birthweight [11], risk of adverse perinatal outcomes [53, 65], and the rate of maternal intensive care unit admission [53]. However, there are conflicting results regarding the concentrations of angiogenic biomarkers in eclampsia compared to severe preeclampsia: either no differences [7] or a higher serum sFlt-1 concentration in eclampsia was reported [53]. In the current study, the serum concentration of PlGF was lower and that of sFlt-1 was higher in patients with eclampsia than in those with severe preeclampsia only in cases diagnosed as preterm. The differences disappeared as the patients approached term. One possible explanation for the conflicting findings in previous reports could be due to the different numbers of preterm or term eclampsia cases that were included in each study. Collectively, these angiogenic biomarkers may be used for risk assessment of preterm preeclampsia.

One-third of patients with eclampsia at term had a normal angiogenic profile

An abnormal angiogenic profile, similar to preeclampsia, was present in almost all women diagnosed with eclampsia at preterm gestation. Yet, one-third of women with eclampsia at term had a normal angiogenic profile, indicating heterogeneity of this life-threatening condition at term. In the current study, the 10th percentile threshold that was chosen to define a normal angiogenic profile is conservative, thus increasing the detection rate of abnormalities in angiogenic/anti-angiogenic factors. Other angiogenic biomarker tests apply either a lower or a similar threshold to define a normal angiogenic profile. For example, to define a normal profile for the Triage PlGF Test® (Alere, San Diego, CA, USA), the threshold for PlGF is ≥100 pg/mL (approximately ≥5th percentile at less than 35 weeks of gestation) [39]; likewise, to define a normal profile for the Elecsys Test® (Roche Diagnostics, Penzberg, Germany), the threshold for the sFlt-1/PlGF ratio is ≤38 pg/mL (approximately ≤90th percentile at 36 weeks of gestation) [48]. This observation had major clinical implications given that angiogenic biomarkers are frequently used in the triage area to rule out preeclampsia [21, 22, 33, 50, 54, 66, 67]. While angiogenic biomarkers can exclude women at risk for preeclampsia/eclampsia at preterm gestation with high accuracy, these biomarkers cannot reliably exclude patients at risk for eclampsia at term.

An anti-angiogenic state and seizure

The pathogenesis of seizure in eclampsia remains unclear. However, the leading hypothesis is that the disruption of the blood-brain barrier (BBB) causes fluid and plasma protein passage into the brain’s parenchyma and that neuroinflammation subsequently occurs [1, 68]. An animal experiment indicated that exposure of the brain to plasma of patients with preeclampsia significantly increased BBB permeability [69]. Indeed, sFlt-1, by antagonizing VEGF receptor-mediated signaling, can sensitize endothelial cells to become more susceptible to pro-inflammatory cytokines [70]. The elevations of sFlt-1 and several pro-inflammatory cytokines observed in women with preeclampsia [71], [72], [73] could disrupt the BBB and, in some cases, lead to neuroinflammation and eclampsia [74]. Systemic inflammation may disrupt BBB by several mechanisms, e.g., changes in tight junctions, damage to endothelial cells, activation of astrocytes and microglia, and migration of immune cells to the brain, among others [75]. These mechanisms have been observed in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and SARS-CoV-2-associated cerebrovascular diseases [75, 76]. However, the view that the anti-angiogenic protein sFlt-1 disrupts the BBB causing neuroinflammation has recently been challenged [77, 78]. The mechanism of seizure in eclampsia at term with a normal angiogenic profile remains to be determined.

Future studies on term preeclampsia/eclampsia should focus on a specific subgroup, either with or without abnormalities in the angiogenic/anti-angiogenic factors, and comprise a more homogenous group of patients based on mechanisms of disease; thus, more consistent results could be obtained [79]. The approach reported herein will assist in the development of a new taxonomy of obstetrical syndromes and facilitate biomarker discovery as well as personalized preventive strategies [79] for this devastating syndrome.

Strength and limitations of the study

This is the first study designed to compare an angiogenic profile of women diagnosed with eclampsia and of those with severe preeclampsia, stratified according to gestational age at diagnosis into preterm and term subgroups. By utilizing generalized linear models and by allowing interaction between gestational age at diagnosis and the diagnosis groups, different behaviors of angiogenic and anti-angiogenic factors of women with eclampsia before and after term gestation were observed.

One of the limitations of this study is the difference in the duration of sample storage between the preterm eclampsia and severe preeclampsia groups. However, according to the generalized linear models, this variable did not explain the observed differences in serum concentrations of angiogenic/anti-angiogenic factors between groups. Another limitation is the small number of eclampsia cases enrolled into the study given the low incidence of this serious complication in well-developed countries. Lastly, the biomarker concentrations were determined in serum rather than in plasma samples due to the unavailability of plasma samples in many cases of eclampsia. Since the established reference ranges of these biomarkers were based on analyte concentrations measured in plasma samples, each serum concentration of PlGF and of sFlt-1 was also converted into a plasma concentration [58]. Nevertheless, the same prevalence of abnormal PlGF/sFlt-1 profiles in term and preterm eclampsia was found after deriving MoM cut-off values directly from serum concentrations of normal pregnancies included in this study.

Conclusions

Women diagnosed with preterm eclampsia had a more severe degree of an anti-angiogenic state than those diagnosed with severe preeclampsia. Almost all women diagnosed with preterm eclampsia were characterized by an abnormal angiogenic profile. Yet, one-third of women diagnosed with eclampsia at term did not have such abnormality. We concluded that angiogenic biomarkers can be used for risk assessment of preterm eclampsia. By contrast, a normal angiogenic profile cannot reliably exclude patients at risk for eclampsia at term.

Corresponding authors: Tinnakorn Chaiworapongsa, MD, Perinatology Research Branch, NICHD/NIH/DHHS, Wayne State University/Hutzel Women’s Hospital, 3990 John R Street, 4 Brush, 48201 Detroit, MI, USA; Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA; and Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA, E-mail: ; Roberto Romero, MD, DMedSci, Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA; and Detroit Medical Center, Detroit, MI, USA, Phone: (313) 993-2700, Fax: (313) 993-2694, E-mail:

Funding source: Eunice Kennedy Shriver National Institute of Child Health and Human Development

Award Identifier / Grant number: Contract No. HHSN275201300006C

  1. Research funding: This research was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C. The study was also supported, in part, by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health (Nardhy Gomez-Lopez and Adi L. Tarca). Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: The authors declare no conflicts of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: Research involving human subjects complied with all relevant national regulations and institutional policies; is in accordance with the tenets of the Helsinki Declaration (as revised in 2013); and has been approved by the Institutional Review Boards of NICHD and Wayne State University.

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Received: 2022-09-30
Accepted: 2022-11-04
Published Online: 2022-12-27
Published in Print: 2023-06-27

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Disquiet concerning cesarean birth
  4. Prenatal care and pregnancy outcome among incarcerated pregnant individuals in the United States: a systematic review and meta-analysis
  5. Corner of Academy
  6. Does COVID-19 infection acquired in different pregnancy trimester influence placental pathology?
  7. Original Articles – Obstetrics
  8. Did the first wave of the COVID-19 pandemic impact the cesarean delivery rate? A retrospective cohort study at a primary care center in Switzerland
  9. Hypertensive disorders of pregnancy and severe acute respiratory syndrome coronavirus-2 infection
  10. Hidden in plain sight in the delivery room – the Apgar score is biased
  11. Comparison of phase rectified signal averaging and short term variation in predicting perinatal outcome in early onset fetal growth restriction
  12. Serum levels of kynurenine in pregnancies with fetal growth restriction and oligohydramnios
  13. Effect of third trimester maternal vitamin D levels on placental weight to birth weight ratio in uncomplicated pregnancies
  14. One-third of patients with eclampsia at term do not have an abnormal angiogenic profile
  15. Chorioangioma: a single tertiary care center retrospective study
  16. A prospective cohort study: can advanced ultrasonography replace magnetic resonance imaging in the diagnosis of placental adhesion disorders?
  17. Original Articles – Fetus
  18. Fetal left brachiocephalic vein diameters in normal and growth restricted fetuses
  19. Functional assessment of atrial wall excursion and foramen ovale flap tracings in 3rd trimester as predictor of short-term hemodynamic stability in congenital heart defects fetuses
  20. Original Articles – Neonates
  21. Developing a new pediatric extracorporeal membrane oxygenation (ECMO) program
  22. Patterns of placental injury in various types of fetal congenital heart disease
  23. Short Communication
  24. Prenatal care in the era of economic collapse
  25. Letters to the Editor
  26. Does fetus feel stress or pain on uterine contraction?
  27. Pregnancy associated plasma protein-A for the prediction of small for gestational age
  28. Reply to: Pregnancy associated plasma protein-A for the prediction of small for gestational age
https://doi.org/10.1515/jpm-2022-0474
Keywords for this article
anti-angiogenic factors; hypertensive disease; placental growth factor (PlGF); preeclampsia; soluble fms-like tyrosine kinase-1 (sFlt-1)

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Disquiet concerning cesarean birth
  4. Prenatal care and pregnancy outcome among incarcerated pregnant individuals in the United States: a systematic review and meta-analysis
  5. Corner of Academy
  6. Does COVID-19 infection acquired in different pregnancy trimester influence placental pathology?
  7. Original Articles – Obstetrics
  8. Did the first wave of the COVID-19 pandemic impact the cesarean delivery rate? A retrospective cohort study at a primary care center in Switzerland
  9. Hypertensive disorders of pregnancy and severe acute respiratory syndrome coronavirus-2 infection
  10. Hidden in plain sight in the delivery room – the Apgar score is biased
  11. Comparison of phase rectified signal averaging and short term variation in predicting perinatal outcome in early onset fetal growth restriction
  12. Serum levels of kynurenine in pregnancies with fetal growth restriction and oligohydramnios
  13. Effect of third trimester maternal vitamin D levels on placental weight to birth weight ratio in uncomplicated pregnancies
  14. One-third of patients with eclampsia at term do not have an abnormal angiogenic profile
  15. Chorioangioma: a single tertiary care center retrospective study
  16. A prospective cohort study: can advanced ultrasonography replace magnetic resonance imaging in the diagnosis of placental adhesion disorders?
  17. Original Articles – Fetus
  18. Fetal left brachiocephalic vein diameters in normal and growth restricted fetuses
  19. Functional assessment of atrial wall excursion and foramen ovale flap tracings in 3rd trimester as predictor of short-term hemodynamic stability in congenital heart defects fetuses
  20. Original Articles – Neonates
  21. Developing a new pediatric extracorporeal membrane oxygenation (ECMO) program
  22. Patterns of placental injury in various types of fetal congenital heart disease
  23. Short Communication
  24. Prenatal care in the era of economic collapse
  25. Letters to the Editor
  26. Does fetus feel stress or pain on uterine contraction?
  27. Pregnancy associated plasma protein-A for the prediction of small for gestational age
  28. Reply to: Pregnancy associated plasma protein-A for the prediction of small for gestational age
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