Risk for Imminent Delivery in Preeclampsia Based on the sFlt-1/PlGF Ratio: Do We Need New Cut-Offs?

Abstract

Introduction

It is still difficult to predict the outcome of preeclampsia and determine the individual procedure with regards to the time of birth. Cut-offs of the sFlt-1/PlGF ratio with a high risk for imminent delivery have been previously published and analyzed by our study group, but could not be confirmed. The aim of the current study is to re-evaluate the described cut-off values again in a new period of time.

Materials and Methods

We performed a retrospective analysis (IRB 1279/2020) including all preeclampsia patients delivering in our department over a 3-year period. Patients were divided into 2 groups – gestational week 24+0–33+6 with an s-Flt1/PlGF > 655.2 and 34+0–37+0 weeks with an sFlt-1/PlGF > 201 and were compared with preeclampsia patients of the same weeks with sFlt-1/PlGF values below the described cut-offs. Correlation between sFlt-1/PlGF ratio and time to delivery was assessed.

Results

The association between sFlt-1/PlGF above the threshold and delivery within 48 h is significant for the high ratio early group (p < 0.01) but not for the high ratio late group (p = 0.62). In the early group, 60% of patients with sFlt-1/PlGF > 655.2 but only 8% in the low ratio group delivered within 48 h. In both the early and the late preeclampsia group, a high number of patients remained pregnant even though they showed elevated ratios.

Conclusion

High sFlt-1/PlGF ratios seem to correlate with a shorter pregnancy duration to some extent. Nevertheless, not all patients need to be delivered within 48 h, so the decision should never be based on the laboratory test alone.

 

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Zusammenfassung

Einleitung

Es ist immer noch schwierig, das Outcome bei Präeklampsie vorherzusagen und das individuelle Vorgehen hinsichtlich des richtigen Zeitpunkts der Entbindung festzulegen. Unsere Arbeitsgruppe hat zwar Schwellenwerte für den sFlt-1/PlGF-Quotienten, die mit einem höheren Risiko für eine bevorstehende Entbindung verbunden sind, veröffentlicht und analysiert, aber die Werte konnten bisher nicht bestätigt werden. Ziel dieser aktuellen Studie war es, eine Neubewertung der beschriebenen Schwellenwerte für einen neuen Zeitabschnitt vorzunehmen.

Material und Methoden

Es wurde eine retrospektive Analyse (IRB 1279/2020) der Patientinnen vorgenommen, die innerhalb von 3 Jahren in unserer Abteilung entbunden haben, einschließlich aller Patientinnen mit Präeklampsie. Die Patientinnen wurden in 2 Gruppen eingeteilt: Schwangerschaftswoche 24+0–33+6 mit einem s-Flt1/PlGF > 655,2 und Schwangerschaftswoche 34+0–37+0 mit einem sFlt-1/PlGF > 201. Die Gruppen wurden mit Patientinnen mit Präeklampsie in derselben Schwangerschaftswoche und mit demselben sFlt-1/PlGF-Quotienten unterhalb der oben beschriebenen Schwellenwerte verglichen. Die Korrelation zwischen dem sFlt-1/PlGF-Quotienten und der Zeit bis zur Entbindung wurde bewertet.

Ergebnisse

Die Beziehung zwischen sFlt-1/PlGF-Quotienten oberhalb des Schwellenwerts und einer Entbindung innerhalb von 48 Stunden war signifikant für die früh entbundene Gruppe mit einem hohen Quotienten (p < 0,01), nicht aber für die spät entbundene Gruppe mit einem hohen Quotienten (p = 0,62). In der Gruppe der früh Entbundenen haben 60% der Patientinnen mit einem sFlt-1/PlGF > 655,2, aber nur 8% mit einem niedrigen Quotienten innerhalb von 48 Stunden entbunden. Sowohl in der frühen als auch in der späten Präeklampsiegruppe blieben eine hohe Anzahl der Patientinnen schwanger, obwohl sie erhöhte Quotienten aufwiesen.

Schlussfolgerung

Höhere sFlt-1/PlGF-Quotienten scheinen bis zu einem gewissen Grad mit einer kürzeren Schwangerschaftsdauer zu korrelieren. Trotzdem müssen nicht alle Patientinnen innerhalb von 48 Stunden entbunden werden, und die Entscheidung sollte nie auf den Ergebnissen der Laboruntersuchung alleine beruhen.

 

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Keywords

preeclampsia - sFlt-1/PlGF - soluble fms-like tyrosine kinase-1 - placental growth factor - time to delivery

Schlüsselwörter

Präeklampsie - sFlt-1/PlGF - lösliche Fms-like tyrosine kinase-1 - Plazenta-Wachstumsfaktor - Zeit zur Entbindung

Abbreviations

BMI: body mass index

FGR: fetal growth restriction

H: hours

HELLP: hemolysis, elevated liver enzymes, and low platelets

IQR: interquartile range

NICU: neonatal intensive care unit

PlGF: placental growth factor

SD: standard deviation

sFlt-1: soluble fms-like tyrosine kinase 1

 

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Introduction

Hypertensive pregnancy disorders occur in approximately 5–10 % of pregnancies, with preeclampsia affecting about 3% of pregnancies [1]. Preeclampsia is among the leading causes of maternal and neonatal morbidity and mortality, especially in cases of severe preeclampsia or complications like HELLP syndrome or eclampsia [2] [3]. Delivery being the only causal treatment for preeclampsia, it is responsible for 15% of all preterm births and thus has a significant impact on neonatal outcome [4] [5] [6]. Moreover, it is associated with an overall of 10–15% of maternal deaths [7].

Preeclampsia is defined as the presence of an elevated blood pressure and one of the following parameters: proteinuria, new-onset maternal organ manifestation (renal insufficiency, liver involvement, neurological symptoms, hematological symptoms or uteroplacental dysfunction [8] [9]. However, due to the clinically diverse appearance, it is often still difficult to clearly diagnose and predict its course [1].

The etiology of preeclampsia is still not fully understood. A dysfunctional placenta, which is based on shallow trophoblast invasion and insufficient spiral artery remodeling, seems to play a major role [10]. This leads to an overexpression of antiangiogenic proteins like sFlt-1 (soluble fms-like tyrosine kinase 1 and inactivation of angiogenic factors such as PlGF (placental growth factor), resulting in a higher sFlt-1/PlGF quotient in patients with preeclampsia [11] [12] [13]. The knowledge of these factors has led to several studies investigating diagnostic and prognostic values of the factors in the field of preeclampsia. A cut-off value of 38 to rule out preeclampsia for the period of one week in 99.3% was published in the PROGNOSIS study [14]. Depending on the weeks of gestation, a cut-off value of ≥ 85 was defined for the diagnosis of early onset preeclampsia (20+0 to 33+6 weeks of gestation), and a cut-off of ≥ 110 for late-onset preeclampsia (34+0 weeks of gestation till delivery) [15] [16]. There is growing evidence that the sFlt-1/PlGF ratio can also be used to determine risk of preterm delivery [17]. Subsequently, values above the cut-off of 38 could show an association with a shorter remaining duration of pregnancy and an increased risk of preterm birth [18].

Verlohren et al. identified sFlt-1/PlGF levels, depending on the week of gestation, that were associated with a high risk for imminent delivery [19]. In the group < 34+0 weeks only 29.4% of patients with an sFlt-1/PlGF ratio above 655.2 remained pregnant after 48 h and only 5.7% after seven days. In the group ≥ 34 weeks a cut-off value of 201 could be set above which only 16.7% remained pregnant after 48 h and none after seven days.

In 2020 Enengl et al. retrospectively evaluated these cut-offs in a small patient collective. Women in the < 34+0 weeks group remained pregnant after 48 h in 43.2%, showing significantly lower sFlt-1-/PlGF ratios than patients delivering within two days. A similar trend was seen in the ≥ 34+0 weeks group with 66.7% of patients delivering after 48 h. All in all, the previously described cut-off values could not be confirmed [20].

The aim of the current study is to re-evaluate time to delivery in patients with sFlt-1/PlGF values above the set cut-offs in a new patient collective, in order to analyze the risk of imminent delivery within 48 h [19]. The results should contribute to a better understanding of the laboratory parameter’s role in patient care.

 

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Materials and Methods

A total of 200 patients were included in the study, obtained from a retrospective analysis of patient records of the hospital’s information system (i.s.h.med.; SAP Austria, Vienna, Austria). All patients diagnosed with preeclampsia who gave birth at the Kepler University Hospital Linz during the period from January 1^st 2018 to December 31^st 2020 were included. They were divided into four subgroups, according to the level of the sFlt-1/PlGF quotient and week of pregnancy at the time of diagnosis as follows ([Fig. 1]):

• gestational week 24+0 to 33+6 with an sFlt-1/PlGF ratio > 655.2 (high ratio early)

• gestational week 24+0 to 33+6 with an sFlt-1/PlGF ratio ≤ 655.2 (low ratio early)

• gestational week 34+0 to 37+0 with an sFlt-1/PlGF ratio > 201 (high ratio late)

• gestational week 34+0 to 37+0 with an sFlt-1/PlGF ratio ≤ 201 (low ratio late)

Fig. 1 Flowchart for patient inclusion. Patients diagnosed with preeclampsia were divided into four groups according to the level of the sFlt-1/PlGF ratio and week of pregnancy at the time of diagnosis.

Exclusion criteria was an incomplete data set or preeclampsia diagnosed before 24 weeks of gestation.

Preeclampsia was defined according to the Guideline of the German Society of Gynecology and Obstetrics (015/018) [8] [21].

Maternal serum levels of sFlt-1 and PlGF (in pg/mL) were measured using Elecsys (electrochemiluminescence immunoassays, Roche Diagnostics, Mannheim, Germany) to calculate the sFlt-1/PlGF ratio. Measurements were carried out in accordance with clinical criteria suspicious of preeclampsia at the time of admission as ordered by the clinician. Gestational week was based on crown-rump-length of first trimester ultrasound.

The main objective was to analyze the time between measurement of elevated sFlt-1/PlGF ratio and delivery. The indication for delivery was made according to maternal and fetal criteria based on standard management procedures and national guidelines [22] [23]. Clinicians were not blinded to laboratory results.

Statistical analysis

Descriptive statistics of baseline characteristics per study group are provided. For nominal and ordinal variables, absolute and conditional frequencies are given in percentages, and for metric variables median and IQR (interquartile range) are reported. Baseline characteristics are then summarized in a demographics table. Metric variables were tested for normal distribution with the Shapiro-Wilk test. P-values are given for testing differences between low ratio and high ratio preeclampsia groups, separately for the early and the late subgroup.

Association between nominal/ordinal variables, e.g. birth within 48 h and study group was tested with Fisher’s exact test. Differences in metric variables between two groups such as the distribution of sFlt-1/PlGF by birth within or later than 48 h after first sFlt-1/PlGF measurement (above cut-off) were tested with the Mann-Whitney-U test. Descriptive statistics of the differences in sFlt-1/PlGF after 2–7 days or later than 7 days are presented. Pearson’s correlation analysis was performed to analyze the correlation between sFlt-1/PlGF and time to delivery (in hours).

Statistical analysis was performed using the open-source R statistical software package, version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).

 

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Ethical approval

The study was approved by the local ethics committee (JKU Ethikkommission; EK – 1279/2020) on March 3, 2021.

 

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Results

Patient population and baseline characteristics

A total of 200 patients were included in the study, 30 in the high ratio early group (24+0 to 33+6, sFlt-1/PlGF > 655.2), 71 in the low ratio early group (24+0 to 33+6, sFlt-1/PlGF ≤ 655.2), 24 in the high ratio late group (34+0 to 37+0, sFlt-1/PlGF > 201), 75 in the low ratio late group (34+0 to 37+0, sFlt-1/PlGF ≤ 201). Maternal baseline characteristics are presented in [Table 1].

Table 1 Maternal baseline characteristics. For nominal and ordinal variables absolute and conditional frequencies in percent and for metric variables mean, SD (standard deviation)/ median and IQR (interquartile range) are reported. Note that body mass index was calculated at the time of preeclampsia diagnosis.

	High ratio early	Low ratio early	P-value	High ratio late	Low ratio late	P-value
BMI = body mass index; RR diastolic = diastolic blood pressure; RR systolic = systolic blood pressure
Parity			0.11			0.49
1	25 (83.33%)	40 (56.34%)		17 (70.83%)	42 (56%)
2	4 (13.33%)	20 (28.17%)		3 (12.50%)	19 (25.33%)
3	1 (3,33%)	5 (7.04%)		4 (16.67%)	11 (14.67%)
4	0	5 (7.04%)		0	3 (4%)
5	0	1 (1.41%)		0	0
Age (years)	31 (9.25)	32 (8.5)	0.48	29 (7.25)	30 (5.5)	0.36
BMI (kg/m2)	28 (7.59)	29.3 (8.67)	0.33	28.1 (4.67)	28.94 (5.99)	0.84
RR systolic (mmHg)	159.5 (21.25)	147 (29.5)	< 0.01	162 (28)	142 (23)	< 0.01
RR diastolic (mmHg)	98.5 (15.25)	93 (21)	< 0.01	102 (21.25)	92.5 (18.75)	0.02
Induction of labor	0	3 (4.23%)	0.55	12 (50%)	31 (41.33%)	0.49
Mode of delivery			0.10			0.44
spontaneous delivery	0	8 (11.27%)		4 (16.67%)	23 (30.67%)
caesarean section	30 (100%)	62 (87.32%)		18 (75%)	47 (62.67%)
vacuum extraction	0	1 (1.41%)		2 (8.33%)	5 (6.67%)
History of preeclampsia	2 (6.67%)	3 (4.23%)	0.63	2 (8.33%)	3 (4%)	0.59

There was one case of eclampsia in each group except for the high ratio late group. Overall, 11% of patients developed HELLP syndrome – six (20%) in the high ratio early group, three (13%) in the high ratio late group, four (6%) in the low ratio early group, and eight (11%) in the low ratio late group. Patients of both high ratio groups showed significantly higher blood pressure than in the low ratio groups (p < 0.01 each).

Induction of labor was performed in none of the high ratio early patients and in 4% (n = 3) of the low ratio early patients (p = 0.55); in the high ratio late group in half of the women labor was induced (n = 12), in the low ratio late group in 41% (n = 31) (p = 0.49).

Mode of delivery did not differ significantly in the study groups. In the high ratio early group cesarean section was conducted in 100% (n = 30) vs. 87% (n = 62) in the low ratio early group (p = 0.10). In the high ratio late group 75% (n = 18) of the women delivered by cesarean section vs. 63% (n = 47) in the low ratio late group (p = 0.44).

 

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Fetal outcome parameters

All women of the high ratio early group delivered preterm, and with 94% (n = 67) also a high proportion of the low ratio early group. There were 83% (n = 20) preterm deliveries in the high ratio late group and 51% (n = 38) in the low ratio late group.

In the high ratio early group, all infants were transferred postpartum to the neonatal intensive care unit, in the low ratio early group 95% (n = 79). In the > 34 weeks of gestation groups, 72% (n = 18) were transferred in the high ratio late group and 59% (n = 53) in the low ratio late group. There was no significant association between sFlt-1/PlGF beyond the threshold and transfer to the neonatal intensive care unit in either group (p = 0.57 and p = 0.26, respectively).

The lowest pHs were observed in the low ratio early group with arterial pH 7.07 and venous pH 7.04 and in the low ratio late group with arterial pH 7.07. The mean umbilical arterial pH was significantly different between the high ratio early and the low ratio early group (7.25 (±0.06) and 7.29 (±0.07); p < 0.01). Similarly, umbilical venous pH was significantly different (p < 0.01) between these two groups with a mean value of 7.29 (±0.05) in the high ratio early and 7.32 (±0.08) in the low ratio early group. In the late subgroups, differences in the pH values were not significant (p = 0.41 and p = 0.18). There was also a significant difference of the 10 minutes APGAR between the early high and low ratio groups (p = 0.03), but the difference was not significant between the late groups (p = 0.69).

The neonatal baseline characteristics are summarized in [Table 2].

Table 2 Neonatal baseline characteristics. For nominal and ordinal variables absolute and conditional frequencies in percent and for metric variables mean, SD (standard deviation)/ median and IQR (interquartile range) are reported. Note that due to multiple pregnancies, the number of neonates does not equal the number of deliveries.

	High ratio early	Low ratio early	P-value	High ratio late	Low ratio late	P-value
FGR = fetal growth restriction; NICU = neonatal intensive care unit; pH UA = umbilical artery pH; pH UV = umbilical vein pH
Birthweight (g)	1021.77 (332.12)	1590.45 (614.24)	< 0.01	2308.96 (573.30)	2521.94 (527.30)	0.08
FGR	22 (37.29%)	39 (33.91%)	0.02	9 (24.32%)	14 (14.89%)	0.04
ph UA	7.26 (0.08)	7.30 (0.07)	< 0.01	7.30 (0.08)	7.30 (0.09)	0.41
ph UV	7.30 (0.06)	7.33 (0.07)	< 0.01	7.33 (0.05)	7.34 (0.07)	0.18
10 min APGAR			0.02			0.69
2	1 (3.33%)	1 (1.20%)		0	0
5	0	0		0	1 (1.11%)
7	3 (10%)	4 (4.82%)		0	0
8	4 (13.33%)	8 (9.64%)		0	2 (2.22%)
9	17 (56.67%)	31 (37.35%)		2 (8%)	15 (16.67%)
10	5 (16.67%)	39 (46.99%)		23 (92%)	72 (80%)
NICU admission	30 (100%)	79 (95.18%)	0.57	18 (72%)	53 (58.89%)	0.26
Multiple pregnancies	0 (0%)	10 (14.08%)	0.03	1 (4.17%)	15 (20%)	0.11

 

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Time to delivery analysis

Patients of the high ratio early group had a median time to delivery of 17.82 h/0.74 days (IQR 105.12 h/4.38 days). 60% (n = 18) delivered within 48 h with a median sFlt-1/PlGF of 783.20 (IQR 195.52). 13% (n = 4) remained pregnant after seven days. In comparison, significantly fewer patients in the low ratio early group (8%, n = 6) than in the high ratio early group gave birth within 48 h (p < 0.01). In this group the median time to delivery was 292.23 h/12.18 days (IQR 448.95 h/18.71 days) and 65% (n = 46) were still pregnant after seven days.

In the high ratio late group, the median time to delivery was 76.58 h/3.19 days (IQR 164.65 h/6.86 days). 38% (n = 9) delivered within 48 h with a median sFlt-1/PlGF of 267.30 (IQR 68.10). 33% (n = 8) were still pregnant after seven days. In the low ratio late group, 31% (n = 23) delivered within 48 h. There was no significant association between low and high ratio late group and birth within 48 h (p = 0.62). The median time to delivery in the low ratio late group was 180.17 h/7.51 days (IQR 338.05 h/14.09 days), after seven days 51% (n = 38) were still pregnant.

Neither in the high ratio early (p = 0.85) nor in the high ratio late group (p = 0.91), the difference in the sFlt-1/PlGF values between patients who delivered before and after 48 h was significant.

Time to delivery analyses with distribution of sFlt-1/PlGF ratios are shown in [Table 3].

Table 3 Time to delivery and sFlt-1/PlGF ratios per study group. Absolute number of observations (n) as well as frequencies in percent per group are provided. Mean, SD (standard deviation), median and IQR (interquartile range) of the sFlt-1/PlGF ratio per subgroup are reported.

Study group	Time to delivery	n	%	Mean sFlt-1/PlGF	SD	Median sFlt-1/PlGF	IQR
h = hours; d = days; sFlt-1 = soluble fms-like tyrosine kinase 1; PlGF = placental growth factor
High ratio early
	≤ 48 h	18	60%	979.02	583.94	783.20	195.52
	> 48 h–7 d	8	27%	1163.50	504.70	1170.95	537.43
	> 7 d	4	13%	718.58	52.32	705.55	62.62
Low ratio early
	≤ 48 h	6	8%	173.07	82.85	159.40	87.97
	> 48 h – 7 d	19	27%	226.02	108.66	212.90	196.05
	> 7 d	46	65%	168.05	111.30	122.65	72.70
High ratio late
	≤ 48 h	9	38%	284.81	77.06	267.30	68.10
	> 48 h – 7 d	7	29%	268.21	47.62	270.90	35.20
	> 7 d	8	33%	281.49	75.61	235.65	115.87
Low ratio late
	≤ 48 h	23	31%	123.15	31.27	108.90	35.40
	> 48 h – 7 d	14	19%	115.65	26.67	108.30	34.00
	> 7 d	38	50%	109.41	25.14	98.00	27.35

A correlation analysis between sFlt-1/PlGF ratio and time to delivery was performed for each study group. Scatterplots of all groups show a small negative correlation ([Fig. 2] and [Fig. 3]) but p-values indicate that none of the correlation coefficients is significantly different from zero. The correlation coefficients and p-values are summarized in [Table 4].

Fig. 2 Scatterplot of sFlt-1/PlGF measurement and time to delivery (in hours) for the high ratio group by early (left) and late (right) subgroups.

Fig. 3 Scatterplot of sFlt-1/PlGF measurement and time to delivery (in hours) for the low ratio group by early (left) and late (right) subgroups.

Table 4 Correlation analysis between sFlt-1/PlGF and time to delivery within study groups. Pearson correlation coefficients of sFlt-1/PlGF measurement and time to delivery (in hours) for high ratio and low ratio group by early and late subgroups.

Study group	Early	P-value	Late	P-value
High ratio	−0.15	0.42	−0.14	0.51
Low ratio	−0.13	0.29	−0.16	0.16

 

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Discussion

This study again confirms that high sFlt-1/PlGF ratios in patients with preeclampsia might lead to a high risk of early delivery. In this study, the proportion of births within 48 h were significantly higher in early onset preeclampsia patients with an sFl-1/PlGF marker above the published cut-off of 655.2 compared to the corresponding control group with lower angiogenic ratios [19]. Still, 40% of patients of this analysis remained pregnant for longer than 48 h, which is similar to the earlier investigation of our study group in 2017 where 43% had their baby beyond that time limit [20].

For the group of patients with late preeclampsia after 34 weeks of gestation, the higher risk for imminent delivery with ratios above the described cut-off value could again not be confirmed in this recent analysis. 63% of women with an sFlt-1/PlGF ratio above 201 remained pregnant after two days, comparable to 67% in our first study [20]. The median sFlt-1/PlGF values for patients who delivered before and after 48 h did not differ significantly in either the early or the late preeclampsia group.

The main challenge in predicting the course of preeclampsia is to determine the right time of delivery. It is important to find a balance between preventing maternal complications and ensuring the best possible start for the newborn. However, as the severity of preeclampsia is not uniformly determined, the approach to indicate delivery stays rather individualized [24]. One of the main goals is to achieve a complete course of fetal lung maturity enhancement with corticosteroids in preterm fetuses. Angiogenic and anti-angiogenic markers have become an important additional tool in the triage and prognosis [25] [26]. Established cut-off values are under constant debate concerning their best use [27]. In this regard, some studies presented a greater benefit in using continuous markers rather than fixed cut-offs of sFlt-1/PlGF [28] [29]. In particular, extremely high sFlt-1/PlGF levels were associated with higher maternal and fetal risks [30] [31]. However, in this study it has not been evaluated whether a steeper increase in sFlt-1/PlGF values was indicative of sooner delivery as opposed to a flatter one in the case of repeated sFlt-1/PlGF measurements. At this point it has to be mentioned that an elevation of the ratio above cut-offs does not seem to be that frequent, with only 27% of patients in the high ratio groups.

As there seems to be a small correlation of higher sFlt-1/PlGF ratios and the duration of pregnancy, this could help to provide an improvement of patients’ care. However, a significant correlation could not be shown within our study groups. High angiogenic factors could be an indication for patient admission. Furthermore, a better risk stratification could be conducted, allowing optimal timing of fetal lung maturation and patient referral to a perinatal care center. Some studies compared planned delivery versus expectant management in patients with late preterm preeclampsia, gestational week 34+0–36+6 [32] [33]. A randomized controlled trial found strong evidence to suggest that planned delivery reduces maternal morbidity and – even though leading to more neonatal admission – without causing greater neonatal morbidity [32]. Similar results are shown in a study using an algorithm of maternal placental growth factor in women with late preterm preeclampsia. They also found that planned delivery leads to less severe maternal complications without worsening the neonatal outcome [33]. In our patient’s collective of both the recent and the former study of 2020, more than one third of women with elevated sFlt-1/PlGF ratios above the cut-offs in the late preeclampsia group remained pregnant for more than one week. This is important information, and knowledge of the ratio alone should never be the indication for delivery. Of course, inpatient observation with close monitoring seems to be recommended. In any case, the indication for delivery should follow international guidelines. It should also be noticed that induction of labor was more frequent in the late groups, which might be explained by the urgency of delivery as well as the lower efficiency of induction in early groups.

Also, in early preeclampsia patients, < 34+0 weeks of gestation, the benefit of the sFlt-1/PlGF ratio in terms of subsequent adverse outcomes was demonstrated in studies, additional to those of Verlohren et al. [34]. In our study, regarding neonatal outcome, the immediate postpartum common parameters such as APGAR, pH, and child’s admission were recorded. We could show that the pH values differed significantly between high and low ratio early groups (p < 0.01) as did the 10 minutes APGAR (p = 0.03). However, details of the course of delivery like intrapartum complications like placental abruption possibly explaining these findings have not been assessed. Additionally, it would be of great interest to look at the long-term outcomes in further studies.

In all these results, it should be kept in mind that in the evaluation of preeclampsia patients and the prediction of the course of the disease, one parameter alone can rarely be decisive. Many aspects must be integrated into a multimodal model in order to help to define an individual procedure (e.g. laboratory results, maternal serious condition, pathological fetal heart rate, maternal comorbidities etc.) [35]. A Delphi procedure conducted to define parameters that could serve as criteria for urgent delivery in patients with preeclampsia before 32 weeks did also not reach consensus in using the sFlt-1/PlGF ratio as a tool for indicating birth [24]. Thus, also the sFlt-1/PlGF ratio shows a significantly better prognostic value in combination of different aspects than seen alone [36] [37]. In diagnosing or ruling out preeclampsia the sFlt-1/PlGF ratio does already play an important role. Still, the predictive value of a positive marker needs further analysis and studies for a better assessment as prognostic tool. In this study’s patient collective three cases of eclampsia and 21 cases of HELLP syndrome could be recorded. Interestingly, these complications did not only occur in our high ratio group but also in our low ratio groups with lower sFlt-1/PlGF values. Therefore, laboratory testing of these markers does not seem to be a useful tool to predict these complications. However, further studies are needed to get representative data.

A clear limitation of the current study is its retrospective character and the small number of patients. However, as Kepler University Hospital is one of the leading perinatal centers in Austria, our data does represent real-world data. Furthermore, no blinding was performed, so that the available sFlt-1/PlGF values could also have easily influenced the decision-making process regarding delivery in addition to fetal and maternal conditions. This is a fact important to notice and it would be interesting what the results looked like if the ratio would not have been tested. However, this question cannot be answered from this retrospective position. Moreover, almost as many patients with early as with late onset preeclampsia were included, which does not correspond to the common distribution of preeclampsia. Another bias that has to be taken into account is that multiple pregnancies have also been included into analyses.

 

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Conclusion

Our recent study showed a significantly higher proportion of deliveries within 48 h in the high ratio early group with an sFlt-1/PlGF > 655.2 than in the low ratio early group with lower sFlt-1/PlGF values. This is consistent with the results found by Verlohren et al. in 2012 for early preeclampsia patients and the previously collected data from our preliminary study [19]. Nevertheless, a high number of patients remained pregnant for more than two days in all our study groups. Overall, the sFlt-1/PlGF ratio seems to be a good tool for diagnosing and ruling out preeclampsia even if its value in predicting the timing for delivery remains unclear. If a woman and her fetus are clinically stable, we agree with other studies, that a high sFlt-1/PlGF ratio should not lead clinicians to indicate delivery in preeclampsia patients [24].

 

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Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

 

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Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

CTR: IRB number 1279/2020

 

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Contributorsʼ Statement

S. Enengl: original draft, review, data curation, project administration, conceptualization; P. Oppelt: supervision; P. Stelzl: review, data curation; I. Scharnreitner: data curation; R. Altmann: data curation; J. Grienberger: original draft, data curation; P. Hermann: formal analysis, methodology, review; H. Wagner: formal analysis, methodology, review; M. Rezk-Füreder: review, data curation; I. Damian: review, editing; L. Maghörndl: original draft, conceptualization, data curation.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 28 August 2024

Accepted after revision: 04 December 2024

Article published online:
06 February 2025