Predictive Accuracy of Soluble FMS-Like Tyrosine Kinase-1/Placental Growth Factor Ratio for Preeclampsia in Japan: A Systematic Review

Abstract

Preeclampsia is a major complication of pregnancy and is associated with significant fetal and maternal morbidity and mortality. Timely prediction of preeclampsia facilitates referral of potential patients to an adequate tertiary center, which helps reduce adverse outcomes associated with the disease. Moreover, by accurately ruling out preeclampsia, patients can be discharged safely and relieved of anxiety. Numerous candidate biomarkers have been proposed for the diagnosis and prediction of preeclampsia. Among these, maternal circulating factors such as soluble FMS-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor, and placental growth factor (PlGF), an angiogenic factor, are considered the most promising. Measuring these factors as a ratio allows assessment of the angiogenic imbalance that characterizes incipient or overt preeclampsia. The sFlt-1/PlGF ratio increases before the onset of preeclampsia and thus may help predict the disease. The test is used as a predictive tool in several countries but not yet routinely performed in Japanese hospitals.

We performed a systematic review of studies that assessed the performance of the sFlt-1/PlGF ratio in predicting preeclampsia in Japanese patients. Three studies were included in the systematic review. All studies reported high negative predictive values of the sFlt-1/PlGF ratio (i.e., for ruling out PE), in agreement with the current evidence of the test performance worldwide. The sFlt-1/PlGF ratio could be of significant relevance in the Japanese population.

Introduction

Hypertensive disorders of pregnancy (HDP) is a major complication encountered during pregnancy. In particular, preeclampsia (PE) occurs in roughly 3.5% of primiparas and 2.0% of multiparas in Japan¹⁾ and is associated with adverse fetal and maternal outcomes.^2,3)

PE is a placental disorder characterized by endothelial dysfunction, which is caused by excess inflow of placental factors into the maternal blood circulation, and results in various clinical syndromes. Currently, the only treatment is the delivery of the placenta (and concomitantly, the baby), and PE is a significant cause of iatrogenic preterm delivery. One of molecules identified as having a pivotal role in the process is anti-angiogenic soluble FMS-like tyrosine kinase-1 (sFlt-1).⁴⁾ In PE, an excess release of sFlt-1, which binds to circulating vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), leads to decreased free angiogenic factor levels in the maternal circulation.^{5,6,7,8,9,10)} VEGF and PlGF are important factors in the maintenance of endothelial homeostasis, and decreased VEGF and PlGF levels cause widespread vascular endothelial dysfunction.^4,11) Compared to pregnant women without PE, those with PE show higher sFlt-1 and lower PlGF levels. Thus, the ratio of sFlt-1 (i.e., anti-angiogenic factor) to PlGF (i.e., angiogenic factor) has been shown to increase before the onset of clinical signs and symptoms of PE.^{6,12,13,14,15,16,17)} The sFlt-1/PlGF ratio is used as a tool to predict, diagnose, and manage PE in pregnant women suspected of having PE in several countries.^18,19,20,21)

This test is now approved for use but is not yet routinely used in Japan. The objective of this systematic review was to assess the predictive accuracy of the sFlt-1/PlGF ratio for PE in a Japanese population.

Materials and methods

HDP is defined as hypertension (blood pressure ≥140/90 mmHg) during pregnancy and is classified into the following four categories: PE, gestational hypertension, superimposed PE, and chronic hypertension.²²⁾ Until recently, PE had been defined as a combination of elevated blood pressure ≥140/90 mmHg and proteinuria ≥300 mg/24 h at or after 20 weeks’ gestation with associated symptoms which normalize by 12 weeks postpartum. In 2018, the Japan Society for the Study of Hypertension in Pregnancy (JSSHP) revised the definition and classification of HDP in accordance with the International Society for the Study of Hypertension in Pregnancy (ISSHP) classification. Specifically, the JSSHP broadened the definition of PE to include ‘blood pressure ≥140/90 mmHg at or after 20 weeks’ gestation and either proteinuria (≥300 mg/24 h or protein/creatinine ratio ≥0.3), increased liver transaminase in the absence of liver disease, progressive kidney injury, cerebral or visual symptoms, thrombocytopenia due to HDP, or uteroplacental dysfunction.’²²⁾

We performed systematic manual and electronic literature searches to collect articles evaluating the value of the sFlt-1/PlGF ratio in predicting PE in Japanese populations according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols 2015 (PRISMA-P).²³⁾ We searched Embase and Medline databases from inception through August 20, 2019, using the following search terms: [sFlt-1 OR sFlt* OR sFlt1 OR FLT* OR “soluble fms-like tyrosine kinase-1” OR “fms-related tyrosine kinase” OR PlGF OR “placenta* growth factor” OR “Placenta Growth Factor” OR “angiogen*”] AND [Pre-eclampsia OR preeclamp* OR pre-eclamp* OR “pre eclamp*” ] AND [Japan OR japan*]. There were no language or study design restrictions. This systematic review is registered in PROSPERO.

The following inclusion criteria were used:

1. Measurement of sFlt-1 and PlGF in serum or plasma in pregnant women for the purpose of predicting the onset of PE (original research);

2. sFlt-1/PlGF ratio analyzed after 18 weeks’ gestation;

3. observational studies (cross-sectional, case-control, and cohort studies);

4. data available for constructing 2×2 diagnostic tables for the ratio;

5. Japanese population as study participants; and

6. published before August 2019.

The following exclusion criteria were used:

1. sFlt-1/PlGF ratio was not calculated;

2. the ratio was used to diagnose rather than predict PE;

3. the ratio was used to predict adverse outcomes rather than PE;

4. study participants were not Japanese; and

5. same patients were included in more than one study.

T. Y. and A. S. C. read and analyzed the full-text of articles to judge their eligibility for this review and extracted data independently. Disagreement between the two investigators was resolved by discussion. If no consensus could be reached, M.V. added a casting vote. Collected data included authors, year of publication, study design, number of patients, gestational age at the time of sampling, sample type, characteristics of study participants, thresholds used, test kit used, and the numbers required to construct 2×2 tables.

Results

From 418 relevant articles, we identified 23 full-text articles for further assessment, of which three were included in the present systematic review (Figure 1). With regard to an article by Ohkuchi et al.,¹⁴⁾ there were two other potentially eligible studies^13,15) which were eventually excluded due to overlap in study participants. Additional searches of reference lists of the identified manuscripts and database search including sVEGFR1 (an alternative nomenclature for sFlt-1) as a search term did not yield relevant articles for this review.

Figure 1.

Search strategy and study selection as per PRISMA-P guidelines

Out of 23 potentially relevant abstracts, 3 articles were included in the review.

The three articles analyzed were published between 2013 and 2019 and included a total of 73 Japanese women with PE and 1,560 controls (Table 1). All studies used the older definition of PE (i.e., before revision). All were prospective cohort studies. Only one study (PROGNOSIS ASIA¹²⁾) included only pregnant women at high risk of developing PE (with symptoms or signs suggestive of the disease). The other two studies included all pregnant women attending prenatal checkups. The PROGNOSIS ASIA study¹²⁾ used a multicenter (Japan, South Korea, China, Hong Kong, Singapore, and Thailand) observational design to derive and validate a serum cut-off sFlt-1/PlGF ratio for predicting PE within one and four weeks after the first diagnosis of suspected PE. No other studies have examined a high-risk cohort of pregnant women in Japan. Although analyses by country were not presented, there was no reason to believe that the cut-off value would be significantly different from the pooled analysis (the 95%CI was small). Two of the three studies measured serum sFlt-1 and PlGF, and one measured plasma sFlt-1 and PlGF. Measurements of sFlt-1 and PlGF were performed using the Roche electro-chemiluminescence immunoassay (ECLIA) kit in two studies and the R&D Systems enzyme-linked immunosorbent assay (ELISA) kit in one study (Table 1).

Table 1. Characteristics of included studies

Study	Ethnicity	Study design	Cases	Control	High risk	Gestational age	Biospecimen	Characteristics of study population	Characteristics of control
Ohkuchi et al.14) 2013	Japanese	Prospective cohort	34	1,165	No	19–25	Plasma	Singleton pregnancy with PE	Singleton pregnancy without PE
Zhai et al.16) 2016	Japanese	Prospective cohort	15	239	No	22–27	Serum	Pregnancy with PE	Pregnancy without PE
Bian et al.12) 2019	Multinational in Asia (180 Japanese women)	Prospective cohort	101 (24 Japanese)	599 (156 Japanese)	Yes	20–36 (18–36 in Japan)	Serum	Women with singleton pregnancy with suspected PE who developed PE	Women with singleton pregnancy with suspected PE who did not develop PE

PE, preeclampsia

The predictive accuracy of the sFlt-1/PlGF ratio for PE is presented in Table 2. Gestational age at sample collection, gestational age at PE onset, and different cut-off values used were analyzed separately. As a result, the total number of study groups increased to 10. Ohkuchi et al. reported a further subgroup analysis at 26–31weeks, which was not depicted in the table since these patients were the same as those who presented at 19 to 25 weeks, and the 26 to 31weeks group had a smaller number of patients.¹⁴⁾ Two studies used a discrete number as the cut-off, whereas one study (Ohkuchi et al.) used a complex algorithm comprising onset thresholds (when patients presented with PE) and abnormal thresholds as cut-offs (see below). Importantly, all three studies reported high negative predictive values (NPVs) for the sFlt-1/PlGF ratio, particularly in short-term prediction to rule out PE.

Table 2. Accuracy characteristics

Author	Gestational age	Cut-off	Sub-groups	High risk	Sensitivity	Specificity	PPV	NPV	Test
Ohkuchi et al.14) 2013	19–25	Onset threshold	≤4 wk	No	100	100	100	100	Roche Diagnostics
		10.5	≤4 wk	No	100	94	28	100
		10.5	All PE	No	38	95	18.1	98.1
		10.5	<36 wk	No	61	95	15.3	99.4
		10.5	<34 wk	No	71	95	13.9	99.6
		10.5	<32 wk	No	82	95	12.5	99.8
Zhai et al.16) 2016	22–27	4.85		No	40	90	20	96	R&D systems
		8.8		No	40	96.2	40	96.2
Bian et al.12) 2019	20–36 (18–36 in Japan)	38	≤1 wk	Yes	76.5	82.1	17.9	98.6	Roche Diagnostics
		38	≤4 wk	Yes	62	83.9	30.3	95.1

PE, preeclampsia; NPV, negative predictive value; PPV, positive predictive value

Ohkuchi et al. defined thresholds for the imminent onset of PE according to the distribution of the marker just after PE onset as “onset thresholds” (2.5^th centile), and conventional thresholds according to the distribution of the sFlt-1/PlGF ratio in normal pregnant women as “abnormal thresholds” (95^th centile), and derived the following equations:^13,14)

[log₁₀ (sFlt-1/PlGF)]

Mean: 0.00668 w²−0.363 w+5.255 (where w is gestational weeks at sampling)

SD: 0.0116 w−0.00642

Onset threshold of log₁₀ (sFlt-1/PlGF) [SDS]=−0.478 w+17.787 (where w=gestational weeks that PE occurred)

Onset threshold of log₁₀ (sFlt-1/PlGF)=0.00103 w²–0.154 x+5.141

Discussion

The utility of a test for predicting a disease depends on the prevalence of the disease, patient population, and the healthcare system into which the test is to be incorporated. Maternal mortality in Japan is reported to be around 4 per 100,000 deliveries,²⁴⁾ which is similar to those reported in other developed countries. In Japan, roughly 900,000 deliveries per year are managed by approximately 2,500 facilities, more than half of which are private facilities with one to three obstetricians.²⁵⁾ Notably, half of all maternal deaths are attributed to complications at private facilities, with subsequent maternal transfer to tertiary hospitals.²⁶⁾ The most common cause of maternal death in Japan is obstetric hemorrhage, followed by neurological disease which has a strong association with HDP.^26,27) In 2015, complications of HDP accounted for 14% of all maternal deaths.²⁸⁾ In situations where HDP including PE remains unrecognized or misdiagnosed, a subset of women can develop serious complications.^29,30,31) Appropriate management of HDP, especially PE, that ensures timely prediction and maternal transport to a tertiary hospital is important for reducing maternal mortality.

The diagnosis of PE is currently based on an assessment of blood pressure and quantification of proteinuria or other organ disorders. However, due to the nature of the syndrome with various onset processes and varying clinical presentation of phenotypes, the reliability and specificity of assessments to predict PE are poor.³²⁾ Numerous studies have been conducted on PE prediction using angiogenesis-related factors (e.g., sFlt-1, soluble endoglin (sEng), PlGF, and VEGF), maternal characteristics, and/or ultrasound markers.^33,34) A systematic review and meta-analysis by Kleinrouweler et al. in 2012 reported summary diagnostic odds ratios of 6.6 (95% CI 3.1–13.7) for sFlt-1, 4.2 (95% CI 2.4–7.2) for sEng, and 9.0 (95% CI 5.6–14.5) for PlGF, with 26%, 18%, and 32% sensitivities, respectively, and a 5% false positive rate.³⁵⁾ These results suggest that individual angiogenesis-related factors alone are not clinically useful for predicting PE onset. Other proposed predictive serum markers of PE include pregnancy-associated plasma protein-A, placental protein 13, and inhibin A. While these markers alone or in combination have been shown to have some clinical utility, their predictive values when used alone are not high enough for clinical application.³⁴⁾ Recently, several placenta-related microRNA biomarkers have been reported to predict PE.^15,36)

Currently, the most widely used serum markers worldwide are PlGF and sFlt-1. Previous meta-analyses and multicenter studies have demonstrated good performance of the sFlt-1/PlGF ratio in predicting the onset of PE,^16,37,38) particularly for ruling out PE in pregnant women with suspected PE. The PROGNOSIS study, which included 1,273 women with suspected PE from 24+0 to 36+6 weeks’ gestation across 14 countries in Europe and America, reported that an sFlt-1/PlGF ratio ≤38 had an NPV of 99.3% (95% CI, 97.9–99.9) for ruling out PE within one week, with 80% (95% CI, 51.9–95.7) sensitivity and 78.3% (95% CI, 74.8–81.7) specificity. The positive predictive value (PPV) for ruling in PE within four weeks was 36.7% (95% CI, 28.4–45.7).¹⁶⁾ The very high NPV permits adequate rationalization of treatment for women who test positive, while simultaneously reassuring those with a negative test result. Based on this and other studies, the sFlt-1/PlGF ratio is now routinely used in the UK and several other countries as an aid to rule out PE in patients with suspected PE. Recently, the PROGNOSIS-ASIA study in 25 Asian centers (including eight centers in Japan with a total of 192 patients) confirmed a high NPV of 98.6% (95% CI, 97.2–99.4) with a cut-off sFlt-1/PlGF ratio of ≤38.¹²⁾ The PPV was 30.3% (95% CI, 23.0–38.5) for ruling in PE within the next four weeks.¹²⁾ Since both sFlt-1 and PlGF concentrations, as well as the accuracy of the sFlt-1/PlGF ratio, could be influenced by ethnicity,^39,40) we conducted the current systematic review targeting only Japanese women.

The three studies included in the present review that investigated the ability of the sFlt-1/PlGF ratio to predict PE in pregnant women in Japan all reported high NPVs, particularly for short-term prediction. Several studies have shown that the sFlt-1/PlGF ratio decreases first before gradually increasing with gestational age in PE as well as normal pregnant women. For this reason, Ohkuchi et al. used gestational age-specific cut-off values.^13,14,15) The sFlt-1/PlGF ratio is also dependent on the severity of PE and gestational age, and therefore, cut-off values varied among studies. Most studies using the sFlt-1/PlGF ratio focused on defined time periods for ruling in/out PE after measurements. Ohkuchi et al. used threshold ratios to determine risks over longer gestational periods. Given that the increase in sFlt-1/PlGF ratio precedes the onset of PE by 5–6 weeks,⁶⁾ it is likely that the ratio is less useful for predicting PE in a longer time frame. Indeed, Ohkuchi et al. noted that the predictive performance increases if the interval from the time of sampling is shorter (Table 2). Thus, the sFlt-1/PlGF ratio appears to be most effective in predicting PE over a period of four weeks.^12,16)

Pregnant women with signs or symptoms of PE are often hospitalized for intensive monitoring until PE is ruled out. The sFlt-1/PlGF ratio can be used to accurately rule out PE, which would allow low risk patients to be safely discharged, relieve anxiety, and potentially reduce healthcare costs. The use of the sFlt-1/PlGF ratio in clinical practice has been shown to improve risk stratification and guide hospital admissions.⁴¹⁾ Moreover, timely prediction of PE enables positive patients to be referred to adequate tertiary centers, thereby reducing adverse outcomes associated with the disease. Better risk stratification could, therefore, lead to better management and reduced adverse outcomes, while improving the allocation of health resources.^{20,38,41,42,43)}

The sFlt-1/PlGF test has obtained approval for routine clinical use in several countries. For example, the test is used to rule-out PE in high-risk pregnant women in Germany and the United Kingdom.^20,21) The National Institute for Health and Care Excellence (NICE) recommends using the test to rule-out PE in pregnant women with suspected PE from 20 to 35 weeks’ gestation.²⁰⁾ The PROGNOSIS Asia study demonstrated that an sFlt-1/PlGF ratio of ≤38 can be used to rule out the occurrence of PE within one week with a NPV of 98.6% in women with suspected PE. Japanese women were included among the study participants of other Asian countries in the PROGNOSIS Asia study.¹²⁾ In Japan, sFlt-1 and PlGF (Roche Diagnostics) were approved for in vitro diagnostics in 2019 for pregnant women with signs and symptoms of PE after 18 weeks’ gestation. However, these tests have yet to gain widespread use in Japan. The present systematic review confirmed that the sFlt-1/PlGF ratio is useful for ruling out PE with a high NPV in a Japanese population.

Interesting questions remain. Gestational age-specific cut-offs have been established for ruling in PE,⁴⁴⁾ but whether these cut-offs would apply to the Japanese population is unclear. Furthermore, cut-off values for repeat testing and relative changes in the ratio have not been determined. These are subjects of current investigation.

Given that the Japanese healthcare system involves the transfer of pregnant women with severe PE from primary clinics and secondary medical institutions to tertiary care centers, such studies could be of particular value. The sFlt-1/PlGF ratio can robustly rule out PE better than standard clinical management, while the PPV outperforms routine clinical assessment.⁴¹⁾ This systematic review suggests that assessment of the sFlt-1/PlGF ratio may lead to better management of PE in Japan.

Acknowledgments

The authors would like to thank Ms. Liz Callow from the Bodleian Health Care Libraries, University of Oxford, Oxford UK, for her invaluable assistance with the literature searches. Dr. Cerdeira received the 2019 Canon Fellowship from the Canon Research Foundation and is supported by a National Institute for Health Research Clinical Lectureship.

Conflict of interest

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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