Introduction

Preeclampsia is a pregnancy-specific hypertensive disorder, defined by new-onset hypertension after 20 weeks’ gestation associated with proteinuria and/or maternal or placental organ-damage features. It remains one of the leading causes of maternal and perinatal morbidity and mortality worldwide, affecting approximately 2–8% of pregnancies depending on population and diagnostic criteria [1-4].

Over recent decades, research has shown that preeclampsia is strongly associated with abnormal placentation and a systemic anti-angiogenic state, characterized by increased circulating concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased placental growth factor (PlGF). By binding to and neutralizing VEGF and PlGF, sFlt-1 contributes to generalized endothelial dysfunction, which is considered central in the pathophysiology of the disease [2-6]. This mechanistic insight has paved the way for the development of angiogenic biomarkers to refine diagnosis and risk stratification in women with suspected disease.

Combined quantification of these biomarkers as the sFlt-1/PlGF ratio has emerged as a particularly useful tool. The multicenter PROGNOSIS trial showed that a ratio ≤38 has an excellent negative predictive value for ruling out the development of preeclampsia in the short term,[1] findings that have been confirmed in other cohorts and summarized in recent reviews [6,7]. Higher ratios are associated with an increased likelihood of preeclampsia and adverse maternal–fetal outcomes [1,6,7].

In this context, we report a case of suspected preeclampsia without significant proteinuria at 34 weeks’ gestation, in which a markedly elevated sFlt-1/PlGF ratio was crucial for diagnostic confirmation, risk stratification and timing of delivery.

Case Report

A 29-year-old primigravida, with no relevant past history of chronic hypertension, renal disease, diabetes or autoimmune disorders, was followed in a high-risk pregnancy clinic because of an increased risk of preeclampsia in first-trimester screening. Prophylaxis with acetylsalicylic acid 150 mg/day was initiated according to current recommendations, and she maintained regular follow-up. Pregnancy progressed without significant intercurrent events until the third trimester, with serial ultrasound assessments documenting appropriate fetal growth, with estimated fetal weight between the 13th and 17th percentiles and no signs of fetal growth restriction.

At 34 weeks and 1 day, during a routine visit, new-onset hypertension was detected, with a blood pressure reading of 140/100 mmHg in a previously normotensive woman. She was asymptomatic, and physical examination revealed no marked oedema or other warning signs. Initial laboratory evaluation showed renal function within the normal range, hyperuricemia and no significant changes in hemoglobin, platelets or coagulation parameters. Assessment of proteinuria did not reveal significant protein excretion, with a urinary protein/creatinine ratio of 0.18 mg/g. In this setting, the differential diagnosis between gestational hypertension and preeclampsia without proteinuria was considered, and it was decided to complement the investigation with measurement of angiogenic biomarkers.

The sFlt-1/PlGF ratio was markedly increased, at 318.4. According to the institutional protocol, which considers values >201 after 34 weeks as indicative of a high risk of progression to preeclampsia and short-term maternal–fetal complications, the patient was admitted for close maternal–fetal surveillance and administration of corticosteroids for fetal lung maturation. During admission she remained hypertensive, under serial monitoring of maternal, laboratory and fetal parameters.

At 34 weeks and 3 days, with persistent suspicion of preeclampsia and a high sFlt-1/PlGF ratio, a decision was made to induce labour in accordance with the local protocol. Intrapartum evolution was complicated by arrest of dilatation and the appearance of non-reassuring fetal status, concomitant with rising transaminases, leading to caesarean section. A male newborn weighing 1884 g, with Apgar scores of 6/8/10, was delivered and admitted to the neonatal intensive care unit, with favourable subsequent progress.

Postoperatively, the mother received a 24-hour infusion of magnesium sulfate in the context of preeclampsia with a severe feature and was started on antihypertensive therapy. Clinical evolution was favourable, with progressive blood pressure control and improvement of laboratory parameters. She was discharged on postoperative day 7, asymptomatic and scheduled for follow-up in the puerperium clinic (Figure 1).

Discussion

The sFlt-1/PlGF ratio has assumed a central role in the management of women with suspected preeclampsia, mainly because of its high short-term rule-out capacity. In the PROGNOSIS study, a ratio ≤38 showed a very high negative predictive value for excluding the development of preeclampsia within 1 week, and to a lesser extent within 4 weeks, in women with clinical suspicion of the disease [1]. Subsequent work, including data from other cohorts and recent reviews, has confirmed that a low ratio is strongly associated with a low short-term risk of developing preeclampsia, whereas ratios above 38 are progressively associated with diagnosis and adverse maternal–fetal outcomes [6,7,9].

Several studies have proposed higher thresholds (cut-offs) for identifying women at increased risk, adjusted to gestational age. Implementation studies report that ratios >85 before 34 weeks and >110 after 34 weeks are associated with a higher likelihood of preeclampsia or other placenta-mediated disorders, whereas values below these thresholds are associated with a low risk of short-term complications [6,7]. Very high ratios are also linked to a greater frequency of preterm birth and maternal morbidity [6,7].

In the present case, the sFlt-1/PlGF ratio of 318.4 at 34+1 weeks clearly falls within a high-risk range, well above the thresholds usually proposed after 34 weeks [1,6,7]. At the time of sampling, the clinical picture was compatible with new-onset hypertension without significant proteinuria and without laboratory features of severity, which could have been interpreted as gestational hypertension. However, the markedly elevated ratio, in line with the institutional protocol that considers values >201 as indicative of high short-term risk, supported hospital admission and the decision not to prolong the pregnancy beyond 34+3 weeks. This strategy enabled administration of antenatal corticosteroids and planned delivery in a controlled setting; the subsequent rise in transaminases and the need for caesarean section because of non-reassuring fetal status suggest that the patient was on a trajectory towards preeclampsia with a severe feature.
International recommendations acknowledge the potential of angiogenic biomarkers as a diagnostic adjunct. The 2021 International Society for the Study of Hypertension in Pregnancy (ISSHP) guidelines state that the sFlt-1/PlGF ratio may support the diagnosis of preeclampsia and the differential diagnosis with gestational hypertension, particularly in equivocal cases, while emphasising that these tests must be interpreted within the overall clinical context [3]. NICE guideline NG133 and diagnostics guidance DG49 recommend PlGF-based and sFlt-1/PlGF-based tests as an aid to the diagnosis of suspected preterm preeclampsia and to optimise resource use (inpatient vs outpatient care), but explicitly advise that they should not be used in isolation to determine the timing of birth [4,5].

This case illustrates both the strengths and limitations of the sFlt-1/PlGF ratio. A key strength is its ability to reclassify apparently borderline situations (such as hypertension without proteinuria) as high risk, prompting closer surveillance and timely delivery that may prevent more serious maternal–fetal complications [1,6-8]. Limitations include the lack of universal consensus on optimal thresholds to guide delivery, differences between analytical platforms and populations, and the fact that robust evidence is still limited regarding the impact of biomarker-guided strategies on hard clinical outcomes across all settings. Ongoing studies and health-technology assessments, including work conducted in Portugal, suggest that using the sFlt-1/PlGF ratio may also be cost-effective, but further data are needed [7,8].

Conclusion

This case illustrates the usefulness of the sFlt-1/PlGF ratio in the management of a woman with new-onset hypertension without proteinuria at 34 weeks’ gestation, allowing reclassification of a situation apparently compatible with gestational hypertension as a high-risk condition for progression to preeclampsia with a severe feature. Determination of this biomarker helped justify hospital admission, guide surveillance and support the decision not to prolong the pregnancy, and was associated with a favourable maternal–fetal outcome. The sFlt-1/PlGF ratio should be regarded as a complementary tool for clinical, laboratory and ultrasound assessment and may be decisive when incorporated into well-defined protocols. Further studies are needed to harmonise gestational-age-specific thresholds and to consolidate evidence of its impact on clinically relevant outcomes.

References
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