Maternal-Foetal Medicine
Figure 4: Receiver Operating Characteristic Curves of sFlt-1/PIGF Ratio in all Pre-eclampsia Cases (A), Early-onset PE (B) and Late-onset PE (C)
A
1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00
0.00 C
1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00
0.00 0.20 0.40 0.60 1-Specificity false positive
PE = pre-eclampsia; PIGF = placental growth factor; sFlt-1 = soluble fms-like tyrosine kinase-1. Source: Adapted from Verlohren et al., 2010.18
ratio in both groups over time revealed a U-shaped curve in women with normal pregnancies, while values peaked before 35 weeks’ gestation in women with PE. Overall, this shows that the difference between groups was widest in early-onset disease (see Figure 318
).
These results were highly consistent with a nested case-control study within the Calcium for preeclampsia prevention (CPEP) trial, which compared sFlt-1 and PIGF levels throughout pregnancy in 655 serum samples from 240 randomly chosen women (120 with PE and 120 without hypertension).16
Mean serum levels of sFlt-1 in
normotensive controls remained low for the first three trimesters before showing a moderate increase in the final trimester. In contrast, women with PE had high sFlt-1 values in late pregnancy. Placental growth factor levels increased and peaked at around 30 weeks’ gestation in normotensive women but remained low with only a slight rise towards the end of pregnancy in women with PE. The same group subsequently reported sFlt-1/PIGF outcomes in 552 women (72 with pre-term PE, 120 with PE after at least 37 weeks, 120 with gestational hypertension (GH), 120 with normal BP who delivered SGA infants and 120 controls with normal BP whose infants were not SGA).19
Ratios of 16 0.80 1.00
sFlt-1/PIGF increased from 9–11 weeks before onset of pre-term PE (p≤0.004 versus controls from 17–20 weeks) and up to five weeks before onset of term PE.
Recent data from a prospective study including 159 pregnant women also showed that women with PE had higher sFlt-1 levels, lower PIGF levels and higher sFlt-1/PIGF ratios than normotensive women.17 Longitudinal analyses revealed that between 10–40 weeks’ gestation, women who developed pre-term PE had 132 % lower serum PIGF levels, 67 % higher sFlt-1 levels and 205 % higher sFlt-1/PIGF ratio values than normotensive women.
Accuracy of the Elecsys Assays
Both Elecsys assays demonstrated high sensitivity and specificity: receiver operating characteristic curves had area under the curve (AUC) values of 0.91 and 0.92 for sFlt-1 and PIGF respectively, in all patients with PE, and the sFlt-1/PIGF ratio was significantly superior to either value alone (p<0.05), with an AUC of 0.95.18
The optimal
diagnostic performance was achieved using the sFlt-1/PIGF ratio to detect early-onset PE, with an AUC of 0.97 (compared with 0.89 for late-onset PE; see Figure 418
). Suggested Cut-off Values
A suggested preliminary cut-off value of 85 offers a sensitivity of 82 % and specificity of 95 % for the sFlt-1/PIGF ratio across all gestational ages. The circulating serum concentrations of sFlt-1 and PIGF and their ratio change in the course of a normal pregnancy, consistent with the scatter plot shown in Figure 3.18
0.20 0.40 0.60 1-Specificity false positive 0.80 1.00 B 1.00
0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00
0.00 0.20 0.40 0.60 1-Specificity false positive 0.80 1.00
The same cut-off value of 85
achieved a sensitivity of 89 % and a specificity of 97 % for early-onset PE, compared with 74 % and 89 %, respectively, for late-onset PE.18
Potential Clinical Value of the sFlt-1/PIGF Ratio The evidence outlined above demonstrated that the sFlt-1/PIGF ratio could be used to accurately diagnose PE. Further questions remain about how this measurement could support clinical management to optimise outcomes for both mother and child. We continued and expanded the above study18 of the sFlt-1/PIGF ratio.20
study, which then included 164 patients with PE and/or HELLP EUROPEAN OBSTETRICS & GYNAECOLOGY
to evaluate potential clinical applications An additional 279 patients entered the
True positive sensitivity
True positive sensitivity
True positive sensitivity
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