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Keywords:

  • angiogenesis;
  • intrauterine growth restriction;
  • placental growth factor;
  • pre-eclampsia;
  • soluble fms-like tyrosine kinase 1;
  • uterine artery Doppler

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objectives

To investigate potential differences in the prediction of early- vs. late-onset pre-eclampsia and/or intrauterine growth restriction (PE/IUGR) by second-trimester uterine artery Doppler examination, and measurement of maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt1).

Methods

Uterine artery mean pulsatility index (PI) and maternal serum PlGF and sFlt1 levels were measured at 24 weeks of gestation in 76 healthy pregnant women and 38 cases of PE/IUGR, of which 19 were defined as early onset (< 32 weeks).

Results

For a specificity of 95%, the sensitivities of uterine artery mean PI, PlGF and sFlt1 for early-onset PE/IUGR were 47.4%, 84.4% and 36.8%, respectively. When combining uterine artery Doppler with PlGF, the sensitivity for identifying early-onset PE/IUGR was 89.5% with a specificity of 95%. Conversely, the sensitivity for late-onset PE/IUGR was below 11% for all parameters analyzed.

Conclusions

Angiogenic factors and uterine artery Doppler evaluation may be useful second-trimester screening tests for early-onset, but not late-onset, PE/IUGR. Copyright © 2007 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are major causes of maternal perinatal morbidity and mortality1. It is increasingly becoming accepted that early-onset and late-onset PE should be regarded as different forms of the disease. Early-onset PE is commonly associated with IUGR, abnormal uterine and umbilical artery Doppler evaluation, and adverse maternal and neonatal outcomes1–4. In contrast, late-onset PE is mostly associated with mild maternal disease and a low rate of fetal involvement, and perinatal outcomes are usually favorable2–4.

Prediction of PE and/or IUGR has been a major clinical and research issue for the past 20 years2. So far, the best test for predicting PE or IUGR at 20–24 weeks of gestation is uterine artery Doppler examination, with reported sensitivities for these conditions ranging from 30 to 80%5. Although most studies have focused on the prediction of PE or IUGR occurring at any time during pregnancy, it seems likely that sensitivity is much higher for early-onset forms5.

Recent evidence suggests that angiogenic factors are involved in the pathogenesis of PE and their assessment could be useful for the early prediction of the disease6–11. Placental growth factor (PlGF) is expressed by trophoblast cells at high levels and is involved in the regulation of placental vascular development12. Circulating soluble fms-like tyrosine kinase 1 (sFlt1) is a potent PlGF antagonist that prevents its interaction with cell receptors. Increased sFlt1 levels and decreased circulating PlGF levels have been demonstrated in PE3, 6, 12, as well as in isolated IUGR3, 13, 14. Differences in the levels of these factors with respect to healthy pregnancies are considerably more pronounced in early-onset cases, whereas in late-onset disease there is substantial overlap with controls3. Several studies have shown that abnormal levels of angiogenic and antiangiogenic factors may be detected 5–14 weeks before the clinical onset of PE and even in the first trimester7–11. One recent study suggested that the increase in antiangiogenic factors occurred earlier in PE that developed before term than in term PE8.

If late-onset PE/IUGR constitutes a heterogeneous condition with minimal or no placental involvement, tests based on the identification of signs of abnormal placentation may continue to be of limited value in predicting this entity. We investigated the existence of differences in the prediction of early- vs. late-onset PE/IUGR by uterine artery Doppler evaluation and measurement of maternal serum PlGF and sFlt1 at 24 weeks' gestation.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study population

This was a nested case–control study including pregnancies at 24 weeks of gestation, in which uterine artery pulsatility index (PI) and maternal serum PlGF and sFlt1 concentrations were measured. Patients were recruited from a prospective study of uterine artery screening for PE/IUGR by transabdominal Doppler measurement at 20–24 weeks in 3235 singleton pregnancies who attended the obstetrics department from June 2001 to June 2006. Blood samples were also collected at 24 weeks of gestation and the serum was stored at − 80 °C. Pregnancies with abnormal uterine artery Doppler findings (mean PI above the 95th percentile for gestational age according to our population reference values) underwent an extra ultrasound examination during pregnancy (28 weeks' gestation). The study protocol was approved by the institutional ethics committee, and all patients provided written informed consent.

Outcomes were ascertained from hospital medical records by independent assessors who were blinded to ultrasound and biochemical results. The criteria of the International Society for the Study of Hypertension in Pregnancy were used to define PE15. PE was diagnosed if a previously normotensive woman had two repeat (4 h apart) diastolic blood pressure measurements of ≥ 90 mmHg after the 20th week of gestation, together with proteinuria of more than 300 mg in a 24-h urine specimen or at least two protein dipsticks in two repeat measurements (4 h apart). IUGR was defined as a birth weight below the 10th percentile for gestational age together with a Doppler PI in the umbilical artery above the 95th percentile16–18. Fetuses with structural or chromosomal abnormalities were excluded. For the purposes of this study, both IUGR and PE were classified as early onset (gestational age under 32 weeks at clinical onset) or late onset (32 weeks or over). The cut-off used to define early and late onset was chosen arbitrarily.

Uterine artery Doppler evaluation

Uterine artery Doppler velocimetry was performed at 24 weeks of gestation by transabdominal ultrasound imaging using 6–4-MHz probes (Siemens Sonoline Antares; Siemens Medical, Munich, Germany). The PI in both uterine arteries was calculated and averaged to obtain the mean PI.

Blood samples and biochemical analysis

Venous blood samples were drawn the same day as uterine artery Doppler evaluation and were processed within 1 h. Serum was separated by centrifugation at 1400 g for 10 min at 4 °C, and samples were immediately stored at − 80 °C until assay. Levels of PlGF and sFlt1 in maternal serum were measured using sandwich enzyme immunoassay kits (R&D Systems Europe Ltd, Abingdon, UK). All samples were measured in duplicate after being appropriately diluted such that readings fitted within the standard curve. In all kits, the intra-assay precision was always < 5% and interassay precision < 10%. The linear regression coefficients of the standard curves were never below 0.99.

Statistical analysis

Data were analyzed with the SPSS 13.0 statistical package (SPSS, Chicago, IL, USA). Results are expressed as mean ± SD, or as median (interquartile range, IQR) when data were not normally distributed. Comparisons between groups were performed by ANOVA or the Kruskal–Wallis test for normally and non-normally distributed data, respectively. Bonferroni's adjustment was performed for multiple comparisons. The sensitivity and specificity for different cut-offs of marker levels were calculated, and receiver–operating characteristics (ROC) curves were estimated to assess the performance of various predictive variables following models described previously19, 20. Logistic regression was used to assess the area under the ROC curve of the predicted probabilities of each outcome (early- and late-onset PE/IUGR) when two or more markers were included in the model.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Clinical characteristics of the study population

A search was made of the database to identify all pregnancies that subsequently developed PE or IUGR, for which data on uterine artery Doppler evaluation and blood samples were available. There were 10 cases of early-onset PE (0.3%), 13 cases of early-onset normotensive IUGR (0.4%), 29 cases of late-onset PE (0.9%) and 22 cases of late-onset normotensive IUGR (0.7%). We could retrieve 10, nine, 27 and 19 samples from each group, respectively. However, as there were only 19 early-onset cases, we randomly selected 19 late-onset cases for analysis of blood samples. Additionally, each case was matched to two singleton control pregnancies for the duration of sample storage.

Baseline clinical features at enrollment are shown in Table 1. The rate of nulliparity was significantly higher, and gestational age at delivery and mean birth weight were significantly lower, in early-onset PE/IUGR cases than in controls.

Table 1. Clinical characteristics of the study population
CharacteristicControls (n = 76)Early-onset PE/IUGR (n = 19)Late-onset PE/IUGR (n = 19)
  1. Blood pressure values represent the highest recorded during pregnancy. IUGR, intrauterine growth restriction; PE, pre-eclampsia.

Maternal age at delivery (years, mean ± SD)32 ± 529 ± 532 ± 5
Nulliparous (%)358341
Caucasian (%)9410082
Smoker (%)281313
Body mass index (kg/m2, mean ± SD)26 ± 429 ± 727 ± 6
Gestational age at onset (weeks, mean ± SD)28 ± 236 ± 2
Systolic blood pressure (mmHg, mean ± SD)121 ± 14163 ± 17160 ± 18
Diastolic blood pressure (mmHg, mean ± SD)70 ± 12100 ± 896 ± 9
Gestational age at delivery (weeks, median (IQR))39 (36–42)29 (25–33)37 (34–40)
Birth weight (g, mean ± SD)3182 ± 571998 ± 3232345 ± 479
Birth weight percentile (mean ± SD)49 ± 3012 ± 714 ± 9

Uterine artery Doppler and angiogenic factors

Uterine artery mean PI was significantly higher in the two groups of cases than in healthy controls (Table 2 and Figure 1a). There were no significant differences in median (IQR) uterine artery mean PI between women with PE and those with normotensive IUGR, irrespective of the time of onset (early-onset PE vs. early-onset IUGR, 1.77 (1.30) vs. 1.99 (0.8), P = 0.4; late-onset PE vs. late-onset IUGR, 1.55 (0.43) vs. 1.68 (0.89), P = 0.8).

thumbnail image

Figure 1. Uterine artery mean pulsatility index (PI) (a), maternal serum placental growth factor (PlGF) levels (b), soluble fms-like tyrosine kinase 1 (sFlt1) levels (c) and sFlt1/PlGF ratio (d) in healthy pregnant women (controls), those with early-onset (< 32 weeks) pre-eclampsia (PE) and/or intrauterine growth restriction (IUGR) and those with late-onset (≥ 32 weeks) PE/IUGR. Boxes show median and interquartile range (IQR). Whiskers represent either 1.5 × IQR or the extremes of the distribution, and circles represent values higher or lower than 1.5 × IQR.

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Table 2. Uterine artery pulsatility index (PI) and maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt1) in cases and controls
VariableControlsEarly-onset PE/IUGRLate-onset PE/IUGR
  • Data are presented as median (interquartile range).

  • *

    P < 0.01 vs. controls. IUGR, intrauterine growth restriction; PE, pre-eclampsia.

Uterine artery mean PI1.25 (0.78)1.93 (0.93)*1.58 (0.5)*
PlGF (pg/mL)426 (289)92 (62)*260 (146)*
sFlt1 (pg/mL)526 (449)1257 (698)*660 (210)
sFlt1/PlGF ratio1.50 (1.64)13.79 (17.09)*2.48 (2.53)*

Maternal serum PlGF levels were significantly lower in patients with PE/IUGR than in women with uncomplicated pregnancies (Table 2 and Figure 1b). However, the difference in PlGF levels was much more pronounced in early-onset PE/IUGR than in late-onset cases. There were no significant differences in median (IQR) PlGF levels between women with PE and those with normotensive IUGR, irrespective of the time of onset (early-onset PE vs. early-onset IUGR, 99 (29) pg/mL vs. 71 (91) pg/mL, P = 0.1; late-onset PE vs. late-onset IUGR, 262 (186) pg/mL vs. 260 (151) pg/mL, P = 1).

Maternal serum sFlt1 levels were significantly higher in the early-onset PE/IUGR group than in controls, but not in the late-onset group (Table 2 and Figure 1c). There were no significant differences in median (IQR) sFlt1 levels between women with PE and those with normotensive IUGR, irrespective of the time of onset (early-onset PE vs. early-onset IUGR, 1057 (589) pg/mL vs. 1463 (1157) pg/mL, P = 0.3; late-onset PE vs. late-onset IUGR, 677 (370) pg/mL vs. 540 (316) pg/mL, P = 0.07).

Finally, although the sFlt1/PlGF ratio was significantly increased in the two groups of cases compared with controls, the observed difference was much more pronounced in early-onset than in late-onset patients (Table 2 and Figure 1d). There were no significant differences in the median (IQR) sFlt1/PlGF ratio between women with PE and those with normotensive IUGR, irrespective of the time of onset (early-onset PE vs. early-onset IUGR, 11.48 (16.21) vs. 19.68 (62.42), P = 0.2; late-onset PE vs. late-onset IUGR, 2.7 (2.71) vs. 1.69 (1.8), P = 0.5).

Accuracy of screening tests

The areas under the ROC curves and predicted sensitivities, for different specificities, of early- and late-onset PE/IUGR by uterine artery mean PI and maternal serum markers are shown in Tables 3 and 4, and Figures 2 and 3.

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Figure 2. Receiver–operating characteristics curves for screening of early-onset pre-eclampsia and/or intrauterine growth restriction by uterine artery mean pulsatility index (------), maternal serum placental growth factor (—) and maternal serum soluble fms-like tyrosine kinase 1 (…………).

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thumbnail image

Figure 3. Receiver–operating characteristics curves for screening of late-onset pre-eclampsia and/or intrauterine growth restriction by uterine artery mean pulsatility index (------), maternal serum placental growth factor (—) and maternal serum soluble fms-like tyrosine kinase 1 (…………).

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Table 3. Area under the receiver–operating characteristics curve (AUC) and sensitivity of screening for early-onset pre-eclampsia and/or intrauterine growth restriction (< 32 weeks of gestational age) by uterine artery Doppler evaluation and maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt1)
Screening methodAUC (95% CI)Sensitivity (%) for a specificity of:
95%90%80%
  1. PI, pulsatility index.

Uterine artery mean PI0.851 (0.761–0.942)47.452.673.3
PlGF0.963 (0.911–0.989)84.484.294.7
sFlt10.847 (0.735–0.958)36.852.678.9
sFlt1/PlGF ratio0.963 (0.926–1)78.984.294.7
Uterine artery mean PI and PlGF0.974 (0.944–1)89.589.594.7
Uterine artery mean PI and sFlt10.940 (0.897–0.984)63.273.7100
PlGF and sFlt10.972 (0.941–1)84.294.794.7
Uterine artery mean PI and sFlt1/PlGF ratio0.979 (0.952–1)84.289.5100
Uterine artery mean PI, PlGF and sFlt10.981 (0.957–1)89.589.5100
Table 4. Area under the receiver–operating characteristics curve (AUC) and sensitivity of screening for late-onset pre-eclampsia and/or intrauterine growth restriction (≥ 32 weeks of gestational age) by uterine artery Doppler evaluation and maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt1)
Screening methodAUC (95% CI)Sensitivity (%) for a specificity of:
95%90%80%
  1. PI, pulsatility index.

Uterine artery mean PI0.617 (0.496–0.738)010.526.3
PlGF0.599 (0.504–0.689)005.3
sFlt10.532 (0.417–0.646)0015.8
sFlt1/PlGF ratio0.597 (0.486–0.690)0026.3
Uterine artery mean PI and PlGF0.620 (0.508–0.733)0010.5
Uterine artery mean PI and sFlt10.608 (0.484–0.733)5.310.536.8
PlGF and sFlt10.636 (0.512–0.760)5.315.826.3
Uterine artery mean PI and sFlt1/PlGF ratio0.667 (0.549–0.785)10.526.331.6
Uterine artery mean PI, PlGF and sFlt10.654 (0.532–0.776)010.552.6

For a specificity of 95%, the sensitivities for early-onset PE/IUGR were 47.4% by uterine artery Doppler examination, 84.4% by maternal serum PlGF and 36.8% by sFlt1 measurement. The combination of PlGF with uterine artery Doppler yielded a sensitivity of 89.5% (Table 3 and Figure 2).

For a specificity of 95%, the sensitivity for late-onset PE/IUGR was below 11% for all parameters analyzed (Table 4 and Figure 3).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study provides evidence that PlGF measurement may be a useful second-trimester screening test for early-onset PE/IUGR, alone or in combination with sFlt1 or uterine artery Doppler examination. In contrast, the data do not support the use of these parameters to predict late-onset PE/IUGR.

In this study, PlGF showed high sensitivity in predicting early-onset PE/IUGR, which warrants its evaluation in large prospective studies. Uterine artery Doppler and sFlt1 measurements showed a higher degree of overlap with controls and consequently their predictive values were lower, even for early-onset cases. However, the highest accuracy was achieved by the combination of PlGF with either uterine artery Doppler or sFlt1 measurement, suggesting the potential benefit of combining the tests.

The findings of our study are consistent with previously reported data21–23. In a prospective study conducted in 122 high-risk pregnancies with a PE prevalence of 11%, second-trimester PlGF had the highest predictive value for PE whereas uterine artery Doppler was slightly less effective21. In another study, Parra et al. prospectively evaluated PlGF and sFlt1 together with other biochemical markers in the first and second trimester in 170 low-risk pregnancies22. Second-trimester PlGF levels were independently associated with PE, although PlGF did not improve the predictive value of uterine artery Doppler results alone. Savvidou et al. evaluated sFlt1 but not PlGF at 23–25 weeks. In agreement with our results, these authors found considerable overlap with controls and a relatively poor predictive value23. However, although the sample size was too small to allow definitive conclusions to be drawn, their findings suggest higher levels in early-onset PE. Finally, Muller et al. found no correlation between uterine artery Doppler velocimetry and circulating angiogenic factor levels, and suggested a potential improvement in the prediction of PE/IUGR by combining both markers24.

Prediction of late-onset PE/IUGR was very poor for all the parameters evaluated. This finding may be partially explained by a longer period between the time of screening and disease onset compared with early-onset cases7–9. However, we have previously reported that, after clinical onset, late-onset PE and IUGR are associated with milder changes in PlGF and sFlt1 levels, and considerable overlap with controls compared with early-onset cases3. Moreover, virtually all cases of early-onset PE/IUGR have abnormal uterine artery Doppler findings, compared with less than half of late-onset patients3. Finally, early-onset PE is consistently associated with abnormal placental morphology, whereas placentas from late-onset cases are morphologically similar to those from healthy pregnancies25.

The rate of late-onset PE in our population was low in comparison to that in some other countries. This may be explained by the existence of different risk factors for cardiovascular disease in south European countries, such as a lower rate of black ethnicity26, lower body mass index27, lower rate of atherogenic lipid profile, and higher vitamin C and E diet intake28, compared with other populations with a higher prevalence of PE2, 29, 30. In addition, although very unlikely, an extra ultrasound examination in women with pregnancies with abnormal uterine artery Doppler findings could result in earlier diagnosis and delivery of fetuses with IUGR thereby preventing clinical onset of PE. However, in spite of many theories, the precise reasons for differences in cardiovascular disease rate in different countries have been extremely difficult to identity. Therefore, it is difficult establish the exact reasons for the differences in the prevalence of late-onset PE in our population.

This study supports the notion that early-onset PE and IUGR are placenta-mediated diseases that share important similarities. Changes in second-trimester levels of angiogenic factors and in uterine artery Doppler PI values were similar in both conditions. These results are in line with changes in maternal plasma angiogenic (PlGF) and antiangiogenic (sFlt1) protein levels occurring after clinical onset of both conditions3, 13, and with placental morphometric studies showing that placentas from pregnancies complicated by IUGR and PE share similar structural and cellular abnormalities4, 31. The question of why placental disease is associated with IUGR alone in some cases, and with maternal hypertension in others, remains to be elucidated.

In conclusion, this study shows that measurement of maternal serum angiogenic factors and uterine artery Doppler examination might constitute useful screening tools for early PE/IUGR, but not for late-onset cases. However, these results must be interpreted with caution as this is an exploratory study with inherent limitations owing to the small sample size. Therefore, larger prospective studies are warranted to further assess whether the combined use of these tests could improve the early detection of PE and IUGR.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Supported by grants from the Fondo the Investigación Sanitaria (FIS 01/1397 and 02/0742), Centre Network RCMN (C03/08), and Group Network (G03/054) financed by the Carlos III Institute of Health (Madrid, Spain).

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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