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Preeclampsia, which presents after midgestation, is the most common pregnancy complication associated with serious maternal-fetal morbidity and mortality; and at present the only effective treatment is delivery of the placenta. The ability to predict in very early pregnancy those women at risk for preeclampsia might decrease maternal and fetal morbidity through closer surveillance by physicians experienced or specialized in high risk obstetrics as well as delivery at tertiary care centers. Reliable prediction would also permit institution of preventive or treatment regimens, unavailable in 2009, although exciting possibilities are under scrutiny (1).
Investigators have been evaluating tests to predict preeclampsia for over 50 years without much success (2,3). These have included tests relating to placental perfusion and vascular resistance (e.g., the “roll over” and cold pressor tests, uterine artery Doppler evaluation); placental products (e.g., pro- and anti-angiogenic proteins, hCG, placental protein 13, inhibin A); renal dysfunction (e.g., fractional urate clearance, microalbuminuria); and endothelial dysfunction (e.g., fibronectin, P- and L-selectin, VCAM-1). The list is enormous, and recently investigators have begun exploring the fields of proteomics and metabolomics for tests to predict preeclampsia.
A large systemic review published in 2004 (2) and to be updated in 2009 (3) concluded that no single test met clinical standards for a predictive test. The authors recommended further evaluation of approaches measuring maternal blood and urine levels of certain pro- and anti-angiogenic factors and suggested that success might require the combination of several different tests. Clinically useful prediction tests, it was stated, should ideally be simple, rapid, noninvasive, inexpensive, easy to perform early in gestation, and impose minimal discomfort or risk. The technology should be widely available, and the results valid, reliable, and reproducible. Useful prediction of preeclampsia would also require a very high likelihood ratio for a positive test (>15) as well as a very low likelihood ratio for a negative result (<0.1). How do the results of Poon et al. fare with such criteria?
Poon et al. (4) evaluated 7797 women with singleton pregnancies during gestational weeks 11-13 (when prenatal screening tests are normally performed) of whom 157 developed preeclampsia, 34 prior to week 34, the group most prone to severe morbidity. Using logistic regression analysis, an algorithm to predict early preeclampsia that combined the logs of uterine artery pulsatility index, mean arterial pressure (MAP), serum pregnancy-associated plasma protein-A (PAPP-A), serum free placental growth factor (PlGF), and presence of nulliparity or of previous preeclampsia,.was developed. Thus, this approach combines several predictive tests, as suggested by Conde-Agudelo et al (4) in his 2004 systematic review - tests that appear simple, rapid, noninvasive, easy to perform (at least in developed nations) and to impose minimal discomfort or risk. However, it remains to be determined whether the benefits justify the expense.
At a 5 percent false positive rate for normotensive deliveries, 476 women tested positive for early preeclampsia, of whom 32 actually developed early disease and 444 did not. Of the 7321 women who tested negative for early preeclampsia, 2 developed early disease and 7319 did not. Thus the sensitivity of the prediction model for early preeclampsia at a 5 percent false positive rate for normotensive deliveries was 32/34 or 94.1 percent, and the specificity was 7319 / (7319 + 444) or 94.3 percent. The likelihood ratio for a positive test was 16.5; and for a negative test, 0.06, easily fulfilling the World Health Organization criteria for a clinical prediction test.(2) These are remarkably good results!
Our enthusiasm must be tempered somewhat for several reasons. First, this model must be tested by other investigators and in populations that differ from those used to develop it in order to give us confidence that similar results are universal and that the model may be universally employed. It would have been of interest to know the variability and reproducibility of each test especially the use of Doppler technology. Clinical trials are required to assess the effectiveness of early prediction and to perform cost benefit analyses. They should be structured as randomization to usual care and to early prediction followed by a more stringent protocol for follow-up in patients who screen positive for early preeclampsia.
Let us note here that the mortality and morbidity of preeclampsia is far greater in developing compared to developed nations. While in industrialized countries maternal characteristics and medical history and MAP are easily obtained, PAPP-A and PlGF determined by a clinical laboratory, and sonographic testing with adequately trained personnel readily available, this is not the case in the developing world. Moreover, the cost of the combined tests is obviously prohibitive in many of these countries. Thus the need to search for alternative approaches to accurate prediction is required in such countries and should receive priority given their high rates of maternal and fetal mortality secondary to preeclampsia.
Another problem is that the tests are performed between gestational weeks 11-13, and many women seek prenatal care at a later date. Thus ideal approaches should also focus on later periods of gestation. In this respect, the anti-angiogenic proteins sFlt-1 and sEng and the ratio sFlt-1 / PlGF should be considered for algorithms beginning perhaps at 17-20 weeks of gestation (5); and given their performance in studies performed as of 2008 (6), a “package” might be constructed that could be more universally applicable.
Poon et al are to be congratulated for developing a predictive model with the likelihood ratios for positive and negative tests needed for a clinically useful approach to predict early preeclampsia. As noted, the approach is currently only applicable in developed nations where the incidence of serious complications from preeclampsia has already been reduced substantially by the dictums of appropriate prenatal care. While further testing must be performed, their work opens the possibility of identifying women at high risk of early disease in time to modify prenatal care to minimize maternal and fetal complications.
Sources of Fundings: None
Disclosures: Dr Levine receives salary support from the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services.
Dr Lindheimer; has no disclosures