First-trimester screening with combined maternal clinical factors, biophysical and biomarkers to predict preterm pre-eclampsia and hypertensive disorders: are they ready for clinical use?


  • BM Sibai

    Corresponding author
    1. Department of Obstetrics and Gynecology and Reproductive Science, The University of Texas Medical School at Houston, Houston, TX, USA
    • Correspondence: Prof BM Sibai, Department of Obstetrics and Gynecology and Reproductive Science, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston TX 77030, USA. Email

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The reported incidence of gestational hypertension (GH) and pre-eclampsia (PE) ranges from 5 to 10% of all pregnancies. The incidence is increasing because of the trend towards advanced maternal age and/or increased body mass index (BMI) at the time of pregnancy. During the past 20 years, the incidence of GH/PE in nulliparous women in the USA increased from 12% (low-dose aspirin trial)[1] to 28% (Vitamin C and E trial).[2] Risk factors for hypertensive disease of pregnancy (HDP) include those that exist before pregnancy such as history of GH/PE, chronic hypertension, renal disease, pregestational diabetes, autoimmune disease, family history of hypertension/PE, BMI >35 kg/m2, maternal age >40 years, race/ethnicity; and factors that develop after conception such as first ongoing pregnancy, conception with assisted reproduction, multifetal pregnancy, elevated systolic, diastolic or mean arterial blood pressure in the first trimester, abnormal uterine artery Doppler, and abnormal serum markers in the first trimester.

Hypertensive disorders of pregnancy can develop at <34 weeks, 34–37 weeks, ≥37 weeks, during labour, or for the first time in the postpartum period. In addition, the majority of cases occur in women in their first pregnancy and most cases (80%) develop at ≥37 weeks gestation. During the past decade several prospective and nested case–control studies have found that certain maternal risk factors, biophysical clinical factors and serum biomarkers obtained in the first trimester are associated with subsequent development of PE. These studies evaluated the use of these factors or markers alone or in combination, and they provided detection rates for various subtypes of hypertension and PE using a false-positive rate (FPR) of either 5 or 10%. Overall, neither the maternal factors nor the serum biomarkers, either alone or combined, had an adequate detection rate for either all HDP, or GH, or PE developing at ≥37 weeks of gestation. In the same studies, using maternal factors and mean arterial pressure (MAP) in the first trimester, the detection rate for PE <34 weeks was 73% and for PE <37 weeks it was 60% with an FPR of 10%. Using data from the Maternal Fetal Medicine Foundation (MFMF), the use of combined maternal factors, biophysical and biochemical markers increases the detection rate to 95% for PE requiring delivery at <34 weeks of gestation and 77% for PE requiring delivery at <37 weeks of gestation with an FPR of 10%. However, the positive predictive value (PPV) for such a screen remained <10%. In addition, these studies were conducted in a heterogeneous group of women at various risks for HDP and PE.

The study by Forest and colleagues[3] is unique because it evaluates combined maternal factors and serum markers measured in the first trimester in 7929 women who are at very low risk for GH (2.7%) and PE (1.8%). In those with PE, the incidence was 0.2% at <34 and 1.2% at <37 weeks of gestation. They found that a clinical model that included maternal risk factors, BMI and MAP had a detection rate of 54% and a PPV of 3% at an FPR of 10% for PE <37 weeks of gestation, whereas a full model that also includes serum biomarkers had a detection rate of 39% and a PPV of 2% for PE <37 weeks of gestation.

Based on the results of the current study and other reports in recent years including those by the MFMF, it is clear that evaluation of maternal clinical factors and other biophysical and biomarkers measured in the first trimester is useful for the prediction of those who will ultimately progress to PE requiring delivery at <34 weeks of gestation. However, given the poor PPV for PE at <34 weeks, and the poor detection rates for all cases of GH/PE the clinical implications of a PE screen test in the first trimester remain unclear.

During the past few years, some authors and commercial screening companies have been promoting a combination of maternal factors, MAP, uterine artery Doppler and serum biomarkers obtained in the first trimester as a screening test to identify those at high risk for developing early-onset PE (95% detection rate with FPR of 10%). They suggested that universal first-trimester screening for PE will influence medical decision-making and improve pregnancy outcome. They recommended that women who screen positive will benefit from receiving low-dose aspirin (LDA) for prevention of early onset PE, as well as from receiving intensive antenatal monitoring and early intervention. However, whether the information provided with this screen will affect patient outcome or is cost-effective remains unknown. At present, there is no clinical trial that demonstrates a benefit from using LDA in such a population. Indeed, a recent study that included 614 women who had positive first-trimester screens and received LDA at <16 weeks of gestation revealed that women who developed PE were more likely to have elevated MAP, low serum pregnancy-associated plasma protein A, and to be obese. In addition, secondary analysis of data from the use of LDA in women at high risk for PE conducted by the MFMU Network revealed that the rate of PE was 22% in 225 women receiving LDA at <16 weeks of gestation compared with 23% in 236 women receiving placebo.

Finally, a major concern of first-trimester screening for PE without evidence of benefit is the unintended consequences of those identified as false-positives (97%) of cases for a PPV of 3%. Some authors and commercial entities have recommended that those who screen positive should have more frequent visits, more maternal and fetal testing, bed rest and other interventions that could be potentially harmful to both mother and infant. Currently, there are no prospective studies or randomised trials evaluating the benefits and risks of first trimester screening for prediction of PE. Until then, the use of such tests for screening should remain experimental.

Disclosure of interests

The author reports no conflict of interest.