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?

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) to 28% (Vitamin C and E trial). 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/m, 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 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.