Our study assessed whether first and second trimester biochemical markers used in prenatal aneuploidy screening could accurately identify pregnancies at risk of developing adverse pregnancy outcomes, mainly PE. We found that the combination of maternal characteristics with biochemical markers in both trimesters can provide reasonable accuracy in identifying women at risk of developing preterm and early-onset PE but not women at risk for gestational hypertension or preterm birth. PAPP-A and PlGF were the most reliable biochemical markers to be associated with and to predict adverse pregnancy outcomes, particularly early-onset PE.
Our results have confirmed previously reported associations between individual biochemical markers and PE and preterm birth.7–9 Similar to previous studies, we found the performance of PE prediction to be improved by using multiple biochemical markers in combination with maternal characteristics .5,11,12The most commonly used marker combination in the first trimester PAPP-A and PlGF along with maternal characteristics can predict 65% and 76% of early-onset PE with a FPR of 10% and 20% respectively. Second trimester biochemical markers can identify 88% of the pregnancies at risk of developing early-onset PE with a FPR of 20%. However, this will require the addition of PAPP-A and PlGF which are not currently used in second trimester aneuploidy screening. In addition, we found that the increase of PlGF with gestational age was smaller in women affected by PE compared to the control group.
Low first trimester PAPP-A and PlGF have been associated with adverse pregnancy outcomes, especially PE in multiple studies.5,11−13 The case-control study by Keikkala et al. (2016) investigating maternal serum samples from 8–13 weeks of gestation found lower median MoM values for PlGF and PAPP-A in women with PE compared to control. 13 Consistent with our study, the lowest median MoM values were seen in cases with preterm and early-onset PE. As with previous studies, our study found median first trimester AFP MoM values to be higher and median free β-hCG MoM values to be lower in women with PE, although the significance of these changes was smaller in comparison to those of PAPP-A and PlGF. 8,9 The previously described association between first trimester inhibin A and PE was not confirmed in our study. 14,15
Second trimester PlGF and PAPP-A median MoM values, were lower in our study than those reported by other studies.9,16 However, this was mainly true for PlGF and not significant for PAPP-A in women with preterm or early-onset PE, likely due to the small number of pregnancies in this group. We found an increase in total hCG in PE pregnancies, as reported in previous studies.17 In contrast, no change in Inhibin A was seen in our study although reported as an optimal second trimester marker by others.18 We suspect this is due to the small number of early PE pregnancies involved in our study. Lastly, the change in the first and second trimester markers in gestational hypertension and preterm birth cases was consistent with other studies in general although the magnitude of the change was variable.19,20
In recent years, the results of several large clinical trials have suggested that the performance of PE screening can be improved by using multiple biochemical markers together with maternal characteristics and biophysical markers.5,12,21 A prospective study by Akolekar et al. (2013) on 58,884 singleton pregnancies at 11–13 weeks reported a 50.5% DR at a 10% FPR with maternal characteristics alone for early-onset PE, 74.3% with the addition of PlGF and PAPP-A and 89.7% with the addition of biophysical markers, MAP and UTPI. The DR improved to 96.3% when maternal characteristics and biochemical and biophysical markers were combined. 12Similarly, in a prospective study of 35,948 singleton pregnancies at 11–13 weeks’ gestation, O’Gorman et al. (2016) found that combined screening obtained a DR of 75% and 47% at a 10% FPR for preterm PE and term PE pregnancies, respectively. 12When such modelling combinations were applied to the ASPRE trial, similar DR values were observed. First-trimester screening for preterm PE with a risk cut-off of 1 in 100 detected 76.7% of preterm PE and 43.1% of term PE pregnancies, at a screen-positive rate of 10.5% and a FPR of 9.2%.21
While the best performance can be achieved by combining multiple variables (e.g., maternal characteristics, medical and family history, biochemical and biophysical markers), MAP and especially UTPI might not be readily accessible, especially for women in remote areas. If the combination of maternal characteristics and biochemical markers can predict the risk of PE with reasonable accuracy, the current aneuploidy screening could be expanded to include PE screening to identify women at increased risk of developing PE, with biophysical markers to be followed as a second line or contingent screen. In our study, the PE screening performance was comparable to previous studies when using maternal characteristics in combination with first trimester PAPP-A and PlGF. At a FPR of 20%, the DR was 76%, 67% and 60% for early-onset PE, preterm PE and all PE, respectively. This suggests that for 20% of women who screen positive for early-onset PE, a contingent PE screening strategy using MAP and UTPI can predict up to 76% of early-onset PE. As with the one-time screening approach, our contingent screen can yield results before 16 weeks of gestation in order to initiate prophylactic therapy with Aspirin.
If first trimester screening is aiming to initiate Aspirin treatment, second trimester screening is useful for patient triage by identifying pregnancies needing close surveillance and more urgent medical attention. For example, numerous studies have focused on second trimester PlGF or soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio.22 In our study, in addition to the PE screening performance using second trimester markers, we compared the changes in biochemical markers between the first and second trimester samples. For women who developed PE, the increase in PlGF concentrations was significantly smaller compared to controls. These results have been confirmed by the findings from other studies.23–25 Theoretically, for women who are identified to be at high risk for PE in the first trimester, a repeat test for PlGF and PAPP-A in the second trimester might provide useful information which can be used for risk modification. Nevertheless, a calculation of biomarker changes between trimesters did not yield a better prediction for PE than using second trimester markers alone in our study. Further investigation of this trend may provide clinicians with valuable information for monitoring and early detection of high-risk women.
In our study, the preterm birth screening performance was less optimal than previously reported.20 A possible reason for the lower DR is that unlike some previous studies, our preterm birth group excluded all women with PE or gestational hypertension. Incomplete maternal characteristics data may have also contributed to the lower-than-expected DR values for preterm birth.
The strengths of our study include the identification of cases and controls from a routine unselected screening population, representing a true sample of women undergoing prenatal screening in Ontario. Also unique to our study is the availability of both first and second trimester serum samples for most cases and controls. Having samples from both trimesters enabled us to investigate the change between the first and second trimesters, which might provide additional information for PE screening and monitoring. The limitations of this study include, the transfer of some women to other obstetrical centres, potentially lowering the incidence of PE in our population. Additionally, our local population includes a greater proportion of women of Asian ancestry compared with other studies. Varying ethnicity between studies may impact PE prevalence; in particular, a lower prevalence of PE among Asian women has been noted previously.26 Our study lacked complete information on all maternal characteristics and as such, the accuracy of PE screening using maternal characteristics cannot be directly compared to studies where maternal characteristics were explicitly collected for PE screening. However, the contribution of biochemical markers and overall PE screening performance using the combination of maternal characteristics and biochemical markers were consistent with previous studies. In a real-life clinical setting, it will be practical to collect all maternal characteristics missed in this study. Since information on MAP and UTPI was not available to our study, we were not able to assess the final performance of a contingent PE screening strategy. Nevertheless, we achieved our goal of assessing the first tier of a contingent screening strategy to provide reasonable performance and warrant the expansion of current aneuploidy screening to include preeclampsia.