Analysis of the course and outcomes of planned pregnancies in the study groups showed that pregnancy complications were recorded in 57.9% (183 out of 316) cases with prothrombin G20210A mutation and in 25.1% (102 of 406) cases without it [RR 2.3; 95% CI 1.7–3.1; p < 0.0001], which is statistically significant (Table. 2).
Table 2
Reproductive history of patients admitted to the study
Clinical manifestation of prothrombin G20210A mutation | Study group n = 140 | Control group n = 150 | Statistics |
total | % | total | % | p | OR. 95%CI |
Total number of pregnancies | 363 | - | 451 | - | > 0.05 | - |
Artificial abortion | 47 | 12.5 | 46 | 10.2 | 0.2 | 1.3 (0.9–1.9) |
Planned pregnancy | 316 | 87.1 | 406 | 90.0 | 0.2 | 0.97 (0.9-1.0) |
Reproductive losses up to 12 weeks | 92 | 9.1 | 47 | 11.6 | < 0.0001 | 2.5 (1.8–3.5) |
non-developing pregnancy | 53 | 16.8 | 11 | 2.4 | < 0.0001 | 6.2 (3.2–11.7) |
spontaneous miscarriage | 32 | 10.1 | 31 | 7.6 | 0.2 | 1.3 (0.8–2.1) |
ectopic pregnancy | 7 | 1.9 | 5 | 1.1 | 0.2 | 2.2 (0.7–7.6) |
Favorable pregnancy | 133 | 42 | 304 | 74.6 | < 0.0001 | 1.8 (1.5-2.0) |
Total number of deliveries | 207 | 65.5 | 359 | 88.4 | < 0.0001 | 1.3 (1.2–1.5) |
Preterm delivery | 30 | 9.5 | 6 | 1.5 | < 0.0001 | 6.4 (2.7–15.2) |
Fetal growth restriction | 21 | 6.6 | 16 | 3.9 | 0.1 | 1.7 (0.9–3.2) |
Preeclampsia | 26 | 8.2 | 13 | 3.2 | 0.004 | 2.6 (1.3–4.9) |
severe preeclampsia | 15 | 4.7 | 2 | 0.5 | 0.003 | 9.6 (2.2–41.8) |
Antenatal fetal death | 6 | 1.9 | 1 | 0.2 | 0.06 | 7.7 (0.9–63.7) |
The data analysis showed that the GA genotype is associated with the development of early reproductive losses in the form of a non-developing pregnancy and preeclampsia. It can be seen that all episodes (n = 30) of preterm delivery were accompanied by PE and/or FGR. All antenatally dead fetuses were diagnosed with growth retardation, and in 83.3% (5 out of 6), fetal death occurred against the background of preeclampsia.
In the study, prothrombin activity in blood plasma was studied in 140 women with prothrombin G20210A mutation. The data obtained were compared to the results in pregnant women with the wild type (n = 40). It was found that the median of prothrombin activity at the points of study during normal pregnancy in the control group (GG genotype) ranged from 108% (preconceptional period) to 144% (pregnancy) (95% CI 130–150). At the same time, in pregnant women with the GA genotype, regardless of pregnancy course, it was significantly higher, ranging from 149–181% (95% CI 142–195) (Fig. 1).
Here, as well as in Figs. 2 and 3: PC – preconception period; PP – postpartum on the 2nd – 3rd days. median – marker; the values corresponding to 95% confidence interval are the lower and upper vertical bars (error bar).
Figure 1 The level of prothrombin activity, depending on the genotype, at the preconception stage, at different gestational periods and postpartum. The results are given based on the previously published data obtained during normal pregnancy 28.
In 103 (73.6% of 140) patients of the study group, prothrombin activity at the time points was from 148.5–180.6% to, which was associated with a favorable course and outcome of pregnancy. In 8 patients (5.7% of 140), pregnancy ended in fetal death at the gestational age of 8–9 weeks, while the median activity of prothrombin was 198.1% (95% CI 191.5-201.4), which is significantly higher than the same value at 8 weeks with developing pregnancy – 176.3% (95%CI 142,2-180,1) (p = 0.0069). With FGR before the gestational age of 22 weeks, prothrombin activity was comparable to that in women with a favorable pregnancy. At the gestational age of 28 weeks, a multidirectional change in prothrombin activity was recorded relative to 22 weeks: with favorable pregnancy, it decreased by 10.2% with the median of 162.0%, and with FGR it increased by 11.3%, with the median of 204.0%. The statistical difference between the medians of prothrombin activity remained at the gestational age of 32 weeks as well (176.4% and 194.7%, respectively) (Fig. 2).
The most significant results were obtained in the analysis of laboratory phenotype with early and/or severe preeclampsia in GA genotype carriers. Prothrombin activity in that group was significantly higher than in those with a favorable pregnancy starting from the preconception stage (Fig. 3).
It should be noted that all women (n = 15) had an assisted premature delivery within 28–32 weeks, given the severity of preeclampsia.
Considering the obtained results, in order to determine the prognostic significance of prothrombin activity for the development of early and/or severe preeclampsia from the preconception period or early pregnancy, ROC analysis was performed 29.
Table 2 presents the summary data of ROC analysis for the level of prothrombin activity at the points of study, as a prognostic marker for the development of early and/or severe preeclampsia.
Table 2
The results of ROC analysis to predict early and/or severe preeclampsia at different stages of pregnancy using the level of prothrombin activity as a marker for patients with prothrombin G20210A mutation
Statistical values | PC (n = 15) | 7–8 weeks n = 15 | 12–13 weeks n = 15 | 18–19 weeks n = 15 | 22–23 weeks n = 14 | 27–28 weeks n = 11 | 32–33 weeks n = 10 |
Prothrombin activity cutoff (%) | > 171.0 | > 181.3 | > 180.0 | > 180.6 | > 191.5 | > 196.0 | > 192.1 |
Sensitivity | 80 | 93.3 | 95 | 100 | 100 | 100 | 72.7 |
Specificity | 87.8 | 70 | 71 | 55.6 | 69.2 | 93.3 | 75 |
Area under ROC curve (AUC) | 0.863 | 0.840 | 0.792 | 0.756 | 0.788 | 0.958 | 0.741 |
95% CI for AUC | 0.779–0.925 | 0.677–0.942 | 0.609–0.916 | 0.575–0.888 | 0.654–0.889 | 0.844–0.996 | 0.605–0.849 |
(p) | < 0.0001 | < 0.0001 | 0.0022 | 0.0031 | < 0.0001 | < 0.0001 | 0.002 |
Thus, in predicting preeclampsia based on the prothrombin activity level, ROC analysis made it possible to determine the optimal cut-off threshold with the best predictive ability, which was > 171.0% at the preconception stage and > 180.0% at all stages of pregnancy. The area under the ROC curve (AUC) in all points of the study showed good prognostic power and clinical significance of the method (Table 2). At the same time, the risk of developing early and/or severe preeclampsia at the preconception stage is predicted in 86% of cases and at the gestational age of 7–8 weeks in 84% of cases. The graphic representation of ROC curves with the maximum test performance is shown in Fig. 4. |
A – at the preconception stage; B – at the gestational age of 7–8 weeks