First trimester-screening for the development of preeclampsia with the use of an algorithm: a health technology assessment
Health technology assessment|
Current practice in Norway indicates that the risk of preeclampsia among pregnant women is mainly assessed by medical and obstetric medical history. This health technology assessment (HTA) compares the predictive accuracy of current practice with screening with an algorithm based on maternal characteristics and blood pressure, ultrasound examination that includes blood flow in arteries to the uterus and measurement of a protein biomarker (PlGF; Placenta Growth Factor) in the mother's blood early in pregnancy.
Current practice in Norway indicates that the risk of preeclampsia among pregnant women is mainly assessed by medical and obstetric medical history. This health technology assessment (HTA) compares the predictive accuracy of current practice with screening with an algorithm based on maternal characteristics and blood pressure, ultrasound examination that includes blood flow in arteries to the uterus and measurement of a protein biomarker (PlGF; Placenta Growth Factor) in the mother's blood early in pregnancy. We also assess whether preventive treatment with acetylsalicylic acid (ASA) can reduce the risk of delivery with preeclampsia (regardless of time of delivery, < week 37 (preterm preeclampsia) and < week 34 of pregnancy) in women with a high risk of preeclampsia.
We have assessed the health economic consequences of introducing screening with the proposed algorithm and subsequent prevention with ASA compared to assumed current clinical practice in Norway.
We found that screening with an algorithm early in pregnancy:
- probably improves prediction of the risk of delivery with preeclampsia before week 37 of the pregnancy.
- possibly improves prediction of the risk of delivery with preeclampsia before week 34 of the pregnancy.
- has an uncertain effect on predicting the risk of delivery with preeclampsia regardless of the time of delivery. This is because it has not been shown that screening for preeclampsia with the algorithm is effective in predicting preeclampsia with delivery from week 37.
We included one study on the effect of prevention with ASA in women identified with high risk of preeclampsia. ASA-prophylaxis probably lowers the incidence of preeclampsia before 34 weeks and before 37 weeks of pregnancy.
Assessments of health economics and potential organizational consequences showed that the proposed screening program and ASA-prophylaxis:
- can be cost-saving compared to current practice due to fewer preterm deliveries with preeclampsia before week 37.
- will probably entail organizational consequences that should be investigated in further detail by the relevant professional communities.
In 2020, preeclampsia occurred in 2.6 % of pregnancies in Norway. Preeclampsia leads to an increased risk of premature birth, morbidity and death in mother and child. Today, the risk of preeclampsia is assessed based on various characteristics of the pregnant woman, as well as history from previous pregnancies (maternal characteristics). The predictive accuracy of current assessment of risk is limited and does not provide an optimal basis for identifying women at high risk of preeclampsia later in pregnancy.
Screening with improved prediction of the risk of preeclampsia carried out in weeks 11-14 can provide an opportunity for more appropriate prevention of delivery due to preeclampsia before week 37 of the pregnancy (preterm preeclampsia). A prerequisite for effective prevention is initiating treatment with low-dose acetylsalicylic acid (ASA) before week 16 of the pregnancy. This is in accordance with the revised Guidelines for maternity care (1), which recommends low-dose ASA from week 12 until birth (with 75 mg/day), or until week 36 (with 150 mg/day) for women identified with a high risk of preeclampsia. Initiating prophylactic treatment after week 16 is not recommended as it has not been demonstrated to have a preventive effect, and because all drugs, including ASA, carry a possible risk of adverse events.
We carried out a systematic knowledge summary with the purpose of
- investigating the predictive accuracy of screening with the proposed algorithm as a basis for calculating individual risk of preeclampsia
- assessing the clinical effect of ASA-prophylaxis on the incidence of pre-eclampsia for pregnant women identified at high risk of preeclampsia based on the proposed algorithm.
We have also assessed financial and organizational aspects of introducing the proposed screening program in the specialist health service.
We used PICOS frameworks (population, intervention, comparison, outcome, study design) for the selection of the studies that could be relevant for the HTA, one framework for studies of predictive accuracy and one for the prophylactic effect of ASA.
Initially we searched for systematic reviews and thereafter for primary studies that could cover the issues. After inclusion, we assessed methodological quality and the risk of systematic bias in the primary studies. Predictive accuracy was measured as sensitivity to predict high risk of preeclampsia with birth <32/34 weeks, <37 weeks and for all pregnancies regardless of time of birth, at a fixed specificity. Clinical effects were measured calculating risk of deliveries with preeclampsia <32/34 weeks of pregnancy, <37 weeks of pregnancy and at term, adverse events of ASA-prophylaxis and treatment adherence. We assessed confidence in the results by using the framework Grading for Recommendations Assessment, Development, and Evaluation (GRADE).
We carried out a cost-effectiveness analysis where the additional costs of the proposed screening program were compared with current practice. We included costs related to screening, ASA-prophylaxis, additional costs related to follow-up of women at high risk of preeclampsia, as well as birth and treatment of women and children with preterm preeclampsia. The analysis was carried out from a health service perspective.
We did not find eligible systematic reviews for predictive accuracy, but we included 16 primary studies. Two studies had a case-control-design, two were retrospective cohort studies and the remaining studies were prospective cohort studies. Half of the studies were from Asia, while the other half were conducted in Europe. The included studies had between 291 and 65960 participants.
Our meta-analyses showed that at a fixed specificity of 0.9, the sensitivity for predicting delivery with preeclampsia regardless of time in pregnancy was 0.454 with a 95 percent confidence interval from 0.301 to 0.616 (very low confidence in the results). Sensitivity for predicting delivery with preeclampsia before 34 weeks' gestation was 0.880 with a 95 percent confidence interval from 0.755 to 0.946 (low confidence). Sensitivity for predicting pre-discharge with pre-eclampsia before 37 weeks' gestation was 0.728 with a 95 per cent confidence interval from 0.682 to 0.770 (moderate confidence). Studies where no participants received ASA prophylaxis consistently reported higher sensitivity than studies where participants received ASA.
We included one study on clinical effect and safety of ASA prophylaxis. Participating women were screened using a similar algorithm as the proposed, but with the addition of the biomarker PAPP-A. However, PAPP-A has not been shown to increase the predictive accuracy of the algorithm. We therefore considered women who were identified as being at high risk of preeclampsia in this study to be representative for women identified as being at high risk based on the proposed algorithm. In the study, 1776 women with an estimated risk of premature preeclampsia of > 1 in 100 were invited to participate in a double-blind study of prevention with ASA (150 mg per day) from 11–14 weeks to 36 weeks of pregnancy compared with placebo. The study showed that compared to placebo, ASA prophylaxis gave a 62 percent reduction in the prevalence of preterm preeclampsia (< week 37), (odds ratio 0.38, 95 % CI 0.20-0,71; P=0.004). ASA prophylaxis did not have significant effect on the prevalence of term preeclampsia.
The health economic assessment shows that screening with the algorithm with the recommended prevention of preeclampsia with ASA in women identified at high risk can be cost saving compared to current practice. With the assumptions laid down in the analysis, screening with the algorithm could lead to 173 avoided cases of preterm preeclampsia per year. With a calculated saving of around NOK 97,000 per avoided case, this means a total saving for the health service of ~ NOK 17 million per year. The costs of introducing the screening program together with recommended prevention with ASA are therefore estimated to be lower than the savings resulting from fewer preterm preeclampsia and reduced costs for maternity and neonatal care.
The purpose of this health technology assessment is to elucidate whether the proposed measure can provide better predictive accuracy for the risk of preeclampsia and thus provide a better basis for the prevention of preeclampsia with ASA than current practice.
Our findings indicate that the screening with the proposed algorithm in weeks 11-14 of pregnancy can probably increase the predictive accuracy of the risk of preterm preeclampsia compared to current practice. Our assessment of the predictive accuracy of the measure is based on the inclusion criteria defined by PICO I. The PICO provide a strict framework for which exams should be included in the algorithm that is assessed as required. Changing the components of the algorithm may affect the predictive accuracy of the algorithm as well as having economic and organizational implications.
We did not find studies elucidating the effect of ASA prophylaxis among women selected by exactly the same algorithm as the proposed one. Hence, we based our assessment of clinical effect on a study where women were selected based on an algorithm that includes an additional biomarker as compared to the proposed algorithm. The additional biomarker PAPP-A is not shown to affect the predictive accuracy of the algorithm. We therefore consider that the study constitutes a satisfactory basis for assessing the effect of preventive treatment with ASA in the relevant population. We have moderate confidence in the study results which shows that ASA prophylaxis can significantly reduce the incidence of preterm preeclampsia.
There is uncertainty related to several of the assumptions made in the health economic analysis. Consequences of changes in important parameters are assessed in sensitivity analyses. If additional costs for the screening program are 27% higher than assumed in the baseline analysis (from NOK 1,175 to NOK 1,490), introduction of the proposed screening program will be cost-neutral. In our analysis, we have only considered the costs and consequences of preterm preeclampsia related to mother and child during pregnancy and the neonatal period. The long-term health effects and economic consequences of reducing the risk of premature births with ASA prophylaxis are not included in the health economic analysis because the basis for quantifying these health benefits is inadequate, but they are assumed to be important. Thus, there is reason to assume that the estimated cost savings may be a conservative estimate for savings linked to avoided cases of preterm preeclampsia.
Screening with the proposed algorithm in the first trimester can probably increase the predictive accuracy of the risk of preeclampsia with delivery before week 37 of pregnancy (preterm preeclampsia) and possibly increase the prediction of preeclampsia with delivery before week 34.
Initiation of low-dose ASA prophylaxis in women identified as having a high risk of preeclampsia in weeks 11-14 of pregnancy can probably reduce the prevalence of preeclampsia with delivery before week 37 of pregnancy.
Introduction of the proposed screening algorithm plus ASA prophylaxis can result in cost-savings compared to current practice. The expected savings are related to the expected decrease in the number of deliveries due to preterm preeclampsia. Cost reductions related to follow-up, birth and neonatal care/treatment will likely exceed the increased costs related to implementation of the proposed algorithm. Furthermore, long-term health effects and financial consequences of reducing preterm preeclampsia, which are not accounted for in our analysis, will further support the conclusion concerning potential cost savings by introducing screening and ASA prophylaxis. Some of the assumptions in the analysis are uncertain, however sensitivity analyses suggest these uncertainties have limited effect on the overall conclusion that screening plus ASA prophylaxis is likely to be cost saving compared to current practice.
A study of the implementation of the proposed screening program can help confirming its usefulness and to identify the need for adjustments that can ensure that the intervention has the desired clinical and economic consequences.