Cost-effectiveness analysis of implementing screening on preterm pre-eclampsia at first trimester of pregnancy in Germany and Switzerland.

OBJECTIVE: To assess the cost-effectiveness of preterm preeclampsia (PE) screening versus routine screening based on maternal characteristics in Germany and Switzerland.
METHODS: A health economic model was used to analyse the cost-effectiveness of PE screening versus routine screening based on maternal characteristics. The analysis was conducted from the healthcare perspective with a time horizon of one year from the start of pregnancy. The main outcome measures were incremental health care costs and incremental costs per PE case averted.
RESULTS: The incremental health care costs for PE screening versus routine screening per woman were €14 in Germany, and -CHF42 in Switzerland, the latter representing cost savings. In Germany, the incremental costs per PE case averted were €3,795. In Switzerland, PE screening was dominant. The most influential parameter in the one-way sensitivity analysis was the cost of PE screening (Germany) and the probability of preterm PE in routine screening (Switzerland). In Germany, at a willingness-to-pay for one PE case avoided of €4,200, PE screening had a probability of more than 50% of being cost-effective compared to routine screening. In Switzerland, at a willingness-to-pay of CHF0, PE screening had a 78% probability of being the most cost-effective screening strategy.
CONCLUSION: For Switzerland, PE screening is expected to be cost saving in comparison to routine screening. For Germany, the additional health care costs per woman were expected to be €14. Future cost-effectiveness studies should be conducted with a longer time horizon.

Introduction

Preeclampsia (PE) is a hypertensive disorder, which manifests by high blood pressure and either proteinuria, maternal organ dysfunction, and/or uteroplacental dysfunction [1]. Preeclampsia can occur at term (≥ 37 weeks of gestation) or preterm (before week 37 of gestation). Untreated, PE can progress to eclampsia; haemolysis, elevated liver enzymes, and low platelet count syndrome (HELLP-syndrome; or lead to placental abruption [1]. Most PE cases occur close to term and with mild symptoms [2]. PE developing with severe symptoms and during the preterm period is most problematic, as it is associated with more complications for the mother and the baby [2]. Especially as the only effective treatment of severe PE is the delivery of the baby, preterm PE is to be prevented. Worldwide, PE is a leading factor of morbidity and mortality of mothers and their babies [3]. PE can lead to an increased risk for foetal death [4], intrauterine growth restrictions, and preterm births with all its associated consequences [2]. In Europe, PE occurs in 0.4 to 2.8% of all pregnancies [2].

Several studies have shown that a prophylaxis with low-dose aspirin starting early in pregnancy lowers the incidence of PE. Guidelines of professional associations, such as the National Institute for Health and Clinical Excellence in the UK and the American College of Obstetricians and Gynaecologists, recommend aspiring prophylaxis with 100mg per day or more starting before or at week 16 of pregnancy for pregnant women at high risk of PE [5]. It is thus important to identify women at high risk of preterm PE.

In both Germany and Switzerland, antenatal care for pregnant women includes regular visits at the gynaecologist or, for pregnancies without complications, with a midwife. In the current standard of care, women at high risk of PE are identified through a routine screening during one of the first antenatal consultations, by means of analysing maternal characteristics and risk factors, as well as previous pregnancies and medical records. Known risk factors include a higher maternal age, PE during a previous pregnancy, obesity, nulliparity, or pre-existing hypertension [1]. Women identified as at high risk should be prescribed aspirin prophylaxis. However, by routine screening, most of the women at high risk of developing PE are not detected [5].

Additionally, an innovative screening for PE is available, conducted by a gynaecologist or specialist in the area of fetal medicine. Obstetrics history, maternal characteristics, mean arterial pressure (MAP), uterine artery pulsatility index (UAPI) evaluated in Doppler ultrasound, and the biomarkers serum placental growth factor (PlGF), and pregnancy-associated plasma protein-A (PAPP-A) measured at weeks 11–13 of gestation are used as an input parameter to the specific PE screening algorithm which allows to calculate individual risk for developing PE later on in pregnancy. Women identified as at high risk for PE should be prescribed aspirin prophylaxis [6]. For PE with delivery <37 weeks of gestation, a detection rate of PE screening of 80% was found with a false positive rate of 10% [6].

PE screening can thus well identify pregnant women who are at high risk of preterm PE, however, its implementation also adds costs to antenatal care. To inform implementation and reimbursement decisions of PE screening we conducted a cost-effectiveness analysis of PE screening in comparison to routine screening (the current standard of care) for Germany and Switzerland. The analysis was conducted from the health care perspective and adopted a time horizon of one year. This study focused on the prevention of preterm PE <37 weeks, as the performance of PE screening detecting women at high risk of PE ≥37 weeks is low [6].

Materials and methods

A decision tree was constructed in Microsoft Excel to compare the cost-effectiveness of PE screening versus routine screening for all pregnant women in the first trimester in both Germany and Switzerland.

Screening alternatives

In PE screening women were screened at 11+0 to 13+6 weeks of gestation, as recommended by the Fetal Medicine Foundation (FMF) [7]. Measurements taken were maternal characteristics, MAP, mean UAPI, the levels of PlGF and PAPP-A [1, 6]. An algorithm was used to predict the risk of preterm PE <37 weeks of gestational age (WGA) based on these measurements. Women with a risk of 1:100 or higher were classified as at high-risk [1]. All women at high-risk in PE screening were prescribed low-dose aspirin of 150mg/day starting before week 16 [5]. The Swiss guidelines state that the addition of PAPP-A to the screening would not lead to significant improvements in the screening and that most cases would also be detected without PAPP-A [8]. We therefore excluded it from the analysis for Switzerland, as it is unlikely it would be included in the screening in Switzerland when not recommended by the Swiss professional societies.

Routine screening consisted of analysing maternal characteristics during the anamnesis in one of the first antenatal appointments during the first trimester (usually between 8+0 to 10+6 weeks of gestation). Depending on the practice routine, patient characteristics, blood samples (protein and glucose), and blood pressure measurements were also used to identify a potential risk of developing PE during pregnancy [9, 10]. Women identified as being at high-risk for PE by their gynaecologist might be prescribed low-dose aspirin prophylaxis of 150mg/day starting before week 16 [5].

Model structure

In the model, pregnant women either received PE screening or routine screening (Fig 1).

Fig 1

Decision-tree.

The standard check-up strategy includes routine screening on maternal characteristics

[+]: The branches from above are repeated

In PE screening, women were classified as at high risk for preterm PE or not. Women at low risk of preterm PE received standard antenatal care. Women at high risk of preterm PE were prescribed low-dose aspirin prophylaxis. All women in PE screening could develop preterm PE or not, and have a stillbirth, a live preterm birth (<37 weeks of gestation), or a live term birth.

In routine screening, women could be classified as at high-risk based on maternal characteristics and might be prescribed low-dose aspirin prophylaxis. As no data was available on the probability of being classified as at high risk for preterm PE in routine screening and on subsequently receiving aspirin prophylaxis, we used summary data on the average number of women experiencing the outcomes stillbirth, live preterm birth, and live term birth. This was done irrespectively of a previous classification of being at high risk for preterm PE, as the available data did not allow for more level of detail.

The impact of false positive and false negative screening results for both screening alternatives were included in the outcomes of both interventions, i.e., some women received aspirin prophylaxis unnecessarily, and some did not receive aspirin prophylaxis whereas they should. This results in a higher chance in both screening alternatives of developing preterm PE than when the prophylaxis had been received.

The primary outcome measures were the incremental health care costs per women screened in PE screening versus routine screening and the incremental costs per PE case avoided. Secondary outcomes were the incremental costs per preterm birth avoided, and per still birth prevented. To assess the validity of the model structure it was presented separately to two (senior) physicians in the field of obstetrics and prenatal diagnostics (one in Germany, one in Switzerland).

Input data

Input data were based on scientific literature, statistics databases, Diagnosis Related Group (DRG)-system databases, reports, and expert opinions. Country-specific data from Germany and Switzerland were used when available. For data that could not be identified in the literature, expert opinion was used (see above).

In PE screening, 11.03% of patients were classified as at high risk in both countries [5] and prescribed low-dose aspirin prophylaxis. Of the women at high-risk, 1.63% developed preterm PE in PE screening [5] and of those not at high risk, 0.18% [11].

In routine screening in Germany, 20% of pregnant women were classified as at high risk of preterm PE (expert opinion) of which 80% were assumed to be prescribed low-dose aspirin prophylaxis (expert opinion). In Switzerland, 10% were classified as high-risk in routine screening and 50% of these would receive low-dose aspirin prophylaxis (expert opinion). The risks of preterm PE in routine screening were based on Tan et al. (2018) [12], which represents a situation without using low dose aspirin prophylaxis. To account for receiving low-dose aspirin prophylaxis when being classified as high risk based on maternal characteristics in current practice, the incidence of preterm PE was reduced by 10.00% [13] to 0.72%.

In both screening alternatives, women could develop preterm PE or not, depending on the screening accuracy to detect preterm PE. Without preterm PE, the probabilities of caesarean section, stillbirth, and preterm birth were identical to the averages in the respective countries (see Table 1). When developing preterm PE, these were higher. For Germany, the probability of delivery by caesarean section with preterm PE was 99.2% [14], of stillbirth 0.74% [14], and of preterm birth 75.0% [14]. With preterm PE, the length of stay increased by 3 days for the mother and 16 days for the neonate [15]. For Switzerland, the probability of delivery by caesarean section of women with preterm PE was 61.9% (calculation based on [16]), of stillbirth 0.74% [4], and of preterm birth 75.00 [3]. For Switzerland, the extended length of stay for preterm PE patients was included using a DRG-code for a hospital stay with preterm PE. All input data are shown in Table 1.

Table 1

Input parameters: Risk of PE and treatment parameters.

Parameter	Value	Source
GERMANY
Yearly number of pregnancies	763,732	Calculation based on Federal Statistical Office 2020 [17, 18]
Routine screening
Probability being at high risk of PE	20.00%	Expert opinion
Percentage of women at high risk receiving aspirin prophylaxis	80.00%	Expert opinion
Probability of PE at <37 WGA	0.72%	Tan 2018 [12], Askie 2007 [13]
Follow-ups at gynaecologist after giving birth	1.00	Assumption
Percentage of women attending follow-up after giving birth	90.00%	Assumption
PE screening
Probability being at high risk of PE	11.03%	Rolnik 2017 [5]
Percentage of women at high risk receiving aspirin prophylaxis	100.00%	Rolnik 2017 [5]
Probability of PE at <37 WGA when at high risk	1.63%	Rolnik 2017 [5]
Probability of PE at <37 WGA when at low risk	0.18%	Rolnik 2017 [11]
Follow-ups at gynaecologist after giving birth	1.00	Assumption
Percentage of women attending follow-up after giving birth	90.00%	Assumption
Probability of birth by caesarean section:
Women without preterm PE at <37 WGA	29.10%	Federal Statistical Office 2020 [19]
Women with preterm PE at <37 weeks WGA	99.20%	Bossung 2020 [14]
Probability of stillbirth:
Women without preterm PE at <37 WGA	0.36%	Harmon 2015 [4]
Women with preterm PE at <37 weeks WGA	0.74%	Bossung 2020 [14]
Probability of preterm birth:
Women without preterm PE at <37 WGA	8.82%	Stubert 2014 [2]
Women with preterm PE at <37 weeks WGA	75.00%	Bossung 2020 [14]
Additional length of stay mother with preterm PE	3.0	Ray 2017 [15]
Length of stay neonate after pregnancy with preterm PE	16.0	Ray 2017 [15]
SWITZERLAND
Yearly pregnancies	84,759	Calculation based on Pison 2015 [20], Federal Statistical Office 2021 [21, 22]
Routine screening
Probability being at high risk of PE	10.00%	Expert opinion
Percentage receiving aspirin prophylaxis	50.00%	Expert opinion
Probability of PE at <37 WGA	0.72%	Tan 2018 [12], Askie 2007 [13]
Follow-ups at gynaecologist after birth	1.00	Assumption
Percentage of women attending follow-up	100.00%	Assumption
PE screening
Probability being at high risk of PE	11.03%	Rolnik 2017 [5]
Percentage receiving aspirin prophylaxis	100.00%	Rolnik 2017 [5]
Probability of PE at <37 WGA when at high risk	1.63%	Rolnik 2017 [5]
Probability of PE at <37 WGA when at low risk	0.18%	Rolnik 2017 [11]
Follow-ups at gynaecologist after birth	1.00	Assumption
Percentage of women attending follow-up	100.00%	Expert opinion
Probability of births by caesarean section:
Women without preterm PE at <37 WGA	34.20%	Euro-Peristat Project 2018 [23]
Women with preterm PE at <37 weeks WGA	61.88%	Calculation based on Hodel 2020 [16]
Probability of stillbirth:
Women without preterm PE at <37 WGA	0.36%	Harmon 2015 [4]
Women with preterm PE at <37 weeks WGA	0.74%	Harmon 2015 [4]
Probability of preterm birth:
Women without preterm PE at <37 WGA	6.70%	Purde 2015 [3]
Women with preterm PE at <37 weeks WGA	75.00%	Stubert 2015 [2]

PE: preeclampsia, WGA: weeks of gestation

Costs incurred by patients included the costs of the regular antenatal care consultation; of PE screening; of the aspirin prophylaxis; of treatment including admission to the hospital for the mother when having preterm PE; of giving birth and the hospital stay of the mother and the baby after giving birth; and, if applicable, the costs of stillbirth, admission of a preterm born neonate, additional health care costs during the first months of life of a preterm neonate; and follow-up costs including a regular check-up visit at the gynaecologist of the mother a couple of weeks after giving birth.

The specific costs of PE screening were not known as in both countries it currently is offered privately, with prices likely being higher as when included in public health insurance. The costs were thus based on current reimbursement for the biomarkers combined with estimates of the experts. For Germany, screening costs of €90 were used and for Switzerland costs of CHF150. All cost input parameters were inflated to their 2021 value and are shown in Table 2.

Table 2

Cost input parameters.

Parameter	Unit cost	Source
GERMANY	[EUR]
PE screening	90.00	Consists of €19.40 for PlGF (ebm 32362), and for PAPP-A, and an assumed €62.35 for drawing the blood sample, Doppler ultrasound, MAP, and counselling.
Regular pregnancy check-ups, per quartile	130.00	KBV code 01770
Low-dose aspirin prophylaxis	11.37	150mg/day for 22 weeks. Average price of multiple manufacturers and sellers
Stay at hospital in case of PE, per day	1,170.99	Pokras 2018 [24]
Caesarean section including hospital stay	3,443.93	Average of DRG codes O01D, O01E, O01F, and O01G
Vaginal birth including hospital stay	2,100.99	Average of DRG codes O60B, O60C, and O60D
Hospital stay of healthy new-born	703.68	Average of DRG codes P67E and P66D
Stillbirth	1,515.83	Mistry 2013 [25]. Includes bereavement counselling, autopsy, and placental pathology
Stay at NICU, per day	1,536.23	Martin 2008 [26]. NICU costs assumed to be similar to adult ICU costs.
Hospital stay neonate born <37 WGA	22,257.22	LOS from Ray 2017 [15] (16 days) corrected for a normal term birth (2 days) multiplied with the NICU costs.
Additional healthcare in first 3 months of life of preterm born	1,675.49	Calculation based on Jacob 2017 [27]
Visit to outpatient clinic after delivery	130.00	Assumed. Per quartile.
SWITZERLAND	[CHF]
PE screening	150.00	Assumption, including PlGF (Sfr. 80, tariff code 1474.10) and Doppler ultrasound.
Regular pregnancy check-up at gynaecologist	35.72	TARDOC 1.1. HF0002. 7 visits during pregnancy assumed.
Ultrasound during pregnancy check-up	141.86	TARDOC 1.1 PW1001. 2 ultrasounds assumed.
Low-dose aspirin prophylaxis	22.89	150mg/day for 22 weeks. Average price of multiple manufacturers and sellers
Stay at hospital in case of PE, per stay	3,986.42	DRG O65C
Caesarean section including hospital stay	9,268.93	Average of DRGs O01E and O01G
Vaginal birth	6,158.29	Average of DRGs O60A, O60D
Admission healthy new-born	2,133.04	DRG P67D
Stillbirth	2,417.36	Mistry 2013 [25]. Includes bereavement counselling, autopsy, and placental pathology. Adjusted by purchasing power parity from United Kingdom to Switzerland.
Hospital stay neonate born at <37 WGA	67,837.32	Weighted averages of DRGs: P05A, P05B, P03A, P03B, P63Z, P04B, P04C, and P65A
Additional healthcare in first 3 months of life of preterm born		Calculation based on Jacob 2017 [27]
Visit to outpatient clinic after delivery	49.13	TARDOC 1.1. HF0007

DRG: diagnosis-related group, ICU: intensive care unit, KBV: German National Association of Statutory Health Insurance Physicians, NICU: neonatal intensive care unit

Data-analysis

Per screening method, the probability of patients following each branch along the decision-tree was calculated. For analysing costs, the probabilities of following each branch were multiplied with the costs incurred along the way. Per screening method, the health care costs, the number of PE cases, and the number of stillbirths were summed up. The results were presented as averages per woman screened and on the population level for all pregnant women per year in the respective country, which were 763,732 in Germany [17] and 84,759 in Switzerland [20, 21].

For the incremental difference, the outcomes of the routine screening group were subtracted from those of the PE screening group. To arrive at the incremental costs per PE case averted of PE screening versus routine screening, the incremental costs were divided by the incremental number of PE cases.

Sensitivity and scenario analyses

To analyse the robustness of the results, a one-way sensitivity analysis was conducted in which each input parameter was varied individually by its standard deviation, +/- 25%, or a reasonable range (see S1 Table). The top ten parameters influencing the incremental costs the most were shown in a tornado diagram.

To analyse the uncertainty surrounding the results, a probabilistic sensitivity analysis (PSA) was conducted on the incremental costs per PE case avoided. This outcome measure was chosen since the main aim of the screening is to prevent cases of preterm PE, and as developing preterm PE also includes the higher chance of developing preterm birth or still birth, as well as the negative health consequences of preterm PE itself. Healthcare costs and the number of PE cases in PE screening and routine screening were drawn from distributions reflecting the likely range of parameters in 5,000 iterations (Monte Carlo Simulation). For probabilities we used beta distributions and for costs and resource use gamma distributions. The results were shown on a cost-effectiveness plane and in a cost-effectiveness acceptability curve (CEAC). For the CEACs, the proportion of drawn values that remains below certain willingness-to-pay-thresholds was calculated [28].

In a scenario analysis we evaluated the effect of conducting a variant of the contingent PE screening in which UAPI (measured by Doppler) is only offered to the 30% of patients at highest risk. This reduces the PE screening costs to €58 for Germany and to CHF101 for Switzerland. The detection rate when conducting PE screening without the UAPI is expected to be similar but slightly lower and depends on the population screened [29]. However, a study on the actual number of preterm PE cases prevented with the contingent screening is not available. To conservatively account for a potentially lower detection rate, we increased the rate of PE cases at the same time by 10% as compared to when offering PE screening with all components to not underestimate the impact of contingent screening.

Ethics statement

As this study does not involve patients or study subjects, according to the Dutch Medical Research in Human Subject Act (WMO), it is exempt from ethical approval in the Netherlands.

Results

Base case results Germany

The average cost per women were €5,916 in PE screening and €5,901 in routine screening, leading to incremental costs for PE screening of €14 per pregnant women (difference due to rounding). The percentage of women developing preterm PE decreased from 0.71% in routine screening to 0.34% in PE screening, leading to an ICER of 3,795€ per PE case averted. For 763,732 women pregnant in Germany per year, the number of stillbirths decreased by 11 in the PE screening group compared to routine screening, and the number of PE cases by 2,891. See Table 3 for all results.

Table 3

Results for Germany and Switzerland.

Germany: Results per patient
	Costs [EUR]	Preterm PE cases	Preterm birth	Stillbirths
PE screening	5,916	0.0034	0.0905	0.00361
Routine screening	5,901	0.0072	0.0930	0.00363
Incremental (PE screening vs. RS)	14	-0.0038	-0.0025	-0.000015a
ICER	N/A	€3,795/ PE case averted	€5,734/ preterm birth averted	€990,316/ stillbirth averted
Germany: Results for all pregnant women per year
	Costs [EUR]	Preterm PE cases	Preterm birth	Stillbirths
PE screening	4,518,010,541	2,608	69,087	2,759
Routine screening	4,507,040,577	5,499	71,000	2,771
Incremental (PE screening vs. RS)	10,969,963	-2,891	-1,913	-11
ICER	N/A	€3,795/ PE case averted	€5,734/ preterm birth averted	€990,316/ stillbirth averted
Switzerland: Results per patient
	Costs [CHF]	Preterm PE cases	Preterm birth	Stillbirths
PE screening	14,800	0.0034	0.0693	0.00361
Routine screening	14,842	0.0072	0.0719	0.00363
Incremental (PE screening vs. RS)	-42	-0.0038	-0.0026	-0.000015a
ICER	N/A	Dominant	Dominant	Dominant
Switzerland: For all pregnant women per year
	Costs [CHF]	Preterm PE cases	Preterm birth	Stillbirths
PE screening	1,254,424,491	289	5,877	306
Routine screening	1,257,955,337	610	6,096	307
Incremental (PE screening vs. RS)	-3,530,846	-321	-219	-1
ICER	N/A	Dominant	Dominant	Dominant

ICER: Incremental cost-effectiveness ration, PE: preeclampsia, RS: Routine screening

a Numbers may not add up due to rounding.

Base case results Switzerland

For Switzerland, the average healthcare cost per woman were CHF14,800 in PE screening and CHF14,842 in routine screening, leading to cost-savings per woman screened on preterm PE of CHF42. The percentage of preterm PE cases in routine screening was 0.72% in routine screening and 0.34% in PE screening. For all 84,759 pregnant women in Switzerland in one year, one still birth could be prevented and 321 preterm PE cases, for PE screening versus routine screening. As PE screening in Switzerland was expected to be cost saving and leading to fewer cases of preterm PE, stillbirth, and preterm birth, it dominated the standard of care for incremental costs per preterm PE case, stillbirth, and preterm birth avoided. See Table 3 for all results.

Sensitivity analysis

In the one-way sensitivity analysis, for Germany, the most influential parameters were (1) the cost of PE screening, (2) the probability of preterm PE in standard of care, and (3) the probability of preterm birth with preterm PE. For Switzerland, the incremental costs were most influenced by varying (1) the probability of preterm PE in routine screening, (2) the probability of preterm birth with preterm PE, and (3) the cost of a hospital stay for a neonate born prematurely. The tornado diagrams (Figs 2 and 3) show the ten most influential parameters per country.

Fig 2

Tornado diagram Germany.

Base case value is €14. PE relates to preterm PE <37 weeks of gestation.

Fig 3

Tornado diagram Switzerland.

Base case value is: -CHF 42. PE relates to preterm PE <37 weeks of gestation.

The results of the PSA were plotted on the cost-effectiveness planes. In Germany, most values were in the top left quadrant, indicating fewer PE cases against higher costs. The remaining values were plotted in the bottom left quadrant, indicating fewer PE cases against lower costs than with routine screening. In Switzerland, most values were in the bottom left quadrant, indicating fewer PE cases and lower healthcare costs in PE screening versus routine screening. The remaining values drawn were in the upper left quadrant, indicating fewer PE cases against higher costs for PE versus routine screening, see Figs 4 and 5.

Fig 4

Cost-effectiveness plane Germany.

Fig 5

Cost-effectiveness plane Switzerland.

The CEACs show that in Germany, PE screening had a higher probability to be cost-effective in comparison to routine screening at a willingness-to-pay rate of €4,200 per PE case avoided (Fig 6). In Switzerland, PE screening had a 78% probability of being the most cost-effective screening strategy at a willingness-to-pay of 0 CHF for one PE case avoided (Fig 7).

Fig 6

Cost-effectiveness acceptability curve for Germany.

Fig 7

Cost-effectiveness acceptability curve for Switzerland.

The scenario analysis showed that introducing contingent PE screening with offering the UAPI measurement to only the 30% of patients being at highest risk would result in incremental costs per woman screened for PE screening versus routine screening of -€11 in Germany and -CHF73 in Switzerland, indicating cost-savings for both countries.

Discussion

In this study the cost-effectiveness of PE screening was analysed for all pregnant women in the first trimester compared to the routine screening based on maternal characteristics, for Germany and Switzerland. In both countries, PE screening reduced the number of PE cases and the number of stillbirths. The average incremental healthcare costs per women undergoing PE screening versus routine screening was €14 in Germany and -CHF42 in Switzerland, the latter representing cost savings. The ICER of costs/PE case averted was €3,795 in Germany for PE screening versus routine screening, while PE screening dominated in Switzerland. The incremental costs of PE screening in Germany were mainly driven by the probability of developing preterm PE in routine screening, the screening costs, and the probability of preterm birth when having preterm PE. For Switzerland, the drivers of the incremental costs were the probability of developing preterm PE in routine screening, followed by the probability of preterm birth with preterm PE and the costs of the hospital stay of neonates born preterm.

Several earlier studies have evaluated the economic benefit of PE screening from a non-European perspective. A study from the US societal perspective compared no aspirin use to PE screening and prophylactic aspirin, to screening based on maternal characteristics and to universal aspirin use [30] Universal aspirin use was dominant with fewer costs and fewer cases of PE compared to the other strategies. PE screening had higher total costs and fewer PE cases than screening based on maternal characteristics [30]. A Canadian study, conducted from the healthcare perspective over a one-year time horizon compared PE screening and prophylactic aspirin for those at high risk to current practice [31]. PE screening was found to be cost saving, preventing 1,096 early-onset PE cases/year at a cost saving of C$14.3m [31]. These previous publications both reported a reduction in the number of PE cases, with the cost-effectiveness depending on the costs included in the analysis and the willingness-to-pay for the prevention of PE screening.

The current study has a couple of limitations. First, the input data for the percentage of women who develop preterm PE in standard of care was relatively old [12]. It is possible that with time gynaecologists in routine screening would prescribe aspirin prophylaxis to an increasing percentage of women at high risk of preterm PE. Therefore, in the data for routine screening, fewer women identified as at high risk received aspirin prophylaxis than they would in current practice. We therefore adjusted the percentage by a relative 10% [13]. Second, the costs of PE screening are based on an estimation,. Depending on the amount of reimbursement, the PE screening costs might deviate, and influence the incremental costs per woman screened. Third, the time horizon of this economic evaluation of one year was not able to capture the negative long-term consequences of PE for the mother and the baby. Though the data still are limited, these include a higher risk of the mother for kidney disease [32], hypertension, ischemic heart disease, thromboembolism, and diabetes type 2 [33, 34]. The risks associated with preterm birth of the neonate include bronchopulmonary dysplasia, cerebral palsy, and an increased long-term risk of diabetes type 2, obesity, and cardiovascular disease [1]. Considering the costs of managing these long-term consequences by conducting an economic analysis with a longer time horizon could increase the chance of PE screening being cost-effective, assuming the relationship between PE and the long-term consequences is causative. Based on the results of this analysis, observing a reduction in the number of preterm PE cases, it is recommended to implement PE screening in practice and to include it in the reimbursed care. The additional costs of €14 per pregnant woman in Germany are relatively low considering the potential to prevent preterm PE cases, stillbirths, and especially considering the long-term health consequences of PE for the mother and for the babies born preterm. Considering equal access to care it is desirable that all women have the possibility to participate in the screening, regardless of their possibility to pay for it out of pocket, which currently is the case. In addition, access would be improved when all gynaecologists would offer PE screening which requires special education and training. Now, patients mostly are referred to specialists.

Some of the measurements required for PE screening, the ultrasound markers, and the biomarkers PAPP-A and PlGF (as optional marker), are also conducted for the first trimester trisomy screening. In Switzerland, the first trimester screening on trisomy is reimbursed for all pregnant women and approximately 90% of woman opt to conduct it (expert opinion). It is thus possible to use the measurements conducted for trisomy screening also for PE screening, which resulted in lower screening costs compared to Germany.

For Switzerland, PE screening was found to be cost saving whereas for Germany low additional costs per woman screened were found. The reason for this difference lies in the costs used in the analysis, which differ between Germany and Switzerland. The estimated cost of PE screening differs, as well as the costs of hospitalisation for a preterm born neonate. In Switzerland, the cost input used for hospitalisation of a preterm born neonate were higher than the input used for Germany. For Germany, these costs were based on the average length of stay and the NICU costs per day. As no specific cost for a day on the NICU could be identified, that of a standard ICU-day was used, which might underestimate the actual cost.

Currently, a discussion is ongoing on the parameters the PE screening should consist of. Including all parameters (i.e., maternal factors, MAP, UAPI, PAPP-A, and PlGF) leads to the highest detection rate for preterm preeclampsia <37 weeks of gestation. Removing one or two parameters from the screening results in a small decrease in the detection rate [6]. However, leaving out the more costly parameter, such as UAPI, would significantly decrease the PE screening costs, while influencing the detection rate only be small percentages [6], resulting in a higher chance for PE screening to be judged as cost-effective.

Earlier economic evaluations showed that the most cost-effective strategy is to prescribe low-dose aspirin to all pregnant women without conducting a specific screening on PE [30]. It is not expected that low-dose aspirin during pregnancy leads to considerable side effects, adverse events, or damage to the baby. However, the economic analysis which included this strategy also accounted for a higher risk of gastrointestinal bleeding and aspirin-exacerbated respiratory disease [30]. Another disadvantage of the universal strategy might be a decrease in compliance to aspirin intake. Pregnant women who do not know to be at higher risk for PE might not be willing to take aspirin, especially as pregnant women are generally (asked to be) very cautious with medication. The question is if those being compliant finally correspond with the group at highest risk.

In the prevention and management of preeclampsia after the first trimester, screening alternatives are available next to routine and innovative PE screening in the first trimester. For short-term prediction of preeclampsia, novel maternal serum biomarkers, such as the ratio between anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and PlGF taken between 18+0 and 36+6 weeks of gestation were found suitable to identify pregnant women with PE symptoms who require hospitalisation and women who can safely be monitored as outpatients [35]. A review by Schlembach et al. (2019) identified that angiogenic biomarkers to predict preeclampsia are cost-saving, among others by preventing unnecessary hospitalisation [36]. Thus, while PE screening is suitable for identifying women at high risk of preterm PE in the first trimester who benefit from aspirin prophylaxis, angiogenic biomarkers form cost-saving options for predicting the short-term risk of PE between 18+0 to 36+6 weeks of gestation.

In conclusion, this study showed that PE screening was expected to reduce the number of preterm PE cases and of stillbirths. For Switzerland, PE screening was found to be cost saving compared to the standard of care. In Germany, additional costs of €14 per woman screened were expected. In the interpretation of these results, it should be considered that the prevention of long-term health consequences caused by preterm births and potentially by preterm PE were not included within the one-year time horizon of the analysis. Further research focused on the occurrence of long-term health effects of PE for women and their children is required to be able to include potential long-term cost savings by preventing preterm PE into economic analyses of PE screening in the first trimester of pregnancy.

(DOCX)

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18 Nov 2021

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Reviewer #1: This article describes a model-based cost-effectiveness analysis of screening for pre-term eclampsia compared to usual care in Germany and Switzerland. The question addressed is interesting, as the screening procedure is currently not covered by statutory health insurers in Germany and Switzerland and published economic evaluation studies for these countries are lacking.

Overall, the article is well-structured. However, the following points require further specification:

-Some background on the different health care and policy contexts in Germany and Switzerland (e.g., what does usual care include, who conducts screening etc.) would be helpful in the introduction. In line 95 an explanation should be added why PAPP-A was not recommended for Switzerland.

-The decision tree does not distinguish all possible scenarios. For example, false positive and false negative screening tests and aspirin vs. no aspirin among patients with a standard check-up are not included. Possibly, only summary data are available which do not allow more level of detail in the model. Please provide a rationale for the model structure.

-The role of the variable “pre-term birth” is unclear. In the decision tree it seems that pre-term birth is an outcome, however it is not included in table 3 and 4. Pre-term births and still births averted seem a more meaningful outcome from the patient perspective than PE cases averted. Please describe the rationale for choosing PE cases averted as primary outcome.

-In Figure 2 a legend would be helpful. I assume the (+) means that the path starting with standard check up needs to be added here.

-Information is missing about key assumptions regarding the relationship between events and costs. For example, one would assume that the rate of Caesarian sections is higher among patients with PE.

-The term “interventions” is confusing. It would be clearer to speak about alternatives or more specifically about routine screening and innovative screening. According to my understanding screening does already take place in routine care, but with less elaborated methods.

-The costs of PE screening in Table 2 require more details. Currently only a sum is represented. The cost prices for each separate test should be added (see row 1).

-The cohort for which the calculations were made is insufficiently described. The cohort is first mentioned in the results section. The wording “per cohort” is confusing. Were calculations carried out once or repeatedly for several cohorts?

-Please provide a rationale for carrying out one-way sensitivity analysis only. Additionally, why were all input parameters varied by the same percentage. Was this due to lack of data that would have allowed more specific assumptions for different input parameters?

-In the discussion the authors recommend including PE screening in reimbursed care in Germany. Whether PE screening should be reimbursed will depend on WTP for PE cases or stillbirths averted. This is a political decision. To justify this statement, I recommend presenting cost-effectiveness acceptability curves.

-The discussion would benefit from considering the role of the new screening algorithm in comparison to potential other alternatives, in particular novel maternal serum biomarkers (see: https://www.sciencedirect.com/science/article/pii/S2210778918307670)?

Minor points:

-Line 51: HELLP-syndrome: please spell out the first time this abbreviation is used

-Line 60: please specify which guidelines you refer to

-Line 90: please add a literature reference for FMF

-Line 169: it should read “one-way sensitivity analysis”

-Line 224: please specific what is meant by “at the second level”

-Line 260: please explain, why the percentage of women who develop preterm PE would change so significantly within 3 years

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8 Mar 2022

Response to reviewer´s comments

PONE-D-21-23946

Cost-effectiveness analysis of implementing screening on preterm pre-eclampsia at first trimester of pregnancy in Germany and Switzerland

PLOS ONE

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We went through all author guidelines including those for file naming and adapted the manuscript´s style and file naming accordingly.

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We have now included supporting information to our manuscript. It lists the input data necessary to repeat our analyses in tables, includes all probabilities, resource use, costs, ranges used for the one-way sensitivity analysis, and the distributions and standard errors used in the probabilistic sensitivity analysis. Also included in the supporting information are the data points used to build the figures showing the results of the one-way sensitivity analyses and the cost-effectiveness acceptability curves.

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Please revise your manuscript according to the reviewer's advise and suggestions. Table 3 and 4 may be combined with one Table.

Thank you for the suggestions. Table 3 and 4 are now merged into one table i.e. table 3.

Reviewers' comments:

Reviewer #1: This article describes a model-based cost-effectiveness analysis of screening for pre-term eclampsia compared to usual care in Germany and Switzerland. The question addressed is interesting, as the screening procedure is currently not covered by statutory health insurers in Germany and Switzerland and published economic evaluation studies for these countries are lacking.

Overall, the article is well-structured. However, the following points require further specification:

-Some background on the different health care and policy contexts in Germany and Switzerland (e.g., what does usual care include, who conducts screening etc.) would be helpful in the introduction. In line 95 an explanation should be added why PAPP-A was not recommended for Switzerland.

Thanks for pointing out the need for adding more context on PE screening in Germany and Switzerland. We added additional information on who conducts the screening and what the routine screening in usual care consists of. In the introduction, starting in line 62, it now reads:

“In both Germany and Switzerland, antenatal care for pregnant women includes regular visits at the gynaecologist or, for pregnancies without complications, with a midwife. In the current standard of care, women at high risk of PE are identified through a routine screening during one of the first antenatal consultations, by means of analysing maternal characteristics and risk factors, as well as previous pregnancies and medical records.”

The decision tree does not distinguish all possible scenarios. For example, false positive and false negative screening tests and aspirin vs. no aspirin among patients with a standard check-up are not included. Possibly, only summary data are available which do not allow more level of detail in the model. Please provide a rationale for the model structure.

The reviewer is indeed correct in pointing out that false positives and false negatives, as well as aspirin vs. no aspirin prophylaxis in routine screening, were not included in the decision-tree, due to limitations in the available data. It was therefore not possible to include more detailed information.

To provide the reviewer with a bit more background: With the current PE screening, the detection rate of preterm PE is almost 80%, at a false positive rate of almost 10% (Rolnik, 2017, Ultrasound Obstet Gynecol). Thus, also with the innovative PE screening, not all women at high risk are detected (false negatives) and some women develop preterm PE but were not detected as being at high risk (false negatives). In the analysis, this is included in the number of women developing preterm PE when being classified as at high risk or not. The false positives and false negatives are thus not included as separate branches in the decision-tree but ist included in the results.

The same is true for the women in routine screening who do or do not receive aspirin prophylaxis when being at high risk. Currently, it is not known how accurately women at high risk of preterm PE are identified in routine screening, nor how many of them subsequently are being prescribed aspirin prophylaxis. For the cost calculations in the model, we used expert opinion that 80% of the women identified as at high risk receive aspirin prophylaxis. For the number of women developing preterm PE in routine screening we used the total number of women developing preterm PE as summary data for routine screening. In the manuscript we have explained this starting in line 116:

“In PE screening, women were classified as at high risk for preterm PE or not. Women at low risk of preterm PE received standard antenatal care. Women at high risk of preterm PE were prescribed low-dose aspirin prophylaxis. All women in PE screening could develop preterm PE or not, and have a stillbirth, a live preterm birth (<37 weeks of gestation), or a live term birth.

In routine screening, women could be classified as at high-risk based on maternal characteristics and might be prescribed low-dose aspirin prophylaxis. As no data was available on the probability of being classified as at high risk for preterm PE in routine screening and on subsequently receiving aspirin prophylaxis, we used summary data on the average number of women experiencing the outcomes stillbirth, live preterm birth, and live term birth. This was done irrespectively of a previous classification of being at high risk for preterm PE, as the available data did not allow for more level of detail.

The impact of false positive and false negative screening results for both screening alternatives were included in the outcomes of both interventions, i.e., some women received aspirin prophylaxis unnecessarily, and some did not receive aspirin prophylaxis whereas they should. This results in a higher chance in both screening alternatives of developing preterm PE than when the prophylaxis had been received.”

The role of the variable “pre-term birth” is unclear. In the decision tree it seems that pre-term birth is an outcome, however it is not included in table 3 and 4. Pre-term births and still births averted seem a more meaningful outcome from the patient perspective than PE cases averted. Please describe the rationale for choosing PE cases averted as primary outcome.

Indeed, preterm birth, still births, and PE cases are the three outcomes mentioned in the decision-tree. We agree that preterm birth also should be reported in the tables 3 and we therefore included it in the new Table 3 (tables 3 and 4 combined).

The reviewer is current in pointing out that preterm birth and still birth are very meaningful outcomes from the patient perspective. We feel that preterm PE by itself meaningful as well, as the diagnosis is very stressful for the mother and the families. In addition, it may lead to hospitalisation, early delivery (even though it might not be preterm), and a potential increase in risk of long-term outcomes. Thus, we find it difficult to decide which out these outcomes is most important and to decide how to weight quantity and severity. We have adapted the description of the outcome measures, which now read in line 132:

“The primary outcome measures were the incremental health care costs per women screened in PE screening versus routine screening and the incremental costs per PE case avoided. Secondary outcomes were the incremental costs per preterm birth avoided, and per still birth prevented.”

For the PSA we chose the ICER of costs/preterm PE cases avoided for the probabilistic analysis, as the preterm PE cases also include the increased risk associated with preterm PE of preterm birth and still birth. This now reads in line 202 onwards:

“To analyse the uncertainty surrounding the results, a probabilistic sensitivity analysis (PSA) was conducted on the incremental costs per PE case avoided. This outcome measure was chosen since the main aim of the screening is to prevent cases of preterm PE, and as developing preterm PE also includes the higher chance of developing preterm birth or still birth, as well as the negative health consequences of preterm PE itself.”

In Figure 2 a legend would be helpful. I assume the (+) means that the path starting with standard check-up needs to be added here.

Thank you for pointing out this omission, we added a figure legend.

Information is missing about key assumptions regarding the relationship between events and costs. For example, one would assume that the rate of Caesarian sections is higher among patients with PE.

When re-reading our manuscript with this information we indeed see this information is missing, thank you for pointing this out. From line 154 onwards we now explain how the outcomes are linked to the screening alternatives:

“In both screening alternatives, women could develop preterm PE or not, depending on the screening accuracy to detect preterm PE. Without preterm PE, the probabilities of caesarean section, stillbirth, and preterm birth were identical to the averages in the respective countries (see table 1). When developing preterm PE, these were higher. For Germany, the probability of delivery by caesarean section with preterm PE was 99.2% [14], of stillbirth 0.74% [14], and of preterm birth 75.0% [14]. With preterm PE, the length of stay increased by 3 days for the mother and 16 days for the neonate [15]. For Switzerland, the probability of delivery by caesarean section of women with preterm PE was 61.9% (calculation based on [16]), of stillbirth 0.74% [4], and of preterm birth 75.00 [3]. For Switzerland, the extended length of stay for preterm PE patients was included using a DRG-code for a hospital stay with preterm PE.”

The rates of delivery with Caesarean section indeed were higher when developing preterm PE, for Germany, e.g., this is around 30% without preterm PE and 99% with preterm PE. We have restructured table 1 to make it easier for the reader to identify the probabilities per outcome based on having preterm PE or not. This should make it much easier to compare the percentages and to understand how the screening alternatives influence the number of patients developing preterm PE and how this influences outcomes.

The term “interventions” is confusing. It would be clearer to speak about alternatives or more specifically about routine screening and innovative screening. According to my understanding screening does already take place in routine care, but with less elaborated methods.

We agree that the term “interventions” was confusing. We have removed it throughout the manuscript and now use the term “screening alternatives”. What was previously “standard of care” is now termed “routine screening”, as it is correct that also in standard of care a screening takes place (based on maternal characteristics).

The costs of PE screening in Table 2 require more details. Currently only a sum is represented. The cost prices for each separate test should be added (see row 1).

To provide a better impression of the costs of PE screening we now included the costs of the biomarkers in table 2. For Germany, we used the ebm code 32362 for PlGF and PAPP-A of €19.40. Next to these, costs are incurred for drawing the blood sample, for the Doppler ultrasound, MAP, interpretation of the screening results, and providing advice to the patient. It is currently unknown how high the reimbursement for the screening would be, it was estimated around €60. In private practice, the prices charged for PE screening currently are around €130, but these are not regulated and thus differ among practices. Reimbursement by public health insurance is expected to be lower than the privately charged amount. Based on the estimation of the experts we talked to, it was estimated that 90€ is a realistic reimbursement to expect. As stated in the manuscript, it is not certain what would be the final reimbursement.

For Switzerland, Sfr. 80 are for the PlGF measurement, based on the tariff code 1474.10, with the remaining parts of the screening being covered with Sfr. 70. We have updated the description of the PE screening costs in Table 2.

The cohort for which the calculations were made is insufficiently described. The cohort is first mentioned in the results section. The wording “per cohort” is confusing. Were calculations carried out once or repeatedly for several cohorts?

The reviewer is right that the term “per cohort” was confusing. We calculated all results as averages per patient, as well as per year for all pregnant women in the respective country, to enable decision-makers to identify how many cases of preterm PE, stillbirths, and preterm births can be prevented in their country on a yearly basis. From line 190 onwards we added explanation to the analysis section under methods:

“The results were presented as averages per woman screened and on the population level for all pregnant women per year in the respective country, which were 763,732 in Germany [17] and 84,759 in Switzerland [20, 21].”

Also, in table 3 we changed the wording from “per cohort” to “Results for all pregnant women per year”.

Please provide a rationale for carrying out one-way sensitivity analysis only. Additionally, why were all input parameters varied by the same percentage. Was this due to lack of data that would have allowed more specific assumptions for different input parameters?

We looked again at the data used for the one-way sensitivity analysis. Where available, we now used a reasonable range when this was different from the +/-25%. Please see the S1 Table for the data and ranges used.

We also added a probabilistic sensitivity analysis to our analysis. It is described in the methods section under “sensitivity and scenario analyses” starting in row 197. In the results we present the cost-effectiveness planes (figs 4 and 5) and cost-effectiveness acceptability curves (figs 6 and 7).

In the discussion the authors recommend including PE screening in reimbursed care in Germany. Whether PE screening should be reimbursed will depend on WTP for PE cases or stillbirths averted. This is a political decision. To justify this statement, I recommend presenting cost-effectiveness acceptability curves.

We fully agree that based on the results for Germany, it is a political decision to decide on the willingness-to-pay for the prevention of preterm PE cases. To provide the relevant data for this decision, we now present CEACs for Germany and Switzerland in the results section.

The discussion would benefit from considering the role of the new screening algorithm in comparison to potential other alternatives, in particular novel maternal serum biomarkers (see: https://www.sciencedirect.com/science/article/pii/S2210778918307670)?

We feel to discuss the role of novel serum biomarkers and the suggested article is a valuable addition to the discussion and have added a paragraph on this topic, starting in row 365:

In the prevention and management of preeclampsia after the first trimester, screening alternatives are available next to routine and innovative PE screening in the first trimester. For short-term prediction of preeclampsia, novel maternal serum biomarkers, such as the ratio between anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and PlGF taken between 18+0 and 36+6 weeks of gestation were found suitable to identify pregnant women with PE symptoms who require hospitalisation and women who can safely be monitored as outpatients [35]. A review by Schlembach et al. (2019) identified that angiogenic biomarkers to predict preeclampsia are cost-saving, among others by preventing unnecessary hospitalisation [36]. Thus, while PE screening is suitable for identifying women at high risk of preterm PE in the first trimester who benefit from aspirin prophylaxis, angiogenic biomarkers form cost-saving options for predicting the short-term risk of PE between 18+0 to 36+6 weeks of gestation.”

Minor points:

-Line 51: HELLP-syndrome: please spell out the first time this abbreviation is used

Thanks for noticing us, this is done.

Line 60: please specify which guidelines you refer to

This was added and referenced.

Line 90: please add a literature reference for FMF

The reference was added.

Line 169: it should read “one-way sensitivity analysis”

Thank you, we have corrected the spelling.

Line 224: please specific what is meant by “at the second level”

We have changed to wording to make it easier to understand. With “second level” we meant in a second step, i.e. first conducting PE screening without UAPI, and then offering it to the 30% for whom the highest risk was found. It now reads: “Introducing contingent PE screening with offering the UAPI measurement to only the 30% of patients being at highest risk”.

Line 260: please explain, why the percentage of women who develop preterm PE would change so significantly within 3 years.

We expect that with time, prevention of preterm PE through aspirin prophylaxis would receive more attention, also as the innovative PE screening becomes available, and therefore, more gynaecologists would prescribe (or start to prescribe) aspirin prophylaxis to women with a high risk as identified in routine screening. However, this would indeed take a while. We have changed the description of this sentence in line 310:

“The current study has a couple of limitations. First, the input data for the percentage of women who develop preterm PE in standard of care was relatively old [12]. It is possible that with time gynaecologists in routine screening would prescribe aspirin prophylaxis to an increasing percentage of women at high risk of preterm PE. Therefore, in the data for routine screening, fewer women identified as at high risk received aspirin prophylaxis than they would in current practice. We therefore adjusted the percentage by a relative 10% [13].”

Submitted filename: Response to reviewers comments_Mewes et al_220121.docx

Click here for additional data file.

11 Apr 2022

21 May 2022

Thank you for confirming that we have addressed your questions and comments. Regarding the last minor point and the legend for Figure 1; these were addressed in the revised manuscript, page 5, lines 114-115:

[+]: The branches from above are repeated.

Submitted filename: Response to reviewers comments_Mewes et al_21052022.docx

Click here for additional data file.

13 Jun 2022

Cost-effectiveness analysis of implementing screening on preterm pre-eclampsia at first trimester of pregnancy in Germany and Switzerland

PONE-D-21-23946R2

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Academic Editor

PLOS ONE

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Reviewers' comments:

20 Jun 2022

PONE-D-21-23946R2

Cost-effectiveness analysis of implementing screening on preterm pre-eclampsia at first trimester of pregnancy in Germany and Switzerland

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