Preterm Preeclampsia Screening and Prevention: A Comprehensive Approach Integrating Precision Medicine in A Real-world Setting

doi:10.21203/rs.3.rs-4877262/v1

Download PDF

Research Article

Preterm Preeclampsia Screening and Prevention: A Comprehensive Approach Integrating Precision Medicine in A Real-world Setting

https://doi.org/10.21203/rs.3.rs-4877262/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background

Preeclampsia significantly impacts maternal and perinatal health. Early screening using advanced models and primary prevention with low-dose acetylsalicylic acid for high-risk populations are crucial to reduce the disease’s incidence. This study assesses the feasibility of implementing first-trimester aneuploidy screening concurrent with preterm preeclampsia prevention by leveraging information from the former and integrating precision medicine in a real-world setting with spatial separation between laboratory and clinical sites.

Methods

A prospective cohort study involved pregnant individuals undergoing nuchal translucency scans between 11 and 14 weeks. Risk for preterm preeclampsia was assessed using the Fetal Medicine Foundation algorithm, which includes maternal risk factors, uterine artery Doppler, mean arterial pressure and serum markers. High-risk patients were offered low-dose acetylsalicylic acid prophylaxis. Feasibility outcomes, such as recruitment rates, protocol adherence, operational impact, integration with existing workflows, screening performance and pregnancy outcomes, were evaluated.

Results

Out of 974 participants, 15.6% were high-risk. The study achieved high recruitment (82.1%) and adherence rates, with 95.4% of high-risk patients prescribed low-dose acetylsalicylic acid. Screening performance, adjusted for low-dose acetylsalicylic acid use, showed a detection rate of 88.9–90% for preterm preeclampsia. High-risk patients had higher incidences of adverse outcomes, including preterm preeclampsia, preterm delivery, and low birth weight. The integration of preeclampsia screening had a minimal effect on the time required for aneuploidy screening, with results obtained within a rapid turnaround time.

Conclusions

The study confirms the feasibility of integrating comprehensive preeclampsia screening into clinical practice, notwithstanding spatial separation between laboratory and clinical settings. It underscores the need for broader adoption and enhanced infrastructure to optimize patient care and outcomes across diverse healthcare settings.

Trial registration:

Clinical trial: NCT04412681 (2020-06-02)

preterm preeclampsia

prenatal screening

low-dose acetylsalicylic acid

placental growth factor

uterine artery Doppler

biomarkers

first trimester

mean arterial blood pressure

Preeclampsia (PE) is a significant pregnancy-related condition affecting 2–8% of all pregnancies (1–3), leading to severe maternal and perinatal morbidity and mortality, particularly when it occurs before 32 weeks (4–6). It also increases the risk of future cardiovascular diseases in affected individuals (7–9).

While traditional screening methods are limited in their effectiveness (10–12), recent advancements in predicting models, such as the one developed by the Fetal Medicine Foundation (FMF) in the UK, show a detection rate of approximately 75–90% of at-risk individuals in early pregnancy at a false positive rate of 10% (13, 14). This algorithm incorporates maternal risk factors, uterine artery Doppler (UtAPI), mean arterial pressure (MAP), and serum markers of placental function (pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PLGF) and has been validated prospectively in several studies (15–18).

Several meta-analyses have reported that the incidence of preterm PE can be substantially reduced by the administration of low-dose acetylsalicylic acid (LDA) starting at 16 weeks or earlier (19–22). Moreover, the ASPRE trial supported the efficacy of LDA (150 mg) in high-risk pregnant individuals identified through the FMF screening algorithm, showing a significant reduction of preterm PE (83% <34 weeks and 62% <37 weeks) compared with placebo (23). Several national societies support the use of LDA for the prevention of preterm PE (24, 25). However, despite this evidence, doubts remain among practitioners about systematic screening and treatments with the result of a significant underuse of LDA in at-risk populations (26–28). Cost-effectiveness analyses suggest that implementing screening programs and preventive measures can lead to significant cost savings for healthcare systems (29, 30).

To demonstrate that screening and treatment produce reproducible positive effects on the incidence of preterm PE in varied settings, several controlled studies of implementation have been carried out in different countries, two of them in Ontario and Alberta (31–33). In all studies, screening was offered alongside first-trimester aneuploidy screening programs with high-risk patients advised to initiate LDA under the supervision of their healthcare provider. Both Canadian studies demonstrated the practical feasibility and efficacy of integrating an evidence-based screening and prevention program for preterm PE into clinical services where patients were screened at the clinic and laboratory tests were conducted within the same institution.

This study aims to evaluate the feasibility of implementing a clinical model for precision screening of preterm PE into the current prenatal screening service in a prenatal tertiary center (Sunnybrook Health Sciences Centre, Toronto, ON) in collaboration with the largest provincial prenatal screening laboratory located at a different institution (North York General Hospital, Toronto, ON).

This was a prospective cohort study including singleton pregnant individuals (≥ 18 years old) undergoing nuchal translucency (NT) scan for aneuploidy screening between 11 to 14 weeks at Sunnybrook Health Science Centre who consented to screen for preterm PE recruited non-continuously from March 2021 to June 2023 (22-month study period). Exclusion criteria included fetal demise or major fetal anomalies, known contraindications or sensitivities to, or current use of LDA at the time of recruitment. The study was approved by the institutional review boards at both institutions (Sunnybrook #20-3657 and North York #20 − 0001) and requested to be registered Clinical.trial.gov: NCT04412681.

The clinical setting was organized as follows: upon arrival in the department at Sunnybrook Hospital, the ultrasound check-in clerk provided pregnant individuals registered for an NT scan with an information pamphlet about the study (Suppl Fig. 1). Pregnant individuals then underwent their NT scan, including uterine artery Doppler, in accordance with the implemented departmental protocol by certified sonographers who had previously obtained the FMF Certificate of Competence (34). Subsequently, patients were approached by a designated research associate who invited them to participate in the implementation study. Interested patients who met eligible criteria received comprehensive information about the study and were given the opportunity to sign informed consent. In consenting study participants, the research associate recorded maternal demographic and risk factors required for preterm PE risk calculation, the blood pressures (measured in a quiet room) and the uterine Doppler measurements on a standard screening requisition for PE (Suppl Fig. 2). All participants were then directed to the laboratory (local hospital or external laboratory) to obtain a blood sample, following standard practice for first-trimester screening (FTS), attaching the requisition for PE screening to the current aneuploidy screening form. Independently by the site of sample collection, all samples were sent to the provincial prenatal screening laboratory (North York General Hospital). Participants interested in PE screening only (either declining aneuploidy screening or previously had noninvasive prenatal testing, NIPT) were given the option to undergo the blood test in the laboratory. In such cases, the research assistant indicated “only PE screening, no FTS” on the requisition form. Alternatively, participants had the choice to omit placental serum marker level from the risk calculation and were counselled that serum marker omission reduced the accuracy of the test (13). To track and verify an efficient flow of requisition forms and samples to the centralized laboratory located at North York General Hospital, the designated research assistant emailed the list of participants directly to the laboratory every day. The personalized risk for preterm PE was calculated at the North York General Hospital laboratory using the screening software LifeCycle (Revvity Inc.), with the incorporated FMF algorithm (34). A risk cut-off of ≥1/100 was employed to define high-risk patients. The results of the PE screening were transmitted by fax to the research assistant at Sunnybrook Hospital. A low-risk result was communicated to the participant by phone by the research assistant, and a copy of the report was sent to the primary healthcare provider. In the event of high-risk results, either a maternal-fetal medicine specialist or an implementation study nurse practitioner was informed by the research assistant. They were responsible for providing adequate counselling by phone to the patient, including advice to commence LDA (162 mg) prior to 16 weeks until 36 weeks (as per local standard of care). A copy of the high-risk results and suggested pregnancy management (LDA, placental study, fetal medicine specialist consultation) was sent to the primary health care provider. Serial follow-up phone calls were scheduled by the research assistant at 16, 22, 26, 32, and 36 weeks to verify adherence to LDA treatment.

Participants’ demographic information, screening data, risk estimation for preterm PE, interventions, LDA adherence and pregnancy outcomes, including preterm PE and other placental-mediated adverse outcomes such as intrauterine growth restriction, late PE, placental abruption, perinatal mortality, mode of delivery and admission to neonatal intensive care unit-were collected and entered in the study database.

Quality assurance of placental growth factor (PLGF) and pregnancy-associated plasma protein A (PAPP-A) measurements are routinely evaluated as part of the quality assurance for multiple marker screening. Quality assurance of uterine artery pulsatility index and blood pressure measurements were monitored by assessing monthly and operator-specific medians against the FMF nomograms. PE and gestational hypertension were defined according to the International Society for the Study of Hypertension in Pregnancy (35). Preterm PE was defined as delivery with PE before 37 weeks of gestation. The screen detection rate (sensitivity) and false positive rate (1-specificity) for preterm PE < 37 weeks was calculated, including estimates adjusted for the effect of LDA in high-risk patients. The detection rates and false positive rates, after adjusting for LDA use, were calculated under the assumption that LDA use prevented 62% of preterm PE cases (23). Specifically, the expected number of PE cases was calculated as the sum of number of PE cases with low risk and number of PE cases with high risk divided by adherence rate multiplied by 62%. Expected number of cases predicted was calculated by the number of PE cases with high risk divided by adherence rate multiplied by 62%(33, 36). The Mann-Whitney U test, Chi-Square test, and Fisher's Exact test were utilized to compare the maternal characteristics and prevalence of adverse outcomes between the high-risk and low-risk groups.

Out of 1225 eligible patients, 1006 consented to participate in the study (82.1%). The recruitment rate demonstrated an improvement throughout the study, rising from 74.3–94.3% upon the inclusion of patients opting for NIPT, allowing for the choice to calculate PE risk with or without the serum markers. Among 1006 consenting patients, 31 opted out before and 1 patient after the PE risk calculation (32/1006, 3.2%), resulting in a final cohort of 974 patients (Fig. 1). PE screening identified 152 patients as being at high risk (15.6%) and 822 at low risk (84.4%). PE risk was calculated without the use of placental markers in 157 out of 974 patients (16.1%).

Table 1 provides the demographic characteristics, medical and obstetrical history of enrolled patients subdivided into low and high-risk groups based on PE screening results. Patients identified as high-risk were more likely to be nulliparous, Black or South-Asian ethnicity, smokers, conceiving through in vitro-fertilization, or had longer interpregnancy intervals if multiparous, had a higher BMI and medical complications such as chronic hypertension, autoimmune conditions and diabetes.

Table 1

Demographics, medical and obstetrical history of the study population
Demographics, Obstetrics and History	Low Risk Median[IQR]/N(%)	High risk Group Median[IQR]/N(%)	Total Median[IQR]/N(%)	P-value
Number of patients	N = 822	N = 152	N = 974	-
Maternal age at due date (years)	34.3 [31.5–36.7]	34.6 [31.4–37.7]	34.3 [31.4–36.9]	0.60
Gestational age at screen (weeks)	12.3 [12.0-12.5]	12.2 [12.0-12.5]	12.3 [12.0-12.5]	0.20
Body mass index	24.1 [21.6–27.5]	28.1 [23.8–34.0]	24.5 [21.8–28.4]	< 0.0001
Race or ethnic group*
White	438 (53.3)	49 (32.2)	487 (50.0)	Reference
Black	35 (4.3)	25 (16.4)	60 (6.2)	< 0.0001
East Asian	167 (20.3)	28 (18.4)	195 (20.0)	0.11
South Asian	129 (15.7)	39 (25.7)	168 (17.2)	< 0.0001
Other	53 (6.4)	11 (7.2)	64 (6.6)	0.09
Total	822 (84.4)	152 (15.6)	974 (100)	-
Method of conception
Spontaneous	785 (95.5)	132 (86.8)	917 (94.1)	Reference
In vitro fertilization	37 (4.5)	20 (13.2)	57 (5.9)	< 0.0001
Total	822 (84.4)	152 (15.6)	974 (100)	-
Medical History
Chronic hypertension	6 (0.7)	25 (16.4)	31 (3.2)	< 0.0001
Systemic lupus erythematosus	3 (0.4)	3 (2.0)	6 (0.6)	0.052
Antiphospholipid syndrome	-	1 (0.7)	1 (0.1)	Insufficient count
Diabetes mellitus type 1	6 (0.7)	4 (2.6)	10 (1.0)	0.056
Diabetes mellitus type 2	10 (1.2)	15 (9.9)	25 (2.6)	< 0.0001
Cigarette smoking during pregnancy	9 (1.1)	6 (3.9)	15 (1.5)	< 0.0194
Parity
Nulliparous	379 (46.1)	96 (63.2)	475 (48.8)	Reference
Multiparous	443 (53.9)	56 (36.8)	499 (51.2)	< 0.0001
Total	822 (84.4)	152 (15.6)	974(100)	-
Obstetric and Family History
History of preeclampsia	4 (0.9)	12 (21.4)	16 (1.6)	< 0.0001
Mother had preeclampsia	18 (2.2)	6 (3.9)	24 (2.5)	0.2452
Interval from last pregnancy (years)	2.1 [1.4–3.4]	2.95 [1.9–4.9]	2.2 [1.4–3.5]	< 0.01
*All races are compared to the white reference group.

The average time for history collection was 2.4 minutes, and arterial blood pressure measurements were 3.06 minutes. The measurement of uterine arteries Doppler required no more than 2 minutes, exerting no impact on the total time allocated for the NT scan (30 minutes). Turnaround times between sample collection in any laboratory and receipt at the screening laboratory was 1.09 days; between sample receipt at the screening laboratory and result reporting was 1.69 days (Table 2).

Table 2

Time used for each component of the screening test and turnaround time of the screening test
Time Interval	Mean	Median (p5, p95)
History Collection (min)	2.41	2.0 (1.0, 4.25)
Blood Pressure Collection (min)	3.06	3.0 (2.0, 4.0)
Nuchal Translucency Scan (min)	26.7	25 (20,40)
Uterine artery Doppler measurement (min)	2.02	2.0 (1.0,2.5)
Time between blood sample collection and blood sample receipt (days)	1.09	1(1,2)
Time between sample receipt and results report (days)	1.69	2(1,3)

Pregnancy outcomes were available in 936 cases (96.1%), (790 low risk and 146 high risk) with 23 loss of follow-up (delivered in another hospital), 8 terminations of pregnancy before 24 weeks, 5 miscarriages < 16 weeks, and 2 intrauterine deaths < 20 weeks and are presented in Table 3.

Table 3

Pregnancy outcomes among pregnancies with high or low risks for preeclampsia (Gestational age ≥ 20 weeks)
Pregnancy outcomes	Low risk N (%)	High risk N (%)	Total N (%)	P value
Number of patients	790 (84.4)	146 (15.6)	936 (100)	-
Preeclampsia < 37 weeks	3 (0.4)	11 (7.5)	14 (1.5)	< 0.001
Preeclampsia < 34 weeks	1 (0.1)	-	1 (0.1)	-
Preterm delivery < 37 weeks	49 (6.2)	31 (21.2)	80 (8.5)	< 0.001
Preterm delivery < 34 weeks	17 (2.2)	10 (6.8)	27 (3.0)	< 0.006
Gestational hypertension	13 (1.6)	9 (6.2)	22 (2.3)	< 0.003
Birthweight < 2500 g	44 (5.6)	34 (23.2)	78 (8.4)	< 0.001
Stillbirth	-	1 (0.7)	1 (0.1)	-

The high-risk subgroup presented with significantly higher rates of adverse pregnancy outcomes, including preterm PE < 37 weeks (7.5% vs 0.4% p < 0.001), preterm delivery (21.2% vs 6.2% p < 0.001), birthweight < 2500 g (23.2% vs 5.6% p < 0.001), gestational hypertension (6.2% vs 1.6 p < 0.003) (Table 3). Additionally, among high-risk patients, there were 3 cases of PE after 37 weeks (2.0%) and one postpartum PE requiring readmission (0.7%). In the low-risk group, there were 5 cases of post-partum PE requiring readmission (0.6%).

When compared with low-risk, high-risk patients had significantly higher median MAP (1.03 [0.92–1.2] vs 0.97 [0.87–1.11] MoM, p < 0.001), UtAPI (1.19 [0.75–1.78] vs 0.99 [0.60–1.45] MoM; p < 0.001) and lower PLGF (0.76 [0.24–1.35] vs 1.08 [0.56–1.94] MoM; p < 0.001), and lower PAPP-A ( 0.89 [0.30–2.09] vs 1.12 [0.48–2.64] MoM; p < 0.001) (Table 4).

Table 4

Median MoM of biophysical and biochemical marker by pregnancy outcomes and screening results
Outcome/result	Marker Medians (p5, p95)
Outcome/result	N (%)	MAP (mmHg)	MAP MoM	UTPI	UTPI MoM	PIGF MoM	PAPPA MoM
Adverse outcomes
Preterm PE < 37 weeks	14 (1.5)	100.71(81.00,113.42)	1.08(0.94,1.36)	1.75(0.85,2.95)	1.00(0.54,1.84)	0.89(0.70,2.02)	1.14(0.30,2.24)
Preterm delivery < 37 weeks	80 (8.5)	87.09 (73.79, 109.00)	1.01(0.86,1.21)	1.76(0.99,2.65)	1.08(0.62,1.62)	1.04(0.46,1.97)	1.08(0.33,2.53)
Preterm delivery < 34 weeks	27 (2.9)	85.67(74.42,101.08)	1.00(0.87,1.15)	1.87(0.98,2.59)	1.11(0.62,1.54)	1.02(0.45,1.65)	0.97(0.37,1.96)
Gestational hypertension	22 (2.4)	95.33(84.00,107.00)	1.06(0.94,1.19)	1.85(1.05,2.42)	1.15(0.64,1.44)	0.86(0.53,2.38)	0.86(0.36,3.11)
Birthweight < 2500g	78 (8.3)	87.46(74.58,104.67)	1.01(0.90,1.17)	1.91(0.98,2.66)	1.14(0.58,1.71)	0.89(0.45,1.85)	0.91(0.33,2.43)
All adverse outcomes	208 (22.2)	86.42(73.67,104.58)	1.01(0.87,1.17)	1.76(1.01,2.66)	1.05(0.62,1.62)	0.97(0.46,2.02)	0.99(0.36,2.53)
Screening result
All pregnancies	974 (100)	84.21(72.42,99.92)	0.98(0.87,1.13)	1.70(1.00,2.51)	1.01(0.62,1.52)	1.04(0.46,1.90)	1.09(0.41,2.58)
Positive PE Screen	152(15.6)	93.54(79.75,105.92)	1.03(0.92,1.20)	1.95(1.19,2.95)	1.19(0.75,1.78)	0.76(0.24,1.35)	0.89(0.30,2.09)
Negative PE Screen	822(84.4)	83.17(71.92,96.46)	0.97(0.87,1.11)	1.65(0.99,2.41)	0.99(0.60,1.45)	1.08(0.56,1.94)	1.12(0.48,2.64)
PE preeclampsia; MAP Mean arterial pressure; UTPI uterine arteries pulsatility index; PlGF placental growth factor; PAPP-A pregnancy-associated plasma protein A; MoM multiple of the median

Telephone follow-up of high-risk patients was successful in all high-risk pregnancies until 26 weeks, with three patients lost to follow-up (2.1%) thereafter. The initiation rate of LDA at 16 weeks was 95.4% (144/151), with only 7 patients not commencing LDA due to personal choice or following medical advice in the presence of antepartum bleeding (Table 5).

Table 5

Compliance to low dose acetylsalicylic acid (LDA) in high-risk patients: initiation and maintenance rate
Check in Week	Taking LDA	Not Taking LDA	Miscarriage	Loss FU	Delivery	Total Pregnancies
	N (%)	N (%)	N (%)	N (%)	N (%)	N
16	144 (95.4)	7 (4.6)	1 (0.7)	0 (0)	0 (0)	151
22	138 (92.6)	11 (7.4)	2 (1.3)	0 (0)	1 (0.7)	149
26	135 (91.2)	13 (8.8)	2 (1.4)	0 (0)	2 (1.4)	148
32	130 (90.9)	13 (8.9)	2 (1.4)	3 (2.1)	4 (2.8)	143
36	111 (86.0)	18 (14.0) *	2 (1.6)	3 (2.3)	18 (14.0)	129
*5 patients stopped taking LDA acid at 35 weeks.

Among 11 high-risk patients who developed preterm PE, all were compliant with LDA until delivery. In 6 cases, PE was superimposed on chronic hypertension, with 3 cases associated with preexisting severe chronic kidney disease and 1 case with lupus nephritis. One patient with a prior history of severe preterm PE at 26 weeks developed PE at 36.5 weeks. In the low-risk population, one case of preterm PE (< 34 weeks) occurred in a patient on home dialysis and a prior failed renal transplant who was on LDA despite low-risk PE screening results. None of the other 4 low-risk cases diagnosed with PE were on LDA. In this study, 11 of the 16 (68.8%) observed preterm PE screened had high-risk screening results.

Treatment-adjusted screening performance for preterm PE at different LDA adherence rates is shown in Table 6. In this study, the LDA adherence rates range between 86% and 95.4% at different gestational ages. With these adherence rates, the DR adjusted for LDA use were 88.9% and 90.0% for FPR of 13.0% and 12.7% respectively.

Table 6

Screen performance at different LDA adherence thresholds
Disease frequency and screening performance	Study LDA adherence*		Hypothetical ASA adherence
	86.0%	95.4%	50%	60%	70%	80%	90%	100%
Expected PE reduction %**	53.3%	59.1%	31.0%	37.2%	43.4%	49.6%	55.8%	62.0%
Expected total number of cases***	27	30	19	21	22	25	28	32
Expected detected cases****	24	27	16	18	19	22	25	29
Adjusted detection rate	88.9%	90.0%	84.2%	85.7%	86.4%	88.0%	89.3%	90.6%
Adjusted false positive rate	13.0% (146 − 24)/936	12.7% (146 − 27)/936	13.9%	13.7%	13.6%	13.2%	12.9%	12.5%
Calculated based on 146 high-ris pregnancies and 14 preterm preeclampsia cases observed in the study
Based on the lowest and highest self-reported adherence rates in high-risk patients participating in follow-up at 16, 22, 26, 32 and 36 weeks' gestation. Assuming LDA use has prevented 62% of the preterm preeclampsia cases. Sum of cases from low-risk group, high-risk group and potential cases from the high-risk group that have been prevented by ASA.** Sum of cases from the high-risk group and potential cases from the high-risk group that have been prevented by ASA (calculated based on 3 low cases and 11 high-risk cases).

The risks of developing PE before 32 and 34 weeks were also reported for the study population. Among the 152 pregnancies identified as high-risk results for preterm PE, 27 (17.8%) were also high-risk for PE before 34 weeks and 24 (15.8%) before 32 weeks. A sub-analysis of patients’ risk factors, placental markers, MAP and UtAPI, patients’ compliance and pregnancy outcomes are presented in Suppl Table 1.

This study demonstrates the feasibility of implementing first-trimester aneuploidy screening and preterm PE screening in a real-world clinical setting, with PE risk calculation conducted at a separate site from the clinical setting. High enrollment rates and strong patient participation underscore the practicality and effectiveness of integrating comprehensive screening protocols into diverse healthcare settings with an ultrasound facility-based program. Although not powered to fully evaluate maternal and fetal outcomes, the study indicates improved preterm PE detection rates and enhanced adherence to LDA among high-risk patients compared to conventional screening.

The results of this study align with two previous studies on the implementation of preterm PE screening programs in Canada (Suppl Table 2). The studies reported similar metrics in the enrollment rate, particularly when we also considered eligible patients who had aneuploidy risk evaluated by NIPT before performing the NT scan. Similar to the routine multiple marker aneuploidy screening, our study had a spatial separation between the laboratory and clinical settings. However, we found minimal operational impact comparable to the two Canadian studies where recruitment, clinical assessment, and laboratory work were conducted at a single site (32, 33). Although our study did not specifically evaluate patient satisfaction as the other two studies have reported, the completion rate for follow-up was notably high and comparable to the other Canadian studies reviewed.

Our screen-positive rate was higher (15%) than the 8.2% and 10.4% reported in the two Canadian studies (32, 33) but consistent with findings from larger studies evaluating the performance of the FMF algorithm (37). This discrepancy could be attributed to several factors, including differences in the screened population, where we included higher-risk patients and variations in patients' race or ethnic group. Our study also demonstrated the highest estimated detection rate of 90% with theoretical 100% LDA adherence compared to the rate reported in the other two studies (76.8% and 86.6%)(32, 33). In this study, we did not account for the effect of LDA on the low-risk group, even though some individuals were prescribed the medication for other indications.

A recent Ontario Health (Quality) health technology assessment concluded that the FMF risk calculation model was more accurate than current clinical factor-based screening, was potentially feasible to incorporate into the current aneuploidy screening program and was potentially cost-effective. The assessment reported that patients value both access to a screening and preventive approach and the increased information available regarding PE and placental dysfunction (38). A significant aspect of our study lies in the practical integration of preterm PE screening into routine clinical practice, closely mirroring real-world conditions in the laboratory and clinical settings. This approach enhances the potential generalizability and scalability of our findings, offering a more accurate representation of potential implementation outcomes in broader clinical settings. This study has some limitations. First, some patients delivered at other institutions, leading to a loss of follow-up data. Additionally, the collection of race-based data was limited to specific categories in the risk calculation software. We are aware of the lack of data on level of risk or differences in biochemical or biophysical markers in a broader range of race categories. More importantly, we are obligated to explore whether these differences are related to intersecting confounding features such as racism or socio-demographic differences (32).

Finally, a limitation that should be considered is potential barriers to the generalizability of the study due to the lack of facilities equipped to measure placental growth factors or uterine arteries dopplers, which restrict the widespread application of the protocol.

Validated modifications to screening algorithms, albeit excluding certain components, offer viable options to enhance accessibility while maintaining a detection rate superior to clinical risk factor-based screening (39). Moving forward, addressing these barriers through enhanced training, expanded infrastructure, and improved healthcare provider engagement could further optimize the adoption and impact of our screening approach across diverse healthcare settings.

This study successfully demonstrated the feasibility of implementing a preterm PE multiple marker screening and prevention program in a clinical setting. The findings highlight the potential for broader adoption of such programs, which could lead to significant reductions in the adverse impacts of preterm PE among pregnant individuals and their babies. Support for systematic PE screening programs is growing, emphasizing the importance of high-quality implementation and the potential benefits for patients, healthcare providers, and the healthcare system overall. Future research should prioritize scaling up preterm PE screening programs by directly involving primary care providers and centralizing data collection and calculations and quality assurance assessments akin to successful models used in aneuploidy screening. Such efforts are crucial for optimizing patient care, improving outcomes, and fostering broader adoption of effective screening strategies in prenatal healthcare.

PE preeclampsia

LDA low dose acetylsalicylic acid

NT nuchal translucency

UtAPI uterine arteries pulsatility Index

MAP Mean arterial blood pressure

PAPP-A pregnancy-associated plasma protein-A

PLGF placental growth factor

FMF Fetal Medicine Fundation

FTS First trimester screening

NIPT noninvasive prenatal testing

Ethics approval and consent to participate: The study was approved by the institutional review boards at both institutions (Sunnybrook #20-3657 and North York #20-0001) and requested to be registered Clinical.trial.gov: NCT04412681 (2020-06-02).

Consent for publication: Not applicable

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interest: The authors declare that they have no competing interests

Funding: The study was supported by DAN Women&Babies Program, Department of Obstetrics and Gynecology, Sunnybrook Health Sciences Centre, Toronto, ON.

Authors’ Contributions:

SR, NO, TH, EMD, JB conceived the study. SR, NO and TH designed its methods. SR, AS, SRa, and TH conducted the data collection and data analysis. All the authors contributed to data interpretation. SR and TH drafted the manuscript. All the authors revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Acknowledgements:

The authors thank Rachel Woo for her contributions to statistical data analysis. They also thank the research assistants, the ultrasound technician at Sunnybrook Hospital and the laboratory staff at the Maternal Multiple Marker Screening Laboratory of North York General Hospital.

Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980–2010: age-period-cohort analysis. BMJ. 2013;347:f6564.
Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122–31.
Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol. 2011;25(4):391–403.
Public Health Agency of Canada. Perinatal Health Indicators for Canada 2013: a Report of the Canadian Perinatal Surveillance System. Ottawa, 2013.
Creanga AA, Berg CJ, Syverson C, Seed K, Bruce FC, Callaghan WM. Pregnancy-related mortality in the United States, 2006–2010. Obstet Gynecol. 2015;125(1):5–12.
Witlin AG, Saade GR, Mattar F, Sibai BM. Predictors of neonatal outcome in women with severe preeclampsia or eclampsia between 24 and 33 weeks' gestation. Am J Obstet Gynecol. 2000;182(3):607–11.
Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women–2011 update: a guideline from the american heart association. Circulation. 2011;123(11):1243–62.
Auger N, Fraser WD, Schnitzer M, Leduc L, Healy-Profitos J, Paradis G. Recurrent pre-eclampsia and subsequent cardiovascular risk. Heart. 2017;103(3):235–43.
Behrens I, Basit S, Melbye M, Lykke JA, Wohlfahrt J, Bundgaard H, et al. Risk of post-pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort study. BMJ. 2017;358:j3078.
Committee Opinion No. First-Trimester Risk Assessment for Early-Onset Preeclampsia. Obstet Gynecol. 2015;638(3):e25–7.
Visintin C, Mugglestone MA, Almerie MQ, Nherera LM, James D, Walkinshaw S, et al. Management of hypertensive disorders during pregnancy: summary of NICE guidance. BMJ. 2010;341:c2207.
Force USPST, Davidson KW, Barry MJ, Mangione CM, Cabana M, Caughey AB, et al. Aspirin Use to Prevent Preeclampsia and Related Morbidity and Mortality: US Preventive Services Task Force Recommendation Statement. JAMA. 2021;326(12):1186–91.
O'Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, de Alvarado M, et al. Multicenter screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks' gestation: comparison with NICE guidelines and ACOG recommendations. Ultrasound Obstet Gynecol. 2017;49(6):756–60.
Gallo DM, Wright D, Casanova C, Campanero M, Nicolaides KH. Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 19–24 weeks' gestation. Am J Obstet Gynecol. 2016;214(5):619. e1- e17.
Park FJ, Leung CH, Poon LC, Williams PF, Rothwell SJ, Hyett JA. Clinical evaluation of a first trimester algorithm predicting the risk of hypertensive disease of pregnancy. Aust N Z J Obstet Gynaecol. 2013;53(6):532–9.
O'Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, Wright A, et al. Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks' gestation. Ultrasound Obstet Gynecol. 2017;49(6):751–5.
Mosimann B, Pfiffner C, Amylidi-Mohr S, Risch L, Surbek D, Raio L. First trimester combined screening for preeclampsia and small for gestational age - a single centre experience and validation of the FMF screening algorithm. Swiss Med Wkly. 2017;147:w14498.
Boutin A, Gasse C, Guerby P, Giguere Y, Tetu A, Bujold E. First-Trimester Preterm Preeclampsia Screening in Nulliparous Women: The Great Obstetrical Syndrome (GOS) Study. J Obstet Gynaecol Can. 2021;43(1):43–9.
Roberge S, Sibai B, McCaw-Binns A, Bujold E. Low-Dose Aspirin in Early Gestation for Prevention of Preeclampsia and Small-for-Gestational-Age Neonates: Meta-analysis of Large Randomized Trials. Am J Perinatol. 2016;33(8):781–5.
Roberge S, Giguere Y, Villa P, Nicolaides K, Vainio M, Forest JC, et al. Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Am J Perinatol. 2012;29(7):551–6.
Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018;218(3):287–93. e1.
Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010;116(2 Pt 1):402–14.
Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017;377(7):613–22.
Magee LA, Smith GN, Bloch C, Cote AM, Jain V, Nerenberg K, et al. Guideline 426: Hypertensive Disorders of Pregnancy: Diagnosis, Prediction, Prevention, and Management. J Obstet Gynaecol Can. 2022;44(5):547–71. e1.
Gillon TE, Pels A, von Dadelszen P, MacDonell K, Magee LA. Hypertensive disorders of pregnancy: a systematic review of international clinical practice guidelines. PLoS ONE. 2014;9(12):e113715.
Viguiliouk E, Park AL, Berger H, Geary MP, Ray JG. Low Rates of Aspirin Use for the Prevention of Preeclampsia. J Obstet Gynaecol Can. 2017;39(9):722–3.
Ray JG, Abdulaziz KE, Berger H, Doh NET. Aspirin Use for Preeclampsia Prevention Among Women With Prepregnancy Diabetes, Obesity, and Hypertension. JAMA. 2022;327(4):388–90.
Jain V, Bujold E. Screening for preeclampsia risk and prophylaxis with acetylsalicylic acid. CMAJ. 2023;195(45):E1557–8.
Ortved D, Hawkins TL, Johnson JA, Hyett J, Metcalfe A. Cost-effectiveness of first-trimester screening with early preventative use of aspirin in women at high risk of early-onset pre-eclampsia. Ultrasound Obstet Gynecol. 2019;53(2):239–44.
Werner EF, Hauspurg AK, Rouse DJ. A Cost-Benefit Analysis of Low-Dose Aspirin Prophylaxis for the Prevention of Preeclampsia in the United States. Obstet Gynecol. 2015;126(6):1242–50.
Guy GP, Leslie K, Diaz Gomez D, Forenc K, Buck E, Khalil A, et al. Implementation of routine first trimester combined screening for pre-eclampsia: a clinical effectiveness study. BJOG. 2021;128(2):149–56.
Johnson JM, Walsh JD, Okun NB, Metcalfe A, Pastuck ML, Maxey CM, et al. The Implementation of Preeclampsia Screening and Prevention (IMPRESS) Study. Am J Obstet Gynecol MFM. 2023;5(2):100815.
Okun N, Hoffman B, Johnson J, Biringer A, Shapiro J, Felix C, et al. Implementation of Multiple Marker Screening for Preterm Preeclampsia in a Single Tertiary Obstetric Centre. J Obstet Gynaecol Can. 2024;46(1):102220.
Foundation TFM. FMF certification Preeclampsia screening. https://fetalmedicine.org/fmf-certification-2/preeclampsia-screening-1
Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S, et al. The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens. 2018;13:291–310.
Wright D, Nicolaides K, Re. Implementation of routine first trimester combined screening for pre-eclampsia: a clinical effectiveness study. BJOG. 2021;128(1):141–2.
Tan MY, Syngelaki A, Poon LC, Rolnik DL, O'Gorman N, Delgado JL, et al. Screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks' gestation. Ultrasound Obstet Gynecol. 2018;52(2):186–95.
First- HQO. Trimester Screening Program for the risk of Pre-eclampsia Unsing a Multipe-Marker Algorithm: Recommendation 2022 [ https://www.hqontario.ca/Evidence-to-Improve-Care/Health-Technology-Assessment/Reviews-And-Recommendations/First-Trimester-Screening-Program-for-the-Risk-of-Pre-eclampsia-Using-a-Multiple-Marker-Algorithm
Chaemsaithong P, Sahota DS, Poon LC. First trimester preeclampsia screening and prediction. Am J Obstet Gynecol. 2022;226(2S):S1071–Se972.

No competing interests reported.

Download PDF

Editorial decision: Revision requested
12 Aug, 2024
Editor assigned by journal
09 Aug, 2024
Submission checks completed at journal
09 Aug, 2024
First submitted to journal
07 Aug, 2024

You are reading this latest preprint version

Preterm Preeclampsia Screening and Prevention: A Comprehensive Approach Integrating Precision Medicine in A Real-world Setting

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Trial registration:

Figures

Background

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1