
==== Front
Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

39300215
72304
10.1038/s41598-024-72304-3
Article
Serum macrophage stimulating protein α-chain and uterine artery Doppler ultrasound in the first trimester for the prediction of preeclampsia
Kongprayoon Pimon
Phupong Vorapong vorapong.p@chula.ac.th

https://ror.org/028wp3y58 grid.7922.e 0000 0001 0244 7875 Placental Related Diseases Research Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Rama IV Road, Pathumwan, Bangkok, 10330 Thailand
19 9 2024
19 9 2024
2024
14 2190528 5 2024
5 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
To assess how effective macrophage stimulating protein α-chain (MSP-α) combined with uterine artery Doppler is in predicting preeclampsia in singleton pregnancies during 11–13+6 weeks of gestation. This prospective observational study included singleton pregnant women who attended antenatal care at King Chulalongkorn Memorial Hospital, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University between December 2021 and April 2023, during 11–13+6 weeks of gestation. Serum MSP-α levels were collected and uterine artery Doppler ultrasound was performed. Pregnancy outcomes were recorded, and the predictive values of these tests were determined to predict preeclampsia. A total of 365 patients, with 21 cases of preeclampsia (5.8%), were analyzed. Serum MSP-α levels were higher in pregnant women who developed preeclampsia than those who did not (899.7 ± 550.1 ng/ml vs 642.5 ± 466.1 ng/ml, p = 0.016). The mean pulsatility index of the uterine artery and the presence of diastolic notching were not significantly different between the groups. As a cut-off value for predicting preeclampsia, using serum MSP-α levels higher than 1.0 multiple of median for gestational age, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 71.4%, 50.3%, 8.1%, and 96.7%, respectively. Additionally, when abnormal serum MSP-α levels were combined with a uterine artery Doppler pulsatility index above the 95th percentile and bilateral notching as predictive values for preeclampsia, the sensitivity was 85.7%, specificity was 18.3%, PPV was 6.0%, and NPV was 95.5%. Serum MSP-α alone at 11–13+6 weeks of gestation was effective in predicting preeclampsia. However, the use of serum MSP-α in combination with uterine artery Doppler increased sensitivity but reduced specificity for the prediction of preeclampsia.

Keywords

Preeclampsia
Uterine artery Doppler
Serum MSP-α levels
Predictive value
Subject terms

Biomarkers
Diseases
Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University, study grant number GA65/15 and Grant for International Research Integration: Research Pyramid, Ratchadaphiseksomphot Endowment Fund, Chulalongkorn University, and Placental Related Disease Research Unit, Chulalongkorn University.GA65/15 GA65/15 Kongprayoon Pimon Phupong Vorapong issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Hypertensive disorders of pregnancy cause 14% of all maternal deaths worldwide, which is approximately 42,000 deaths per year1. Preeclampsia is a common complication in pregnancy, and its global incidence is estimated at 2–8% of births2. In Thailand, the mortality rate of pregnant women with hypertensive disorders was 20.2 per 100,000 live births3. The incidence of preeclampsia in pregnant women at King Chulalongkorn Memorial Hospital (KCMH) during the last 5 years (2016–2020) was 5.1%4.

Preeclampsia is a condition that affects multiple organ systems, reportedly causing short-term and long-term morbidity in pregnant women, including eclampsia, cerebral hemorrhage, abnormal liver and kidney function, cardiovascular disease, and metabolic disease5,6. Furthermore, preeclampsia also increases the risk of unfavorable fetal and neonatal outcomes, such as fetal growth restriction, preterm delivery, and still birth, resulting in increased cost of budget and maintenance resources7. The pathogenesis of preeclampsia remains unclear. That said, it is believed to be caused by abnormal trophoblastic invasion, immunological factors, endothelial cell activation, and genetic factors5. The pathogenesis of preeclampsia is a two-stage disorder, with the first stage (placental stage) occurring in the first trimester of pregnancy, where no symptoms are exhibited. Incomplete remodeling of the uterine spiral artery by cytotrophoblasts leads to shallow embedding the placenta. This abnormality disrupts blood circulation between the placenta and uterus, resulting in placental ischemia. As a consequence, inflammatory substances such as cytokines, free radicals, and growth factors are released. There are also additional factors associated with the underlying diseases of pregnant women, such as diabetes, obesity, cardiovascular disease, and immune disorders. This causes the activation of endothelial cells and leads to the second stage (clinical stage), which comprises the signs and symptoms of preeclampsia such as high blood pressure and proteinuria8–10.

The ability to screen women at high risk of preeclampsia, especially in the first trimester, allows for more effective prevention and decreases morbidity and mortality in pregnant women and their babies. For example, the use of aspirin to reduce the risk of developing preeclampsia9–12. The American College of Obstetricians and Gynecologists (ACOG) and the National Institute for Care and Health Excellence (NICE) recommend that maternal history can be used to screen for a high risk of developing preeclampsia7,13. However, it has a detection rate of 44.8%12–15. Doppler ultrasound of the uterine artery can also be used to assess the risk of preeclampsia. An increase in the pulsatility index of the uterine artery above the 90th percentile, along with the presence of notching, can predict 48% of preeclampsia occurring before 34 weeks of gestation. However, using ultrasound alone to predict preeclampsia has a low predictive value10. Recent studies have shown that the combination of clinical risk factors, maternal arterial pressure, ultrasound Doppler, and biochemical markers produces higher predictive values than maternal history alone12–17. Nonetheless, the use of biological markers still requires further study to find biomarkers that provide high predictive value for practical use7,14.

Macrophage-stimulating protein (MSP), also known as hepatocyte growth factor receptor-like protein or macrophage stimulating 1 is a protein in the plasminogen-related kringle protein family consisting of α chain and β chain linked by disulfide bonds18,19. MSP is found in the cells of the liver, adrenal glands, lungs, kidneys, placenta, and pancreas. Proteolysis of primary MSP from the cell membrane in an inactive form enters the bloodstream. When it reaches a specific cell region, it is transformed by trypsin-like serine proteases into active forms, α chain and β chain. MSP-α binds to the RON receptor tyrosine kinase to regulate the activity of target cells. The MSP gene is located at position 21 on the short arm of the third pair of chromosomes (3p21)19–21. MSP plays a role in the response to hypoxia and also aids in embryo implantation. Its target cells include macrophages, osteoclasts, epithelial cells, vascular endothelial cells, and hematopoietic and liver progenitor cells. Vascular endothelial cells are responsible for angiogenesis. It is hypothesized that maternal hypoxia, in conjunction with oxidative stress, immune dysregulation, and vascular endothelial injury, would result in placental dysfunction, placental ischemia, and subsequent placental hypoxia, leading to increase production of MSP-α by placental trophoblasts to stimulate the activity of trophoblast cells and form the uterine spiral artery19. Several studies have found that MSP-α levels are significantly elevated in pregnant women with preeclampsia19,22. It is believed to be caused by the aforementioned activation of placental trophoblast cells, but such studies are limited in number. Therefore, more studies are still needed to gain a better understanding of the relevance between serum MSP-α levels and preeclampsia.

In this study, the aim was to evaluate the role of combining the first trimester serum MSP-α levels and Doppler ultrasound of the uterine artery in predicting preeclampsia in singleton pregnancy. Perhaps there has never been a study on this combination method for screening preeclampsia. As a result, this study may improve the accuracy of preeclampsia prediction.

Materials and methods

This prospective observational study was conducted at King Chulalongkorn Memorial Hospital, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, between December 2021 and April 2023. The study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University. This study has been performed as per the Declaration of Helsinki. All women received research information and study protocol and provided written informed consent before any procedures. The inclusion criteria were singleton pregnant women aged 18–45 years and 11–13+6 weeks of gestation. Pregnant women with abortion or having an abnormal structural or chromosomal fetus, those taking aspirin and/or immunosuppressant before enrolling in the study, those with liver disease, renal disease, pulmonary disease, pancreatic disease, osteoarthritis, and gestational hypertension, and those whose data on delivery outcomes could not be obtained were excluded.

The sample size was calculated based on the expected sensitivity of the test at 80%, with a 20% margin of error and α error at 0.05. The prevalence was based on the incidence of preeclampsia in KCMH in the past five years at 5.1%. To test this hypothesis, 16 women with preeclampsia were required.

Preeclampsia is defined as new-onset hypertension (systolic blood pressure (SBP) 140 mmHg or more or diastolic blood pressure (DBP) 90 mmHg or more) on two occasions at least four hours apart after 20 weeks of gestation, combined with proteinuria of at least 300 mg/24 h or urine protein creatinine ratio of ≥ 0.3 or at least 2 + on a urine dipstick test. In the absence of proteinuria, new-onset hypertension together with at least one of the following: thrombocytopenia (platelet count < 100 × 109 /L), renal insufficiency (serum creatinine > 1.1 mg/dL or double in the absence of renal disease), abnormal liver function ( liver transaminases doubled from the normal value), pulmonary edema, headache (unresponsive to medication and not diagnosed by other conditions), visual disturbances, and severe persistent right upper quadrant pain was also diagnosed as preeclampsia7. Early-onset preeclampsia was defined as preeclampsia in women with less than 34 weeks of gestational age, and late-onset preeclampsia was defined as preeclampsia in women at or after 34 weeks of gestation23.

The primary outcome was to determine the predictive value of serum MSP-α combined with uterine artery Doppler in singleton pregnancy during 11–13+6 weeks of gestation for preeclampsia prediction. The secondary outcome was to determine the predictive value of other pregnancy complications.

Data were collected on the maternal baseline characteristics, the pulsatility index of the uterine artery, the presence or absence of uterine artery notching, and maternal and neonatal outcomes. Blood pressure was measured using an automatic blood pressure device (Microlife AG, 9443 Widnau, Switzerland) validated for accuracy. The women were seated on a chair with their backs resting without crossing their legs, for 5 min, with their arms at heart level and using an appropriate-sized cuff (small < 22 cm, normal 22–32 cm, large 33–42 cm) based on the circumference of the middle arm. Blood pressure was measured twice in both arms simultaneously, one minute apart. The measured values of SBP and DBP were used to calculate the mean arterial pressure (MAP)14.

The investigator who was certified to perform uterine artery scans by the Fetal Medicine Foundation, used ultrasonographic machines (GE Voluson E10, GE Medical Systems, Zipf, Austria) with the convex probe AB 2–7 MHz. After visualizing the midsagittal plane of the uterus and cervix, the probe was laterally tilted to identify the uterine artery along both sides with a pulse-wave Doppler and measured at the level of the internal os of the cervix using a 2-mm gate with an angle of less than 30°. Three consecutive waveforms were obtained with a peak systolic velocity of more than 60 cm/s24–26. Three measurements were performed on both sides, and then, the mean of the uterine artery pulsatility index was calculated. The presence or absence of uterine artery notching on each side was noted10.

After Doppler examination, ten mL of blood for serum MSP-α was drawn and collected in a non-heparinized tube at the same period (08.00–09.00 am), then centrifuged at 2500 rpm for 10 min to separate the serum and stored at − 80 °C until analyzed. All samples were analyzed simultaneously after all participants were enrolled by enzyme-linked immunosorbent assay (ELISA) using the MSP-α ELISA kit (Cloud-Clone, USA). This assay has a sensitivity for serum MSP-α of 0.039 ng/ml, intra-assay variability of < 8% and inter-assay variability of < 10%.

Data were analyzed using IBM SPSS Statistics version 23 and presented as mean ± standard deviation (SD), median (interquartile range, IQR), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with a 95% confidence interval. The cut-off value of the serum MSP-α level was calculated using a receiver operating characteristic (ROC) curve. A chi-square test was used to compare categorical data, and an independent t test, and Mann–Whitney U test were used to compare continuous data. A p value of < 0.05 was considered statistically significant.

Results

A total of 389 pregnant women were enrolled in the study. Twenty-four pregnant women were excluded from the study due to fetal structural anomalies or chromosomal abnormalities (2 cases), spontaneous miscarriage before 20 weeks (3 cases), gestational hypertension (9 cases), and 10 were unable to follow-up on the outcomes. As a result, data from 365 women were analyzed. Twenty-one were diagnosed with preeclampsia (5.8%) and four of them had early-onset preeclampsia (1.1%).

The baseline characteristics of women with preeclampsia and without preeclampsia were compared. There were no differences in maternal age, parity, and gestational age at enrollment. However, the proportion of advanced maternal age, pre-pregnancy body mass index (BMI), obesity, overt diabetic mellitus, chronic hypertension, MAP and aspirin use in the preeclampsia group was significantly higher than in the control group (Table 1).Table 1 Baseline characteristics and pregnancy outcomes of women with and without preeclampsia.

	Control (n = 344)	Preeclampsia (n = 21)	p value	
Maternal age (years)	32.2 ± 4.6	34.2 ± 5.0	0.052	
Advanced maternal age (≥ 35 years old)	115 (33.4)	12 (57.1)	0.027	
Nulliparous	199 (57.8)	14 (66.7)	0.426	
Prepregnancy BMI (kg/m2)	22.8 ± 4.3	27.6 ± 6.7	< 0.001	
Obesity (BMI ≥ 30 kg/m2)	26 (7.6)	8 (38.1)	< 0.001	
Chronic hypertension	1 (0.3)	8 (38.1)	< 0.001	
Overt diabetes mellitus	6 (1.7)	3 (14.3)	0.011	
GA at measurement (weeks)	12.3 ± 0.7	12.1 ± 0.7	0.064	
Mean arterial pressure (mmHg)	82.6 ± 8.9	94.4 ± 8.9	< 0.001	
Aspirin use	35 (10.2)	14 (66.7)	< 0.001	
Gestational diabetes mellitus	34 (9.9)	3 (14.3)	0.459	
Total weight gain (kg)	13.8 ± 5.6	13.6 ± 7.3	0.845	
GA at delivery (weeks)	38.1 ± 1.2	36.1 ± 2.7	0.002	
Delivery at GA < 34 weeks	3 (0.9)	3 (14.3)	0.003	
Delivery at GA < 37 weeks	32 (9.3)	8 (38.1)	< 0.001	
Mode of delivery			0.11	
 Vaginal delivery	134 (39)	4 (19)		
 Cesarean section	210 (61)	17 (81)		
Birth weight (grams)	3054.3 ± 397.2	2563.4 ± 867	< 0.001	
Low birth weight (< 2500 g)	12 (3.5)	4 (19)	0.009	
Fetal growth restriction	2 (0.6)	4 (19)	< 0.001	
Apgar score at 1 min < 7	2 (0.6)	6 (28.6)	< 0.001	
Apgar score at 5 min < 7	0	2 (9.5)	0.003	
Respiratory distress syndrome	8 (2.3)	7 (33.3)	< 0.001	
IVH	1 (0.3)	0	1.000	
NEC	0	1 (4.8)	0.058	
Sepsis	2 (0.6)	1 (4.8)	0.163	
Neonatal death	0	0	NA	
Length of maternal hospital stay	3.6 ± 1.4	5.0 ± 4.8	0.18	
Neonatal day stay	3.7 ± 2.2	12.2 ± 16.5	0.027	
Data are presented in mean ± SD or n (%).

BMI body mass index; GA gestational age.

Regarding pregnancy and neonatal outcomes, there were significantly higher rates of delivery at gestational age < 37 weeks, delivery at gestational age < 34 weeks, fetal growth restriction, birthweight less than 2500 g, respiratory distress syndrome (RDS), and Apgar scores at 1 and 5 min < 7 in the preeclampsia group. Furthermore, birth weight was significantly lower in the preeclampsia group than in the control group. However, there were no statistically significant differences in GDM, maternal weight gain, mode of delivery, and length of maternal hospital stay between the two groups (Table 1). Additionally, there were no neonatal deaths in either group.

The mean ± SD of the serum MSP-α level in the preeclampsia group was higher than in the control group (899.7 ± 550.1 ng/ml vs 642.5 ± 466.1 ng/ml, p = 0.016). There was no difference in the mean pulsatility index of the uterine artery (1.7 ± 0.7 vs 1.7 ± 0.5, p = 0.724) and the presence of a bilateral diastolic notch (47.6% vs 49.1%, p = 0.893) (Table 2). There was no relationship between the Doppler indices and MSP-α levels.Table 2 Serum MSP-α levels and uterine artery Doppler ultrasound in women with and without preeclampsia.

	Control (n = 344)	Preeclampsia (n = 21)	p value	
MSP-α (ng/ml)	642.5 ± 466.1	899.7 ± 550.1	0.016	
UtA PI	1.7 ± 0.5	1.7 ± 0.7	0.724	
UtA PI > 95th percentile	16 (4.7)	2 (9.5)	0.278	
Any notching	218 (63.4)	12 (57.1)	0.566	
Bilateral notching	169 (49.1)	10 (47.6)	0.893	
Data are presented mean ± SD or n (%).

MSP-α macrophage stimulating protein α-chain; UtA PI uterine artery pulsatility index.

The prediction of preeclampsia using serum MSP-α levels was calculated using the ROC curve with an area under the curve (AUC) of 0.651 (Fig. 1). The cut-off value of the serum MSP-α level was 1.0 multiple of median (MoM). When using a serum MSP-α level higher than 1.0 MoM to predict preeclampsia, the sensitivity, specificity, PPV, and NPV were 71.4%, 50.3%, 8.1%, and 96.7%, respectively.Fig. 1 Receiver operating characteristic curve for the relationship between the serum MSP-α levels and the diagnosis of preeclampsia.

Using the mean uterine artery Doppler pulsatility index above the 95th percentile to predict preeclampsia, the sensitivity, specificity, PPV, and NPV were 9.5%, 95.4%, 11.1%, and 94.5%, respectively. Furthermore, using diastolic notching of the uterine artery to predict preeclampsia, the sensitivity, specificity, PPV, and NPV were 47.6%, 50.9%, 5.6% and 94.1%, respectively, for bilateral notching. As for the mean uterine artery Doppler pulsatility index above the 95th percentile combined with bilateral uterine artery notching to predict preeclampsia, the sensitivity, specificity, PPV, and NPV were 57.1%, 36.6%, 5.2%, and 93.3%, respectively (Table 3).Table 3 Predictive value of serum MSP-α levels and uterine artery Doppler for preeclampsia.

	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Positive LR	Negative LR	
MSP-α level > 1.0 MoM	71.4 (47.8–88.7)	50.3 (44.9–55.7)	8.1 (6.2–10.5)	96.7 (93.6–98.3)	1.4 (1.1–1.9)	0.6 (0.3–1.1)	
UtA PI > 95th percentile	9.5 (1.2–30.4)	95.4 (92.6–97.3)	11.1 (3.0–33.7)	94.5 (93.8–95.2)	2.1 (0.5–8.3)	1.0 (0.8–1.1)	
Bilateral notching	47.6 (25.7–70.2)	50.9 (45.5–56.3)	5.6 (3.6–8.6)	94.1 (91.3–96.0)	1.0 (0.6–1.5)	1.0 (0.7–1.6)	
UtA PI > 95th percentile and/or bilateral notching	57.1 (34.0–78.2)	36.6 (31.5–42.0)	5.2 (3.6–7.4)	93.3 (89.3–95.9)	0.9 (0.6–1.3)	1.2 (0.7–2.0)	
MSP-α levels > 1.0 MoM and/or UtA PI > 95th percentile and/or notching	85.7 (63.7–97.0)	18.3 (14.4–22.8)	6.0 (5.1–7.1)	95.5 (87.8–98.4)	1.1 (0.9–1.3)	0.8 (0.3–2.3)	
MSP-α macrophage stimulating protein-α; UtA PI uterine artery pulsatility index; PPV positive predictive value; NPV negative predictive value; LR likelihood ratio.

The combination of abnormal serum MSP-α levels (higher than 1.0 MoM) and/or abnormal Doppler of the uterine artery (pulsatility index above the 95th percentile or bilateral notching of the uterine artery) used to predict preeclampsia found that the sensitivity, specificity, PPV, and NPV were 85.7%, 18.3%, 6.0%, and 95.5%, respectively (Table 3).

Other maternal and neonatal complications were observed. Pregnant women with abnormal serum MSP-α levels or uterine artery Doppler pulsatility index or the presence of bilateral notch had a significantly higher rate of preterm delivery (relative risk 1.20; 95%CI 1.03–1.40), but there was no significant association with fetal growth restriction and gestational diabetes (Table 4).Table 4 Serum MSP-α levels and uterine artery Doppler for other pregnancy complications.

	Relative risk	95% confidence interval	
Gestational diabetes	1.03	0.93–1.14	
Preterm delivery	1.20	1.03–1.40	
Fetal growth restriction	2.86	0.92–8.86	
MSP-α macrophage stimulating protein-α.

Discussion

This study demonstrated that serum MSP-α level alone was effective in predicting preeclampsia. The use of serum MSP-α in combination with uterine artery Doppler increased the sensitivity but reduced the specificity to predict preeclampsia.

The mean serum MSP-α level in the preeclampsia group was higher than in the control group. The result of this study was similar to that of Zhang et al. They measured the plasma MSP-α level in pregnant women before 20 weeks and found that the plasma level of MSP-α was higher in the preeclampsia group than in the control group19. However, the serum MSP-α level in this study had higher levels than in the study by Zhang et al. This difference may be due to the difference in gestational age at blood collection and in the study population. In the group of the cases with preeclampsia, the number of the cases with chronic hypertension and diabetes mellitus were higher. The high level of MSP-α might also be related with those medical conditions.

While this study observed no significant differences in the mean pulsatility index of the uterine artery between pregnant women with and without preeclampsia, consistent with prior research27. Pulsatility index of the uterine artery above the 95th percentile exhibited high specificity but low sensitivity (95.4% and 9.5%, respectively) in predicting preeclampsia. This finding aligns with conclusions drawn from meta-analysis studies28,29. The presence of the uterine artery notch on at least one side and both sides showed a 31.7% and 51.3% specificity, respectively, to predict preeclampsia. Compared to the previous study28. this study showed a lower specificity. In this study the sensitivity of the Doppler indices and the presence of diastolic notching in predicting preeclampsia is low. This might be related to the low number of the cases with early preeclampsia. In a group of patients with more cases of early PE, the predictive values for both Doppler findings and MSP-α levels might be higher.

A combination of abnormal serum MSP-α and Doppler ultrasound of the uterine artery (pulsatility index above the 95th percentile and bilateral diastolic notching) to predict preeclampsia increased the sensitivity to 85.7%. This finding was consistent with previous studies that demonstrated combined serum markers and Doppler of the uterine artery had a high sensitivity to predict preeclampsia26,30. The first-trimester combination tests allowed screening with higher sensitivity compared to using a single test alone. However, some studies demonstrated that combined serum markers and Doppler of the uterine artery could only predict early-onset preeclampsia27,31.

This is the first prospective study to use serum MSP-α levels in combination with uterine artery Doppler ultrasound in singleton pregnant women between 11 and 13+6 weeks of gestation to predict preeclampsia. A one-time test was performed; blood for serum MSP-α was drawn and uterine artery Doppler ultrasound was performed along with the first trimester Down syndrome screening ultrasound or combined first trimester screening test, making it convenient for pregnant women. Due to early screening results, high-risk patients were given aspirin to prevent pre-eclampsia. This prevention may be more effective if started before 16 weeks of gestation7,9,11,12.

A pragmatic guide for first-trimester screening and prevention from the International Federation of Gynecology and Obstetrics initiative on pre-eclampsia noted that effective preeclampsia screening is a combination of maternal risk factors, MAP, Doppler ultrasound of the uterine artery and serum biomarkers such as PlGF, VEGF, sFlt-1, PP13, PAPP-A, and ADAM 1214. These biochemical pathophysiological pathways are associated with abnormal placental implantation (placental or trophoblast ischemia and hypoxia), an imbalance in angiogenesis, and vascular endothelial injury leading to placental dysfunction32. It is believed that when placental dysfunction occurs, the placental trophoblast produces MSP-α to stimulate trophoblast cells and the formation of spiral uterine arteries. As discussed above, these biomarkers and MSP-α share a common pathophysiology. Therefore, using serum MSP-α in combination with other aforementioned factors may improve the efficiency and predictive value of preeclampsia screening.

The strength of this study is that it is the first prospective study to use first-trimester serum MSP-α levels combined with Doppler ultrasound of the uterine artery to predict preeclampsia. The results of this early combined screening can allow patients at high risk to start aspirin prophylaxis to prevent preeclampsia. The limitation was that this study had only 4 cases of early-onset preeclampsia. Therefore, further studies with a larger sample size of early-onset preeclampsia, or other models using serum MSP-α levels in conjunction with maternal risk factors, uterine artery Doppler, or other biomarkers should be conducted to confirm its effectiveness in predicting preeclampsia. All cases were included at the study period to decrease potential biases and blood sample was collected at the same time period to decrease confounding factor.

In conclusion, serum MSP-α alone at 11–13+6 weeks of gestation was effective in predicting preeclampsia. The use of serum MSP-α in combination with uterine artery Doppler increased sensitivity but reduced the specificity for preeclampsia prediction.

Acknowledgements

We would like to thank the staff and nurses of the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Chulalongkorn University who provided advice and assistance in this research. The authors thank Miss Natnicha Houngham and Miss Walailak Thongthab for their technical assistance.

Author contributions

P.K. and V.P. contributed to the conception and design of the study. P.K. assisted by V.P., conducted the study and collected the data. V.P. performed the data analysis and interpretation. P.K. wrote the draft, and V.P. critically revised the draft. All authors reviewed the manuscript.

Funding

This study was supported by an internal research grant: Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University, study grant number GA65/15 and Grant for International Research Integration: Research Pyramid, Ratchadaphiseksomphot Endowment Fund, Chulalongkorn University, and Placental Related Disease Research Unit, Chulalongkorn University.

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to the permission of the Internal Review Board but are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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