REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-10009-1654
Donald School Journal of Ultrasound in Obstetrics and Gynecology
Volume 14 | Issue 3 | Year 2020

Preeclampsia Prediction and Prophylaxis in Routine First-trimester Screening Services

Piengbulan Yapan¹, Piyatida Thongkloung², Amprapha Phaophan³, Chutima Yaiyiam⁴, Panumas Kamkang⁵, Kantamanee Thuphairo⁶, Tuangsit Wataganara⁷

^1–4,7Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital, Bangkok Noi, Bangkok, Thailand
^5,6Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Bangkok Noi, Bangkok, Thailand

Corresponding Author: Tuangsit Wataganara, Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital, Bangkok Noi, Bangkok, Thailand, Phone: +66 011 662 419 7000, e-mail: twataganara@yahoo.com

How to cite this article Yapan P, Thongkloung P, Phaophan A, et al. Preeclampsia Prediction and Prophylaxis in Routine First-trimester Screening Services. Donald School J Ultrasound Obstet Gynecol 2020;14(3):237–244.

Source of support: Research Funding from Faculty of Medicine Siriraj Hospital, Bangkok, Thailand

Conflict of interest: None

ABSTRACT

Prenatal screening confers benefits to the population served by that program. Screening programs that are poorly implemented can also be harmful. This article proposes the practical means to establish a routine clinical service of first-trimester prediction for preterm preeclampsia. A combination of maternal characteristics, mean arterial pressure, uterine artery Doppler, and placental growth factor can identify the majority of preterm (%3C;37 weeks of gestation) preeclampsia with reasonably low false-positive rate. A single visit to an integrated clinic at 11–13 weeks’ gestation also allows for an assessment of the risks for a wider range of pregnancy complications, including common fetal aneuploidies and early-onset fetal growth restriction. Certification and audit of ultrasound operators and laboratories is important to assure the quality of the prenatal screening service. In the context of preeclampsia, the primary aim of such clinic is to identify those that would potentially benefit from prophylactic intervention with aspirin to improve placentation.

Keywords: Placental growth factor, Preeclampsia, Prenatal screening, Uterine artery Doppler studies.

INTRODUCTION

Prenatal screening confers potential benefits and harms on the population served by that program. Screening programs that are poorly implemented can be misleading. Fetal Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), and Patau syndrome (trisomy 13) have been routinely screened for in the practice of general obstetrics. Such screening is generally operated with a point-of-care service model called one-stop clinic for assessment of risk (OSCAR). First-trimester screenings for Down syndrome can be offered to singleton and twin pregnancies from 11 to 13 weeks of gestation. Risk of fetal Down syndrome is calculated from the algorithmic analysis of multiple parameters, including maternal characteristics, ultrasound parameters (nuchal translucency (NT) ± nasal bone), and serum biomarkers (pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (β-hCG)).¹ Proprietary algorithms for calculating a pregnancy-specific risk have been offered by professional organizations and commercial laboratories. Confirmatory invasive prenatal diagnostic testings can be offered in those with high-risk screening result. Those with intermediate-risk result can be offered DNA-based noninvasive prenatal testing (NIPT) or integrated sequential screening to reduce false-positive screening.²

A different set of first-trimester parameters can be used to predict subsequent development of preeclampsia (PE) with a unique multivariate algorithm. Preeclampsia is a multisystem disorder that affects up to 5% of pregnancies. Those who require delivery at gestational age <34 weeks (early-onset PE) or <37 weeks (preterm PE) are more severe and more complicated than those who require delivery at gestational age ≥34 weeks (late-onset PE) or ≥37 weeks (term PE). The most common PE-related death is intracranial hemorrhage.³ Other serious PE-related complications include placental abruption, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, acute pulmonary edema, acute renal failure, and iatrogenic preterm delivery.^4–7 Regional variation in mortalities of mothers and children contributed from PE is seen.⁸ The life expectancy of preterm PE survivors is shortened due to a higher risk of cardiovascular disease later in life.⁹ Prematurity is related with small for gestational age, thrombocytopenia, bronchopulmonary dysplasia, and cerebral palsy. Preeclampsia-related placental insufficiency may alter fetal organogenesis and increase risks of obesity, type 2 diabetes mellitus, coronary artery disease, and hypertension later in adult life. The short- and long-term consequences of preterm PE on the health of mother and child justify the effort for selective prophylactic intervention initiated in the first trimester of pregnancy.¹⁰ Recruitment for clinical research trials can also be guided by individualized risk identification.

Integration of maternal characteristics, biophysical (mean arterial pressure; MAP), Doppler (uterine artery pulsatility index; UtAPI), and biochemical profiles (serum placental growth factor; PlGF) at 11–13 weeks can achieve detection rates of preterm—and overall PE of 77 and 54%, respectively, with a fixed false-positive rate (FPR) of 10%. The efficacy of the multimarker screening model is higher than the prediction of PE using maternal characteristics alone.¹¹ First-trimester prediction of PE employing the multimarker screening model has recently been endorsed by International Federation of Gynecology and Obstetrics (FIGO).¹⁰ This article is aiming to outline components required for proper clinical instalment of PE prediction service, as an extension to the currently available fetal Down syndrome screening.

MATERNAL CHARACTERISTICS

The traditional approach to predict subsequent development of PE is to identify risk factors from maternal characteristics (medical and obstetric history).¹² Certain maternal characteristics are associated with development of PE, and have been utilized to produce risk of preterm PE in the multimarker competing risk model with multivariate logistic regression analysis adjusting for confounders.¹³ Recognition of maternal risk factors alone, although easily adopted in clinical practice, has low detection and high FPR for prediction of PE.¹⁴ Checklist, as provided in Table 1, should be employed for routine prenatal screening of PE.

Mean Arterial Pressure

The MAP is influenced by cardiac output and systemic vascular resistance.¹⁵ Endothelial cells mutually produce and respond to vasoactive substances. These vasoactive mediators, regulated by the autonomic nervous system, influence the diameter of the blood vessels and systemic vascular resistance. At rest, the proportion between systolic and diastolic periods of the cardiac cycle is about one-third and two-third, respectively. Therefore, an average systolic (SBP) and diastolic blood pressures (DBP) can be calculated from the following formula.¹⁶

It is important that blood pressure is measured according to the National Heart Foundation of Australia (NHFA) protocol using automated devices.¹⁷ Women should be sitting with their arms well supported at the level of their heart, as shown in Figure 1. The size of adult cuff used depends on the mid-arm circumference (small <22 cm, normal 22–32 cm, or large 33–42 cm). After 5-minute rest, blood pressure is measured simultaneously in both arms. Two sets of recordings are made within 1 minute. The four sets of SBP and DBP measurements are input into the risk calculator to generate patient-specific risk of PE.¹⁸

Uterine Artery Doppler Pulsatility Index

Pulse-wave Doppler studies of the uterine arteries can noninvasively determine resistance of the uteroplacental circulation. In normal pregnancies, there is a significant decrease of resistance in the uterine arteries with advancing gestation. Persistent high impedance flow in the uterine arteries is an evidence of poor placentation.¹⁹ Histological examination of placental bed of pregnancies affected by PE has shown that absence of physiological changes of the uterine-spiral arteries corroborates with high UtAPI.²⁰ Accurate measurement of UtAPI relies on appropriate training, certification, and audit of sonographers. Adherence to a standard ultrasound technique is important to achieve uniform results among different operators.

Transabdominal or transvaginal ultrasound examination at 11–13 weeks’ gestation (fetal crown–rump length (CRL) of 42–84 mm) should be performed with high-resolution equipment. The ultrasound scan should include a full structural survey to detect major fetal defects. The NT and UtAPI are measured according to established guidelines.²¹ Pulse-wave Doppler assessments are performed in accordance with the as low as reasonable achievable (ALARA) principle. Thermal and mechanical indices displayed on the monitor should be kept below 1.0 and 0.5, respectively.²² Video clips and images of the studies should be digitized for possible future reanalysis.

Measurement of UtAPI starts from identification of internal cervical os and cervical canal in a mid-sagittal section. The transducer is then gently tilted to the side to identify each uterine artery on the side of the cervix at the level of the internal os with color flow Doppler mapping. Pulsed-wave Doppler is used with the sampling gate set at 2 mL to cover the whole vessel. Alternatively, the transverse approach for the measurement of UtAPI in the first trimester appears to be comparable with the sagittal approach in terms of reliability, reproducibility, and time required, and may be easier to perform.²³ Care is taken to ensure that the angle of insonation is less than 30°. The UtAPI is measured when three similar consecutive waveforms are obtained, and the mean UtAPI of the right and left uterine arteries is calculated.²¹ While slight variations are expected, systematic error in this measurement impacts on the screen positive rate. Uterine artery Doppler assessment should be accredited and regularly audited for competency by an independent authoritative body. A quality control process can identify sonographers who may need to be retrained.²⁴

**Table 1**: Checklists for maternal characteristics and medical history
Parameters	Data
Personal history
Maternal age (years)
Maternal weight (kg)
Maternal height (cm)
Maternal ethnicity	□ White, □ Black, □ South Asian, □ East Asian, □ Mixed/other
Obstetric history
Past obstetric history	□ Nulliparous, □ Parous without PE, □ Parous with PE
Interpregnancy interval (years)* %3E;10 years	□ Yes, □ No
Gestational age at previous delivery (weeks)
Birth weight of previous delivery (g)
History of medical conditions
Chronic hypertension	□ Yes, □ No
Diabetes mellitus	□ Type 1, □ Type 2, □ Insulin dependent
SLE or APS	□ Yes, □ No
Others
Familial (mother) history of PE	□ Yes, □ No
Method of conception	□ Spontaneous, □ Ovulation induction, □ IVF
Smoker	□ Yes, □ No

kg, kilogram; cm, centimeter; g, gram; PE, preeclampsia; IVF, in vitro fertilization; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome

* Years between the birth of the last child

Fig. 1: Measurement of mean arterial pressure by validated automated devices (Source: Wataganara T, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand)

Measurement of Biochemical Markers

Trophoblastic injury from poor implantation may be the main origin of PE. Ischemic trophoblastic cells release vasoactive substances into maternal circulation.²⁵ The most powerful first-trimester biochemical marker for prediction of preterm PE is PlGF.²⁶ PlGF is a glycosylated dimeric glycoprotein secreted by trophoblastic cells. It is a vasoactive mediator that plays a role in normal pregnancy. Changes of circulating levels of PlGF have been implicated in the development of PE.²⁷ Women who subsequently develop PE have significantly lower maternal PlGF concentrations in the first trimester than pregnancies with normal outcomes.²⁸ Factors that affect the values of PlGF in pregnant women are gestational age, maternal age, weight, racial origin, cigarette smoking, PE in previous pregnancies, diabetes mellitus, and in vitro fertilization. These factors need to be adjusted for algorithmic risk estimation of preterm PE using PlGF.²⁹

Pregnancy-associated plasma protein-A is also useful if measurement of PlGF is not available. It is a metalloproteinase insulin-like growth factor (IGF) binding protein secreted by the syncytiotrophoblasts. It plays an important role in placental development through enhancement of the mitogenic function of the IGFs. Pregnancy-associated plasma protein-A is a well-established biochemical marker in prenatal screening of trisomies 21, 18, and 13. Some women who subsequently develop PE have significantly lower maternal PAPP-A concentrations in the first trimester than those with normal pregnancy outcomes.³⁰

Soluble fms-like tyrosine kinase 1 (sFlt-1) is a tyrosine kinase protein with antiangiogenic properties. It reduces blood vessel growth through reduction of circulating vascular endothelial growth factor (VEGF) and PlGF concentrations. Abnormally high levels of sFlt-1 in the second and third trimester of pregnancy may predict imminent development of PE.³¹

Automated platforms for measurement of serum concentrations of these biomarkers are commercially available.^32,33 Only 5 mL of blood sample is required. Written instructions for proper collection, handling, and transport of blood samples must be clear, easy to understand, and available in the appropriate language and literacy level for all health care providers and couriers. Clinical laboratory should obtain accreditation, i.e., International Organization for Standardization (ISO).³⁴ No extra precautions need to be taken when PlGF is used for PE screening run alongside existing first-trimester aneuploidy screening programs that include PAPP-A and free β-hCG.³⁵

If immediate transport of the blood sample to the laboratory is not possible, blood samples can be kept in the clinic at room temperature for courier pick-up for a few hours without significant change in PlGF levels. If same-day pick-up is not possible, keeping blood samples refrigerated (4°C) can stabilize PlGF and sFlt-1 level for at least 48 hours.³⁶ Handling of blood samples for quantitation of PlGF in accordance with storage time is summarized in Table 2. Any significant deviation from these standards and guidelines, including specific clinical circumstances presented by the individual patient or specimen, that may affect the quality of test should be documented in the laboratory record.

Calculation for Risk of Preterm Preeclampsia

Validated algorithms can be used for converting the measured values of maternal characteristics, MAP, UtAPI, and PlGF into multiples of the median (MoMs). Individualized risk for preterm PE is calculated using the Bayes-based method. A risk calculation software is available free of charge on the web pages of professional organizations or from commercially available software, i.e., Predictor Software by PerkinElmer (Massachusetts, USA) and ViewPoint Software by GE Healthcare (Illinois, USA). These algorithms are similar but not identical. It depends on chosen cut-offs and test properties. It remains inconclusive as to which algorithm is the best.³⁷ The calculated risk of ≥1 in 100 (high risk) detects 76.6% preterm PE cases at a fixed FPR of 10%.³⁸ The algorithmic estimation of PE needs to be tailor accordingly to the population.^39–41

Prophylactic Measures

Hypertension in Pregnancy Task Force Report previously recommends daily low-dose aspirin (81 mg per day) beginning in the late first trimester for women with a history of early-onset PE, or for women with more than one prior pregnancy complicated by PE.⁴⁴ Low-dose (%3C;300 mg per day) aspirin may prevent development of PE by inhibiting the biosynthesis of placental thromboxane A2, without affecting prostacyclin.⁴⁵ Aspirin reversibly inhibits endothelial cyclooxygenase enzyme, but this process is irreversible in platelets. Results from the Combined Multi-marker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) trial provides definitive evidence that low-dose aspirin (150 mg per day) from 11 to 14 weeks of gestation until (1) 36 weeks of gestation, (2) delivery, or (3) PE is diagnosed can prevent or delay the onset of preterm PE in those screened positive from a combined first-trimester test.³⁸

**Table 2**: Summary of collection and analysis of specimen for quantitation of serum levels of PlGF^41,42
Specimen collection
Collection tube	Nonheparinized tube for serum collection
Sample condition	Reject if the serum is hemolyzed, icteric (yellow), or lipemic (turbid)
Serum separation	Allow the sample to clot %3E;30 minutes for optimal separation of the serum and reduction of fibrin plug in the separated serum portion after separation. Centrifugation for 10 minutes at 1,800 g (1800RCF). Decant serum sample in plain tube. Leave a small amount of serum above gel plug to ensure none of the gel plug is transferred to the plain tube.
Specimen analysis
Immediate processing	Present to the analyzer for immediate measurement according to manufacturer’s instructions.
Processing within 24 hours	Decant serum to a labeled clean plain tube within 1 hour of centrifugation. Refrigerate at 2–8°C. Remove from refrigerator and bring up to room temperature. Place on roller for 30 minutes or invert tube 20 times to remix serum. Present to analyzer. Freeze excess serum at 80°C for long-term storage if needed in future.
Processing after 24 hours and within 7 days*	Decant serum to a labeled clean plain tube within 1 hour of centrifugation. Freeze at 20–30°C. Remove from freezer, and refrigerate at 2–8°C overnight day before intended analysis. Remove from refrigerator and bring up to room temperature. Place on roller for 30 minutes or invert tube 20 times to remix serum. Present to analyzer. Freeze excess serum at 80°C for long-term storage if needed in future.
Processing after 7 days*	Decant serum to a labelled clean plain tube within 1 hour of centrifugation. Freeze at −80°C. Defrost stage 1: remove from −80°C freezer, and freeze at −20 to −30°C. Defrost stage 2: remove from freezer, and refrigerate at 2–8°C overnight day before intended analysis. Remove from refrigerator and bring up to room temperature. Place on roller for 30 minutes or invert tube 20 times to remix serum. Present to analyzer. Freeze excess serum at 80°C for long-term storage if needed in future.

G, G-force; RCF, relative centrifugal force; °C, degree Celcius

* The sample should not be recentrifuged or revortexed as this creates a concentration gradient

The daily dosages of aspirin to prevent preterm PE are 100 and 150 mg for maternal weight %3C; and ≥ 40 kg, respectively.¹⁰ Aspirin may be most effective when taken at night, rather than in the morning.⁴⁶ There was no evidence of heterogeneity in the aspirin effect in subgroups defined according to maternal characteristics and obstetric history, with the exception of chronic hypertension. Prophylactic aspirin may not be as effective in lowering preterm PE risk in women with chronic hypertension compared with other high-risk groups. High-risk women must be informed and counseled about the importance of treatment adherence (%3E;90%) and assessed for compliance at each prenatal visit.⁴⁷ In countries whose dietary calcium intake is low (<800 mg per day), either calcium replacement (≤1 g of elemental calcium per day) or calcium supplementation (1.5–2 g of elemental calcium per day) helps reduce the burden of both early- and late-onset PE.⁴⁸

Model of the Service Flow

Counseling for the opportunity to receive PE screening and prophylaxis should be included in the first prenatal visit.⁴⁹ Barriers for women and their partners to make an informed decision are complex concepts of risk and probability, lack of time, and limitations of choices of screening. An information leaflet can facilitate the counseling process. The OSCAR model can be applied for first-trimester screening of common fetal aneuploidies and early PE on a single visit. Maternal and obstetric histories are documented along with physical characteristics (height and weight). The SBP and DBP are recorded according to standard protocol to derive MAP. An ultrasound is performed to confirm the gestational age and number of fetus. The fetal NT and maternal left and right UtAPI are measured using standardized protocols. Blood is then taken from the mother for quantitation of PAPP-A, free β-hCG, and PlGF with a commercially available automated system. Turnaround time for the blood works is within a few hours. The software, customized to the screened population, is then used to determine the risk of fetal Down syndrome and early PE.³⁹ Those with high risk for development of early PE are advised to take low-dose aspirin. Adherence of aspirin and development of PE is assessed on every subsequent prenatal visit.

Quality Assurance and Follow-up of the Outcomes

The risk of PE is recorded in the electronic medical record (EMR) database along with the recorded maternal and obstetric history and physical, biochemical, and ultrasound markers for future audit. Outcome information is obtained from delivery record, by telephone calls to the mothers, or from the maternity units where delivery takes place. Minimum information obtained from the delivery record for the purpose of PE screening audit is summarized in Table 3. Criteria must be set to monitor and audit the performance of screening programs on both case-by-case and program-wide basis. The extent of the infrastructure required to support the implementation must also be regularly assessed. This involves coordination of various subspecialty clinical services, laboratories, and healthcare workers. Policies to govern the screening providers must be set to ensure continuous quality improvement. Information on the demand and need for future service provision within the local population, and its associated costs, can be extrapolated. Constant reevaluation after implementation allows for mixing and matching of the screening markers that best fit with the local resources and health economic model.

Special Considerations

Prediction of preterm PE should not be based on maternal factors alone. Routine screening for preterm PE should at least consist of maternal characteristics and MAP (first-tier test). Maternal serum PAPP-A routinely measured for first-trimester screening of aneuploidies can be included for PE risk assessment. The UtAPI and PlGF can be reserved for those who are screened positive (second-tier test).^50,51 Community outreach strategies such as mobile clinics may increase access to prenatal care in the resource-constraint setting. Quality of prenatal screening in these settings remains to be evaluated. Underresourced practices should prioritize the availability of accurate devices for measuring blood pressure and proteinuria, training of on-site sonographers, reliable supply of medications (i.e., aspirin, antihypertensive medications, and magnesium sulfate), and access to necessary (maternal and neonatal) critical care and laboratory services.⁵²

The incidence of PE in monochorionic and dichorionic twin pregnancies is increased by three and fourfolds, respectively. There are elevation of MAP and UtAPI, and decrease of serum PlGF and PAPP-A in twin pregnancies subsequently develops PE.⁵³ A multimarker screening model for PE in low-risk twin pregnancies, using a modified version of predictors in singletons, is available. At a cut-off of 1 in 75, the model can detect 99% of preterm PE in twin pregnancies at much higher screen positive rate of 75%. The addition of PAPP-A does not improve the performance of screening for preterm PE in twin pregnancies.⁵³ The UtAPI is of little value in screening for PE in low-risk twin pregnancies.⁵⁴

Vaginal spotting must be duly assessed but does not necessitate stopping aspirin prophylaxis.¹⁰ The use of low-dose aspirin during pregnancy is not associated with major bleeding complications, i.e., placental abruption or postpartum hemorrhage.⁵⁵ Aspirin is contraindicated in those with bleeding tendencies, i.e., peptic ulcers or bleeding disorders. In high-risk women who are allergic to aspirin, expectant management with frequent (home or clinic) blood pressure monitoring to ensure early diagnosis of PE is appropriate. Heparin, vitamins C and E, magnesium, folate, metformin, and statin have not been proven to prevent preterm PE. Low-dose aspirin may prevent preterm PE in multiple pregnancies, although its real efficacy remains elusive.⁵⁶

**Table 3**: Data for delivery record as part of the audit for PE screening program
Parameters	Remarks
Onset of labor (DD/MM/YYYY)
Mode of delivery	□ Spontaneous vaginal
	□ Forceps/vacuum
	□ Cesarean delivery
Date of delivery (DD/MM/YYYY)
Reasons for iatrogenic delivery
Gestational age at delivery (weeks)
Neonatal birthweight (g)
Gender of the baby
Apgar score	_______ at 5 minutes
	_______ at 10 minutes
Admission to NICU for >24 hours
Development of PE or gestational hypertension	□ Yes, PE
	□ Yes, gestational hypertension
	□ No

DD/MM/YYYY, date/month/year; g, gram; NICU, neonatal intensive care unit

Research Agenda

Early PE prediction and prevention substantially saves cost in high-income countries.⁵⁷ It is a constant challenge for middle- and low-income countries to implement and sustain early PE prediction with a sophisticated approach. Basic devices such as blood pressure monitors and urine dipsticks for use in low-resource settings have shown to be cost-effective in early diagnosis of PE.⁵² Alternatively, two-stage screening and biomarker testing for only part of the population may have financial benefits over conducting the test for the entire population.⁵⁸ More work is required to evaluate the cost-effectiveness balance between the ability to early diagnose PE and ability to predict and prevent early PE in a low-income setting.

The UtAPI, measured in the first or second trimester of pregnancy, can also identify a high proportion of women who develop early-onset fetal growth restriction. However, the value of prophylactic pharmacologic intervention in those with exceptionally high UtAPI is less remarkable.^59,60

It is possible that another round of screening with MAP, UtAPI, and serum biomarkers at 30–34 or 35–37 weeks’ gestation may effectively predict imminent development of pregnancy complications during the third trimester.^61,62 The potential value of such approach is to improve the perinatal outcome by rationalizing and individualizing the timing and content of subsequent visits for selection of the best time for delivery. Prompt interventions could alleviate the progression to eclampsia, placental abruption, and HELLP syndrome.⁶³

If agreed by the women, excess serum samples from first-trimester screening can be archived at −80°C for future research, i.e., novel biomarkers, possible genetic predisposition of PE, etc. The PlGF and sFlt-1 are stable for at least 3 years when serum samples are stored at −80°C.

CONCLUSION

Early prenatal visit is important to achieve the goal of prediction and prevention of preterm PE, especially in low-resource countries. Self-monitoring, together with increased alertness of healthcare professionals, would enable an active action to improve pregnancy outcomes. Given the resource constraints in low- and middle-income countries, variations of the first-trimester combined test should be considered but the most basic test should be maternal risk factors combined with MAP. Early access to prenatal services must be encouraged so that the PE screening strategies can be adapted. The initiation of PE screening service needs to consider the level of acceptability, feasibility, and ease of implementation in different resource settings.

ACKNOWLEDGMENTS

For special issue of Donald School Journal of Ultrasound in Obstetrics and Gynecology. Parts of this article were presented at the 2nd European Congress of Ian Donald School in Gdansk, Poland, October 17–19, 2019. We thank Busadee Pratumvinit, Suparat Jaingam, and Supitchaya Surasereewong for their administrative assistance.

REFERENCES

1. Pandya PP, Goldberg H, Walton B, et al. The implementation of first-trimester scanning at 10-13 weeks’ gestation and the measurement of fetal nuchal translucency thickness in two maternity units. Ultrasound Obstet Gynecol 1995;5(1):20–25. DOI: 10.1046/j.1469-0705.1995.05010020.x.

2. Panchalee T, Poungvarin N, Amornrit W, et al. Clinical performance of DNA-based prenatal screening using single-nucleotide polymorphisms approach in Thai women with singleton pregnancy. Mol Genet Genomic Med 2020(7):e1256. DOI: 10.1002/mgg3.1256.

3. Beck DW, Menezes AH. Intracerebral hemorrhage in a patient with eclampsia. JAMA 1981;246(13):1442–1443. DOI: 10.1001/jama.1981.03320130048025.

4. Wataganara T, Boriboonhirunsarn D, Titapant V, et al. Maternal body mass index at term does not predict the severity of preeclampsia. J Med Assoc Thai 2008;91(8):1166–1171.

5. Chumpathong S, Sirithanetbhol S, Salakij B, et al. Maternal and neonatal outcomes in women with severe pre-eclampsia undergoing cesarean section: a 10-year retrospective study from a single tertiary care center: anesthetic point of view. J Matern Fetal Neonatal Med 2016;29(24):4096–4100. DOI: 10.3109/14767058.2016.1159674.

6. Leetheeragul J, Boriboonhirunsarn D, Reesukumal K, et al. A retrospective review of on-admission factors on attainment of therapeutic serum concentrations of magnesium sulfate in women treated for a diagnosis of preeclampsia. J Matern Fetal Neonatal Med 2020;33(2):258–266. DOI: 10.1080/14767058.2018.1489531.

7. Chera-Aree P, Tengtrakulcharoen P, Leetheeragul J, et al. Clinical experiences of intravenous hydralazine and labetalol for acute treatment of severe hypertension in pregnant Thai women. J Clin Pharmacol 2020. DOI: 10.1002/jcph.1685.

8. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014;2(6):e323–e333. DOI: 10.1016/S2214-109X(14)70227-X.

9. McDonald SD, Malinowski A, Zhou Q, et al. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008;156(5):918–930. DOI: 10.1016/j.ahj.2008.06.042.

10. Poon LC, Shennan A, Hyett JA, et al. The international federation of gynecology and obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention. Int J Gynaecol Obstet 2019;145 (Suppl 1):1–33. DOI: 10.1002/ijgo.12802.

11. Akolekar R, Syngelaki A, Poon L, et al. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther 2013;33(1):8–15. DOI: 10.1159/000341264.

12. Magee LA, Pels A, Helewa M, et al. And canadian hypertensive disorders of pregnancy working G. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. Pregnancy Hypertens 2014;4(2):105–145. DOI: 10.1016/j.preghy.2014.01.003.

13. Wright D, Syngelaki A, Akolekar R, et al. Competing risks model in screening for preeclampsia by maternal characteristics and medical history. Am J Obstet Gynecol 2015;213(1):62.e1–62.e10. DOI: 10.1016/j.ajog.2015.02.018.

14. O’Gorman N, Wright D, Poon LC, 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):756–760. DOI: 10.1002/uog.17455.

15. Berlin DA, Bakker J. Starling curves and central venous pressure. Crit Care 2015;19(1):55. DOI: 10.1186/s13054-015-0776-1.

16. Sainas G, Milia R, Palazzolo G, et al. Mean blood pressure assessment during post-exercise: result from two different methods of calculation. J Sports Sci Med 2016;15(3):424–433.

17. Roberts L, Chaemsaithong P, Sahota DS, et al. Protocol for measurement of mean arterial pressure at 10-40 weeks’ gestation. Pregnancy Hypertens 2017;10:155–160. DOI: 10.1016/j.preghy.2017.08.002.

18. Poon LC, Zymeri NA, Zamprakou A, et al. Protocol for measurement of mean arterial pressure at 11-13 weeks’ gestation. Fetal Diagn Ther 2012;31(1):42–48. DOI: 10.1159/000335366.

19. Carbillon L, Challier JC, Alouini S, et al. Uteroplacental circulation development: Doppler assessment and clinical importance. Placenta 2001;22(10):795–799. DOI: 10.1053/plac.2001.0732.

20. Olofsson P, Laurini RN, Marsal K. A high uterine artery pulsatility index reflects a defective development of placental bed spiral arteries in pregnancies complicated by hypertension and fetal growth retardation. Eur J Obstet Gynecol Reprod Biol 1993;49(3):161–168. DOI: 10.1016/0028-2243(93)90265-e.

21. Sotiriadis A, Hernandez-Andrade E, da Silva Costa F, et al. ISUOG practice guidelines: role of ultrasound in screening for and follow-up of pre-eclampsia. Ultrasound Obstet Gynecol 2019;53(1):7–22. DOI: 10.1002/uog.20105.

22. Barnett SB, Abramowicz JS, Ziskin MC, et al. WFUMB symposium on safety of Nonmedical use of ultrasound. Ultrasound Med Biol 2010;36(8):1209–1212. DOI: 10.1016/j.ultrasmedbio.2010.04.005.

23. Drouin O, Johnson JA, Chaemsaithong P, et al. Transverse technique: complementary approach to measurement of first-trimester uterine artery Doppler. Ultrasound Obstet Gynecol 2018;52(5):639–647. DOI: 10.1002/uog.18917.

24. Rolnik DL, da Silva Costa F, Sahota D, et al. Quality assessment of uterine artery Doppler measurement in first-trimester combined screening for pre-eclampsia. Ultrasound Obstet Gynecol 2019;53(2):245–250. DOI: 10.1002/uog.19116.

25. Levine RJ, Qian C, Leshane ES, et al. Two-stage elevation of cell-free fetal DNA in maternal sera before onset of preeclampsia. Am J Obstet Gynecol 2004;190(3):707–713. DOI: 10.1016/j.ajog.2003.12.019.

26. Zhong Y, Zhu F, Ding Y. Serum screening in first trimester to predict pre-eclampsia, small for gestational age and preterm delivery: systematic review and meta-analysis. BMC Pregnancy Childbirth 2015;15(1):191. DOI: 10.1186/s12884-015-0608-y.

27. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350(7):672–683. DOI: 10.1056/NEJMoa031884.

28. Wortelboer EJ, Koster MPH, Kuc S, et al. Longitudinal trends in fetoplacental biochemical markers, uterine artery pulsatility index and maternal blood pressure during the first trimester of pregnancy. Ultrasound Obstet Gynecol 2011;38(4):383–388. DOI: 10.1002/uog.9029.

29. Tan MY, Syngelaki A, Poon LC, et al. Screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks’ gestation. Ultrasound Obstet Gynecol 2018;52(2):186–195. DOI: 10.1002/uog.19112.

30. Dugoff L, Hobbins JC, Malone FD, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER trial). Am J Obstet Gynecol 2004;191(4):1446–1451. DOI: 10.1016/j.ajog.2004.06.052.

31. Manthati S, Pratumvinit B, Hanyongyuth R, et al. Circulating free soluble fms-like tyrosine kinase-1 during late first trimester in relation with placental volume as a surrogate for trophoblastic production: a physiology study in low-risk cohort. J Matern Fetal Neonatal Med 2017;30(16):1976–1983. DOI: 10.1080/14767058.2016.1235697.

32. Wataganara T, Pratumvinit B, Lahfahroengron P, et al. Circulating soluble fms-like tyrosine kinase-1 and placental growth factor from 10 to 40 weeks’ pregnancy in normotensive women. J Perinat Med 2017;45(7):895–901. DOI: 10.1515/jpm-2017-0093.

33. Bhuwapathanapun M, Pratumvinit B, Lahfahroengron P, et al. Serumfree placental growth factor isoform 1 at 11-13-week gestation: effects of maternal factors, mean arterial pressure, placental volume, and uterine artery pulsatility index. J Matern Fetal Neonatal Med 2018;31(21):2813–2819. DOI: 10.1080/14767058.2017.1357168.

34. Boursier G, Vukasovic I, Brguljan PM, et al. Accreditation process in European countries - an EFLM survey. Clin Chem Lab Med 2016;54(4):545–551. DOI: 10.1515/cclm-2015-0780.

35. Cowans NJ, Alfthan H, Stenman UH, et al. Stability of first trimester placental growth factor in serum and whole blood. Prenat Diagn 2011;31(12):1193–1197. DOI: 10.1002/pd.2894.

36. Rowson S, Reddy M, Rolnik DL, et al. Stability of placental growth factor, soluble fms-like tyrosine kinase 1, and soluble fms-like tyrosine kinase 1 e15a in human serum and plasma. Placenta 2019;86:1–3. DOI: 10.1016/j.placenta.2019.08.001.

37. Lakovschek IC, Ulrich D, Jauk S, et al. Risk assessment for preterm preeclampsia in first trimester: comparison of three calculation algorithms. Eur J Obstet Gynecol Reprod Biol 2018;231:241–247. DOI: 10.1016/j.ejogrb.2018.11.006.

38. Rolnik DL, Wright D, Poon LCY, et al. ASPRE trial: performance of screening for preterm pre-eclampsia. Ultrasound Obstet Gynecol 2017;50(4):492–495. DOI: 10.1002/uog.18816.

39. Wataganara T, Leetheeragul J, Pongprasobchai S, et al. Prediction and prevention of pre-eclampsia in asian subpopulation. J Obstet Gynaecol Res 2018;44(5):813–830. DOI: 10.1111/jog.13599.

40. Chaemsaithong P, Pooh RK, Zheng M, et al. Prospective evaluation of screening performance of first-trimester prediction models for preterm preeclampsia in an Asian population. Am J Obstet Gynecol 2019;221(6):650.e1–650.e16. DOI: 10.1016/j.ajog.2019.09.041.

41. Chaemsaithong P, Sahota D, Pooh RK, et al. First-trimester pre-eclampsia biomarker profiles in Asian population: a multicenter cohort study. Ultrasound Obstet Gynecol 2019;56(2):206–214.

42. Law LW, Sahota DS, Chan LW, et al. Effect of long-term storage on placental growth factor and fms-like tyrosine kinase 1 measurements in samples from pregnant women. J Matern Fetal Neonatal Med 2010;23(12):1475–1480.

43. Wa Law L, Sahota DS, Chan LW, et al. Serum placental growth factor and fms-like tyrosine kinase 1 during first trimester in Chinese women with preeclampsia—a case-control study. J Matern Fetal Neonatal Med 2011;24(6):808–811

44. LeFevre ML. And force USPST. low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive services task force recommendation statement. Ann Intern Med 2014;161(11):819–826. DOI: 10.7326/M14-1884.

45. Masotti G, Galanti G, Poggesi L, et al. Differential inhibition of prostacyclin production and platelet aggregation by aspirin. Lancet 1979;2(8154):1213–1217. DOI: 10.1016/s0140-6736(79)92334-1.

46. Bonten TN, Snoep JD, Assendelft WJJ, et al. Time-dependent effects of aspirin on blood pressure and morning platelet reactivity: a randomized cross-over trial. Hypertension 2015;65(4):743–750. DOI: 10.1161/HYPERTENSIONAHA.114.04980.

47. Wright D, Poon LC, Rolnik DL, et al. Aspirin for evidence-based preeclampsia prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia. Am J Obstet Gynecol 2017;217(6):685.e1–685.e5. DOI: 10.1016/j.ajog.2017.08.110.

48. Hofmeyr GJ, Lawrie TA, Atallah AN, et al. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2018;10:CD001059. DOI: 10.1002/14651858.CD001059.pub5.

49. Oxenford K, Daley R, Lewis C, et al. Development and evaluation of training resources to prepare health professionals for counselling pregnant women about non-invasive prenatal testing for down syndrome: a mixed methods study. BMC Pregnancy Childbirth 2017;17(1):132. DOI: 10.1186/s12884-017-1315-7.

50. Wright D, Gallo DM, Gil Pugliese S, et al. Contingent screening for preterm pre-eclampsia. Ultrasound Obstet Gynecol 2016;47(5):554–559. DOI: 10.1002/uog.15807.

51. Wright A, Wright D, Syngelaki A, et al. Two-stage screening for preterm preeclampsia at 11-13 weeks’ gestation. Am J Obstet Gynecol 2019;220(2):197 e1–197.e11. DOI: 10.1016/j.ajog.2018.10.092.

52. McLaren ZM, Sharp A, Hessburg JP, et al. Cost effectiveness of medical devices to diagnose pre-eclampsia in low-resource settings. Dev Eng 2017;2:99–106. DOI: 10.1016/j.deveng.2017.06.002.

53. Francisco C, Wright D, Benko Z, et al. Competing-risks model in screening for pre-eclampsia in twin pregnancy according to maternal factors and biomarkers at 11-13 weeks’ gestation. Ultrasound Obstet Gynecol 2017;50(5):589–595. DOI: 10.1002/uog.17531.

54. Chen J, Zhao D, Liu Y, et al. Screening for preeclampsia in low-risk twin pregnancies at early gestation. Acta Obstet Gynecol Scand 2020. DOI: 10.1111/aogs.13890.

55. Roberge S, Bujold E, Nicolaides KH. Meta-analysis on the effect of aspirin use for prevention of preeclampsia on placental abruption and antepartum hemorrhage. Am J Obstet Gynecol 2018;218(5):483–489. DOI: 10.1016/j.ajog.2017.12.238.

56. Bergeron TS, Roberge S, Carpentier C, et al. Prevention of preeclampsia with aspirin in multiple gestations: a systematic review and Meta-analysis. Am J Perinatol 2016;33(6):605–610. DOI: 10.1055/s-0035-1570381.

57. Ortved D, Hawkins TL, Johnson JA, et al. 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):239–244. DOI: 10.1002/uog.19076.

58. Mendoza M, Garcia-Manau P, Arévalo S, et al. Diagnostic accuracy of first-trimester combined screening for early-onset and preterm preeclampsia at 8-10 weeks compared to 11-13 weeks gestation. Ultrasound Obstet Gynecol 2020. DOI: 10.1002/uog.22071.

59. Martin AM, Bindra R, Curcio P, et al. Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11-14 weeks of gestation. Ultrasound Obstet Gynecol 2001;18(6):583–586. DOI: 10.1046/j.0960-7692.2001.00594.x.

60. Papageorghiou AT, Yu CK, Bindra R, et al. Multicenter screening for pre-eclampsia and fetal growth restriction by transvaginal uterine artery Doppler at 23 weeks of gestation. Ultrasound Obstet Gynecol 2001;18(5):441–449. DOI: 10.1046/j.0960-7692.2001.00572.x.

61. Tsiakkas A, Saiid Y, Wright A, et al. Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 30-34 weeks’ gestation. Am J Obstet Gynecol 2016;215(1):87.e1–87.e17. DOI: 10.1016/j.ajog.2016.02.016.

62. Ciobanu A, Wright A, Panaitescu A, et al. Prediction of imminent preeclampsia at 35-37 weeks gestation. Am J Obstet Gynecol 2019;220(6):584.e1–584.e11. DOI: 10.1016/j.ajog.2019.01.235.

63. Li XM, Liu XM, Xu J, et al. Late pregnancy screening for preeclampsia with a urinary point-of-care test for misfolded proteins. PLoS ONE 2020;15(5):e0233214. DOI: 10.1371/journal.pone.0233214.

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