SEARCH

SEARCH BY CITATION

Keywords:

  • Doppler;
  • high-risk pregnancy;
  • prediction;
  • pre-eclampsia;
  • uterine arteries

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Objective

To evaluate the performance of models described previously for the prediction of pre-eclampsia (PE), based on the sequential evaluation of uterine artery resistance at 11–13 weeks and 19–22 weeks, in a high-risk population.

Methods

This was a prospective study in 135 women with singleton pregnancies and at least one of the following high-risk conditions: PE and/or intrauterine growth restriction in a previous pregnancy, chronic hypertension, pregestational diabetes, renal disease, body mass index > 30 kg/m2, autoimmune disease (systemic lupus erythematosus, antiphospholipid syndrome or rheumatoid arthritis) and thrombophilia. Mean uterine artery pulsatility index (mUtA-PI) at 11–13 and at 19–22 weeks' gestation was measured and analyzed according to quantitative and semi-quantitative models, to predict late PE (resulting in delivery ≥ 34 weeks) and early PE (delivery < 34 weeks).

Results

Late PE developed in 21 (15.6%) pregnancies and early PE in six (4.4%). Using mUtA-PI, the detection rates of late and early PE for a false-positive rate of 10% were 14.3% and 33.3%, respectively, at 11–13 weeks, and 19.0% and 66.7%, respectively, at 19–22 weeks. Using a semi-quantitative approach, the group of pregnant women with mUtA-PI ≥ 90th percentile at both 11–13 and 19–22 weeks had a greater risk for early PE (odds ratio, 21.4 (95% CI, 2.5–184.7)) compared with the group with mUtA-PI < 90th percentile at both periods. Using a quantitative approach, there was relative worsening in the mUtA-PI (multiples of the median) from the first to the second trimester in all cases of early PE.

Conclusion

The application of semi-quantitative and especially quantitative models to evaluate sequential changes in uterine artery Doppler findings between the first and second trimesters could be of additional value in assessing high-risk women regarding their true risk of developing early PE. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Pre-eclampsia (PE) affects about 2–8% of pregnancies. Early PE, resulting in delivery before 34 weeks of gestation, accounts for fewer than 25% of all cases of PE, thus complicating only about 0.5–2% of pregnancies. However, these cases tend to have the worst outcomes1.

About 5–10% of all pregnant women have risk factors for developing PE, such as prior PE and/or intrauterine growth restriction (IUGR), chronic hypertension, diabetes mellitus, chronic renal disease, certain autoimmune diseases and thrombophilias, high body mass index (BMI) and multiple pregnancy, increasing the incidence of early PE to 3–5% in these women2. Therefore, about a third of cases of early PE occur in women with such high-risk factors. However, most of these high-risk patients, who usually undergo intensified surveillance during their pregnancies, never develop PE. Hence, the application of a screening test for PE in a population with a priori high-risk factors for its development may be of particular interest in order to achieve a more accurate stratification of risk.

Recently, various screening tests have been published, some of them reporting a sensitivity and specificity as high as > 90% for the detection of early PE3, 4. However, most of them have been described in general populations and have not been validated in high-risk groups. Among these tests, one of the most promising and simple approaches results from evaluation of the sequential changes of uterine artery resistance between the first and second trimesters of pregnancy5, 6. The aim of our study was to analyze the value of this strategy for the prediction and exclusion of PE in a high-risk population.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Study population

From November 2005 to May 2010, women with singleton pregnancies at high risk for PE who were attending for prenatal care in our hospital were asked to participate in a prospective observational screening study, which was approved by our hospital ethics committee. Written informed consent for the study was obtained from all subjects.

Women were considered to be at high risk for PE when they presented with at least one of the following conditions: PE/IUGR in a prior pregnancy, chronic hypertension, pregestational diabetes mellitus, chronic renal disease, BMI > 30 kg/m2, inherited or acquired thrombophilia and autoimmune disease (systemic lupus erythematosus, antiphospholipid syndrome or rheumatoid arthritis). The diagnosis of chronic hypertension required documentation of antihypertensive therapy or blood pressure ≥ 140/90 mmHg, taken on two occasions at least 4 h apart, prior to 20 weeks' gestation. Diagnosis of pregestational diabetes mellitus was based on oral hypoglycemic or insulin therapy prior to conception. Diagnosis of the other high-risk conditions was based on documented clinical reports. Fetuses with chromosomal or structural abnormalities and pregnancies ended before 22 completed weeks were excluded from the study.

Patient characteristics, including maternal age, parity, race, height, weight, smoking status, aspirin intake, family (mother or sister) and/or personal history of PE and blood pressure were recorded at the time of enrolment into the study.

Uterine artery Doppler evaluation

The uterine artery pulsatility index was measured in both arteries at first-trimester (11 + 0 to 13 + 6 weeks) and second-trimester (19 + 0 to 22 + 0 weeks) transabdominal ultrasound examinations, which were carried out by experienced obstetricians with high-quality equipment (Siemens-Antares (Siemens Medical Solutions, Mountain View, CA, USA), Logic 5 Pro (GE Medical Systems, Milwaukee, WI, USA) or Voluson E8 (GE Medical Systems) ultrasound machines). Doppler measurements were performed as described elsewhere for the first-7 and second-trimester8 scans. The mean PI of left and right uterine arteries (mUtA-PI) was calculated and expressed in multiples of the median (MoM) after adjusting for gestational age (Table S1 online), as described previously6. The results were not available to the clinicians or to the women and did not further influence subsequent management of the pregnancies.

In order to evaluate the utility of combining first- and second-trimester uterine artery Doppler for the prediction of PE in our population, two previously proposed strategies were applied, one semi-quantitative and the other quantitative. The semi-quantitative approach5 was based on evaluation of mUtA-PI in the first and second trimesters and subsequent classification of the pregnancies into four groups: Group 1: mUtA-PI normal at both first- and second-trimester scans; Group 2: mUtA-PI normal at first-trimester but abnormal at second-trimester scan; Group 3: mUtA-PI abnormal at first-trimester but normal at second-trimester scan; Group 4: mUtA-PI abnormal at both first- and second-trimester scans. Because of the high-risk nature of the study population, the selected cut-off for considering mUtA-PI as abnormal was more conservative than that proposed in the original study with a low-risk population (> 90th percentile rather than > 95th percentile5).

The quantitative approach6 was based on estimation of the decrement in mUtA-PI (in MoM) from the first to the second trimester by means of calculation of the log ratio of the second-trimester mUtA-PI in MoM to the first-trimester mUtA-PI in MoM (log ratio 2T-1T) (Table S1).

Outcome measures

PE was defined according to the guidelines of the International Society for the Study of Hypertension in Pregnancy9. Superimposed PE was diagnosed if, after other disorders had been properly excluded, one of the following occurred: i) new-onset proteinuria appeared in a woman with chronic hypertension after 20 weeks, ii) there was a sudden increase in previously diagnosed hypertension or proteinuria, or iii) new signs and/or symptoms associated with severe PE developed after 20 weeks' gestation in a woman with previous hypertension or renal disease10.

Following current recommendations10, 11, a distinction was made between early and late PE depending on the gestational age at delivery (< 34 weeks and ≥ 34 weeks, respectively). Gestational age was calculated from the crown–rump length measured at the 11–13-week scan. Birth weight was converted into a percentile after correction for gestational age at delivery and sex of the newborn, according to local charts12. Small-for-gestational age was defined as birth weight < 10th percentile for gestational age.

Information on pregnancy outcome was collected from the hospital records and was analyzed carefully by the authors before classifying pregnancies into ‘unaffected’, ‘late PE’ and ‘early PE’. Only those women with complete follow-up were included in the analysis.

Statistical analysis

Comparisons between the three outcome groups (unaffected, late PE and early PE) were performed using chi-square, Fisher's exact, one-way ANOVA or Kruskal–Wallis tests, as appropriate. P-values for all tests were two-sided and the criterion for statistical significance was P < 0.05. Areas under the receiver–operating characteristics (ROC) curves (AUC) were used to assess predictive values and compared using the Hanley and McNeil test. Data were analyzed using statistical packages SPSS version 17.0 (SPSS, Chicago, IL, USA) and MedCalc (MedCalc Software, Mariakerke, Belgium).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

This analysis included 135 high-risk women with complete follow-up. Twenty percent (27/135) of women developed PE; 21/135 (15.6%) developed late PE and 4.4% (6/135) developed early PE (Figure 1). Table 1 summarizes the demographic characteristics of the study population, comparing unaffected, late PE and early PE pregnancies. Women who subsequently developed early PE were more likely to have had previous PE/IUGR or to have more than one high-risk factor, but there were no significant differences for the other variables. Pregnancy outcomes are shown in Table 2.

thumbnail image

Figure 1. Outcome of our study population of 135 women with singleton pregnancies at high risk for pre-eclampsia, according to uterine artery Doppler in first and second trimesters of pregnancy. Group 4 vs Group 1 for pre-eclampsia, P < 0.05 (chi-square test). Group 2 and Group 4 vs Group 1 for early pre-eclampsia, both P < 0.05 (chi-square test). Group 1 was the reference group for calculation of odds ratios (OR). MoM, multiples of the median.

Download figure to PowerPoint

Table 1. Characteristics of pregnancies included in the study according to occurrence of late (delivery ≥ 34 weeks) and early (delivery < 34 weeks) pre-eclampsia (PE)
CharacteristicUnaffected (n = 108)Late PE (n = 21)Early PE (n = 6)
  • Data are presented as mean ± SD or %.

  • *

    P < 0.05, Fisher's exact test, unaffected vs early PE groups. IUGR, intrauterine growth restriction; DM, diabetes mellitus.

Maternal age at recruitment (years)33.1 ± 4.333.3 ± 3.936.7 ± 4.6
Ethnic group   
 Caucasian88.990.5100
 Afro-Caribbean0.90.00.0
 Hispanic8.39.50.0
 Arabian1.90.00.0
Nulliparous44.433.350.0
Body mass index (kg/m2)27.0 ± 5.929.5 ± 9.027.4 ± 6.1
Cigarette smoker18.514.30
Family history of PE4.95.00
Aspirin intake during pregnancy39.857.183.3
Presenting risk factor   
 Previous PE/IUGR*25.938.166.7
 Chronic hypertension25.033.350.0
 Pregestational DM11.119.016.7
 Pregestational body mass index > 30 kg/m231.533.333.3
 Renal disease2.84.816.7
 Autoimmune disease15.714.30
 Thrombophilia16.719.016.7
 Two or more factors involved*25.947.683.3
Table 2. Pregnancy outcome of the study cohort (n = 135) according to occurrence of late (delivery ≥ 34 weeks) and early (delivery < 34 weeks) pre-eclampsia (PE)
CharacteristicUnaffected (n = 108)Late PE (n = 21)Early PE (n = 6)
  • Data are presented as mean ± SD or n (%).

  • *

    P < 0.05, Fisher's exact test, unaffected vs early PE groups.

  • P < 0.05, Fisher's exact test, late PE vs early PE groups. GA, gestational age.

GA at delivery (weeks)*38.1 ± 2.637.4 ± 2.131.2 ± 2.5
Birth weight (g)*3045 ± 5162922 ± 4821644 ± 599
Birth weight percentile53 ± 3060 ± 3843 ± 27
Umbilical artery pH7.26 ± 0.127.23 ± 0.127.13 ± 0.20
Preterm delivery (< 34 weeks)*4 (3.7)0 (0)6 (100)
Small-for-gestational age8 (7.3)4 (19.0)1 (16.7)
Placental abruption1 (0.9)0 (0)1 (16.7)
Perinatal death3 (2.8)0 (0)1 (16.7)

The distribution of mUtA-PI (MoM) values in the first and second trimesters in unaffected, late PE and early PE pregnancies is shown in Figure S1. In the unaffected group, the first-trimester mUtA-PI (MoM) median (interquartile range (IQR)) was 1.04 (0.79–1.25) and the 90th percentile was 1.47, and in the second trimester these values were 1.00 (0.82–1.25) and 1.49, respectively. These median values for the unaffected group were not significantly different in the first trimester from those observed in late (0.99 (0.85–1.29)) and early (1.08 (0.57–1.55)) PE groups; nor were they different in the second trimester from those observed in the late PE group (1.20 (0.83–1.47)). However, the median value in the second trimester of early PE cases (2.00 (0.97–2.20)) was significantly increased relative to the unaffected group (P < 0.01).

Figure 1 depicts the semi-quantitative evaluation of mUtA-PI (MoM) in the first and second trimesters of gestation, following the previously described classification into Groups 1–4. Pregnant women in Group 4 had a significantly higher risk of developing PE and early PE when compared with those in Group 1 (P < 0.05). Women in Group 2 also showed a trend towards a higher risk of developing PE (P = 0.16) but the difference only reached statistical significance for early PE (P < 0.05).

The quantitative evaluation of the sequential changes in mUtA-PI (MoM) between the first and second trimesters using log ratio 2T-1T is illustrated in Figure S2. The median (IQR) of log ratio 2T-1T in unaffected pregnancies was 0.01 (–0.08 to 0.08), in late PE cases it was 0.07 (−0.06 to 0.14) and in early PE cases it was 0.16 (0.09 to 0.34). Compared with in unaffected pregnancies, log ratio 2T-1T was significantly higher only in early PE cases (P < 0.01). Figure 2 shows the ROC curves for the prediction of late PE and early PE by means of mUtA-PI at first and second-trimester scans and log ratio 2T-1T, and the screening characteristics derived from these ROC curves are summarized in Table 3. According to the AUCs, the best accuracy for prediction of early PE was obtained by log ratio 2T-1T, although significant differences were not found. Although mUtA-PI (MoM) in the second trimester was slightly superior when the false-positive rate was fixed at 10%, log 2T-1T was the only screening test to detect all early PE cases when the false-positive rate threshold was raised to 25%.

thumbnail image

Figure 2. Receiver–operating characteristics (ROC) curves for detection of late pre-eclampsia (a) and early pre-eclampsia (b) using mean uterine artery pulsatility index (mUtA-PI) in multiples of the median (MoM) at first-trimester scan (11–13 weeks' gestation, equation image, mUtA-PI in MoM at second-trimester scan (19–22 weeks' gestation, equation image) and log ratio of second-trimester mUtA-PI in MoM to first-trimester mUtA-PI in MoM (equation image).

Download figure to PowerPoint

Table 3. Comparison of screening performance for late (delivery ≥ 34 weeks) and early (delivery < 34 weeks) pre-eclampsia (PE) in high-risk pregnancies, by mean uterine artery pulsatility index (mUtA-PI) at first- and second-trimester scans and log ratio of second-to-first-trimester mUtA-PI in multiples of the median (MoM) (log ratio 2T-1T)
 AUC (mean (95% CI))Detection rate (%) for 10% FPRDetection rate (%) for 25% FPR
Screening testLate PEEarly PELate PEEarly PELate PEEarly PE
  1. AUC, area under the receiver–operating characteristics curve; FPR, false-positive rate.

1st trimester mUtA-PI (MoM)0.528 (0.391–0.665)0.517 (0.200–0.833)14.333.328.650.0
2nd trimester mUtA-PI (MoM)0.590 (0.441–0.740)0.767 (0.484–1.000)19.066.747.666.7
Log ratio 2T-1T0.599 (0.458–0.741)0.853 (0.749–0.956)19.050.047.6100.0

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

This research further develops the concept that uterine artery Doppler performs differently in women at high risk for PE compared with the general population, and this should be taken into account in the prediction of PE13.

The reason for observed differences between these high-risk women and the general population might be related to (1) the tool itself (uterine artery Doppler), (2) the timing of its application (first or second trimester) and/or (3) the intrinsic characteristics of PE in high-risk pregnancies. Regarding the first point (the tool itself: uterine artery Doppler), it has been argued that in women with constitutional predisposition, the vascular remodeling of the spiral arteries could be hampered14, resulting in higher resistance in the uterine arteries. However, although a significantly higher prevalence of notching has been found in women with prior PE, resistance was not increased when compared with controls15. This was further confirmed in our study, in which the distributions of mUtA-PI in the first and second trimesters corresponded well with those described in unselected pregnancies5, 6. Therefore, mUtA-PI may be applied in high-risk women as described in the general population6.

Regarding the second point (timing), when exploring the feasibility of using uterine artery Doppler in the prediction of PE, the available information reveals that its performance is poorer in high-risk than in low-risk pregnancies, regardless of whether it is used in the first or the second trimester13, 16, 17. Remarkably, first-trimester values were very similar in normal and PE pregnancies. Our results correlate well with previous reports, showing that late PE cannot be predicted in high-risk women using uterine artery Doppler and finding the sensitivity for the prediction of early PE at 90% specificity to be 33% in the first trimester and 66% in the second trimester, below the 50% and 81%, respectively, reported in unselected pregnancies7.

There is a consensus that impairment of deep invasion of the myometrial arterial segments after the steep rise in placental oxygen at 10–12 weeks is the most likely mechanism involved in early PE18. Therefore, the predictive value of sequential strategies assessing changes in uterine artery resistance through the first half of pregnancy has been explored on the basis that these changes should reflect the evolution of this process of deep placentation19. These models have reported excellent results for the prediction of early PE in the general population5, 6 but, as far as we know, their performance in high-risk pregnancies has never before been examined.

The semi-quantitative strategy that we applied to our high-risk pregnancies showed that abnormal mUtA-PI in both examinations (Group 4) was associated with the highest risk of developing PE, but in those gestations in which abnormal mUtA-PI in the first trimester had become normal by the second (Group 3) the risk of PE was not increased compared with the group with normal mUtA-PI in both scans (Group 1). This disagrees with studies in low-risk women, in which the abnormal first-trimester but normal second-trimester mUtA-PI group was more predisposed to developing PE6. In contrast, in our Group 2 (normal first-trimester but abnormal second-trimester mUtA-PI) there was a substantial increase in risk of having PE, as has also been observed in low-risk women6. It should be noted that, given the high-risk nature of our study population, the overall incidence of PE was much higher in all groups when compared with low-risk women. However, when analyzing early PE cases separately, pregnant women with a presumably physiological second wave of trophoblast invasion (Groups 1 and 3) had a very low risk of developing early PE (< 2%), an incidence similar to that observed in the general population. However, in patients with presumably impaired trophoblast invasion (Groups 2 and 4), the incidence of early PE was very high (10–20-fold increase) compared with in the general population6.

The advantages of taking into account sequential changes in mUtA-PI are best evidenced by our quantitative strategy. With this approach, even in the two cases of early PE with normal mUtA-PI in both examinations, we detected a relative worsening in mUtA-PI (MoM) from the first to the second trimester, by means of the log ratio 2T-1T. Therefore, although measurement in the second trimester seems to be more discriminative in assessing the true risk of early PE in high-risk pregnancies, the first trimester scan also provides valuable information for its prediction. In fact, all cases of early PE were detected by means of log ratio 2T-1T when the false-positive rate was fixed at 25%. Although this cut-off may not seem sufficiently discerning, its utility for screening should be considered, taking into account that the source is already a high-risk population. Therefore, regarding the third point (intrinsic characteristics of PE in high-risk pregnancies), our study shows that the performance of log ratio 2T-1T enables a better reassessment of risk in women with a priori high-risk factors for developing early PE, and that defective deep placentation plays a critical role in the pathogenesis of early PE in high-risk women. This is further evidenced by the fact that daily low-dose aspirin intake is most likely to be beneficial for the prevention of PE when it is administered to women at high risk for PE and is started early in pregnancy20.

Despite there being a lack of evidence to demonstrate whether the use of uterine artery Doppler in high-risk pregnancies improves maternal–fetal outcome21, expert monitoring of PE patients has been shown to be associated with reduced maternal risk22. However, the limited resources for such monitoring require further selection of the true high-risk patients in order to improve our efficiency. In this sense, we believe that the improved reassignment of risk provided by log ratio 2T-1T may help to redirect resources rationally, focusing attention on the group of patients with increased log ratio 2T-1T but without exposing those with normal results to any increased risk.

We acknowledge two main limitations in our study. First, the sample size was relatively small, a problem common in previous series also. However, it is not easy to recruit pregnancies with true high-risk factors for PE (i.e. those associated with at least a three-fold increase in risk)1, 2. It is important to keep in mind the restrictive criteria that were used for inclusion of our patients, with all of them having at least one major risk condition, which were responsible for our high incidence (20%) of PE. Second, in this observational study, the influence of aspirin on the evolution of resistance in the uterine arteries and the incidence of PE cannot be quantified, as aspirin intake was not randomized. However, a clinical trial with aspirin is probably impossible due to ethical concerns derived from the widespread practice of giving aspirin to all pregnant women at high risk for PE.

In conclusion, the application of semi-quantitative and especially quantitative models to evaluate sequential changes in uterine artery Doppler findings between the first and second trimesters could be of additional value in assessing high-risk women regarding their true risk of developing early PE. This information may be useful to improve our prenatal resources and clinical efficiency.

SUPPORTING INFORMATION ON THE INTERNET

The following supporting information may be found in the online version of this article:

equation image Figures S1 and S2 Box-and-whisker plots showing distribution of values expressed as multiples of the median (MoM) of mean uterine artery pulsatility index (mUtA-PI) at first-trimester (11–13 weeks' gestation) and second-trimester (19–22 weeks' gestation) scan (Figure S1) and showing distribution of log ratio of second-trimester mUtA-PI in MoM to first-trimester mUtA-PI in MoM (log ratio 2T-1T) (Figure S2) in unaffected pregnancies and in those complicated by late and early pre-eclampsia.

Table S1 Regression models used to calculate mean uterine artery pulsatility index (mUtA-PI) expressed as multiples of the median (MoM) adjusted by gestational age at first- and second-trimester scans and log ratio of second- to first-trimester mUtA-PI in MoM (log ratio 2T-1T)6.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

This study was supported by grant FIS (PI07/0538) from the Spanish Ministry of Health and by a grant from the Fundación Mutua Madrileña (No. 2009/140).

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information
FilenameFormatSizeDescription
uog_10147_sm_suppinfofs1.doc109KSupporting Information: Figure S1. Box-and-whisker plots showing distribution of values expressed as multiples of the median (MoM) of mean uterine artery pulsatility index (mUtA-PI) at first-trimester (11–13 weeks' gestation) and second-trimester (19–22 weeks' gestation) scan (Figure S2) and showing distribution of log ratio of second-trimester mUtA-PI in MoM to first-trimester mUtA-PI in MoM (log ratio 2T-1T) (Figure S2) in unaffected pregnancies and in those complicated by late and early pre-eclampsia.
uog_10147_sm_suppinfofs2.doc47KSupporting Information: Figure S2. Box-and-whisker plots showing distribution of values expressed as multiples of the median (MoM) of mean uterine artery pulsatility index (mUtA-PI) at first-trimester (11–13 weeks' gestation) and second-trimester (19–22 weeks' gestation) scan (Figure S1) and showing distribution of log ratio of second-trimester mUtA-PI in MoM to first-trimester mUtA-PI in MoM (log ratio 2T-1T) (Figure S2) in unaffected pregnancies and in those complicated by late and early pre-eclampsia.
uog_10147_sm_supinfotabs1.doc32KSupporting Information: Table S1. Regression models used to calculate mean uterine artery pulsatility index (mUtA-PI) expressed as multiples of the median (MoM) adjusted by gestational age at first- and second-trimester scans and log ratio of second- to first-trimester mUtA-PI in MoM (log ratio 2T-1T)6.

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.