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COMBINATION OF UTERINE ARTERY PULSATILITY INDEX ≤1.0 AND ABSENT DIASTOLIC NOTCH IN IDENTIFYING LOW-RISK SUBJECTS OF PREECLAMPSIA REMOTE FROM TERMABSTRACT

ABSTRACT

Aim: To identify subjects who are at a low-risk for developing preeclampsia remote from term using color Doppler in I-trimester scans.

Study Design: This is a prospective longitudinal study

Methods: A combination of Pulsatility Index (PI) and absence of Diastolic Notch (DN) at Colour Doppler in first-trimester of pregnancy was examined to identify low-risk subjects. Uterine artery color Doppler was performed between 11-13+6 weeks. After this, the subjects were followed up prospectively till delivery. They were specifically looked for development of preeclampsia before 34 weeks of pregnancy. Their outcome was compared with that of subjects with other groups. Results so obtained were evaluated using statistical tools. The data was then subjected to a review by an independent data scientist and conclusions drawn in light of available current references.

Results: There were 510 subjects enrolled in this study. They were divided into 8 statistical groups for a thorough analysis. Those subjects who showed a PI≤1.0 and absent DN in both uterine arteries at 11-13+6 weeks were found to have a significantly less likelihood of developing preeclampsia making them low-risk subjects (p-Value < 0.00001). These results were found to have a very high sensitivity (91.4%) and negative predictive value (87%). Statistical limitations of the study have also been identified.

Conclusion: Subjects who show a PI≤1.0 and absent DN in both uterine arteries in first trimester of pregnancy have a significantly less likelihood of developing preeclampsia remote from term and are therefore at a low-risk for the same.

KEY WORDS: Diastolic Notch, Doppler, First trimester scan, Preeclampsia Prediction, Preeclampsia remote from term, Pulsatility Index, Ultrasonography, Uterine artery,

COMBINATION OF UTERINE ARTERY PULSATILITY INDEX ≤1.0 AND ABSENT DIASTOLIC NOTCH IN IDENTIFYING LOW-RISK SUBJECTS OF PREECLAMPSIA REMOTE FROM TERM

INTRODUCTION:

Preeclampsia has been categorized by some investigators into two types: early-onset preeclampsia and late-onset preeclampsia1. Early-onset preeclampsia (also known as preeclampsia remote from term) is defined as preeclampsia that develops before 34 weeks of gestation, whereas late-onset preeclampsia develops at or after 34 weeks of gestation. The former behaves stormily and has a poor perinatal and maternal outcome. The latter on the other hand is relatively easy to manage and has a favourable outcome. In this paper, all references to preeclampsia are to early-onset preeclampsia, till and until specified.

A series of tests are available to predict high-risk subjects for preeclampsia. Currently, the uterine artery Pulsatility Index (PI), Mean Arterial Pressure (MAP) and Pregnancy-Associated Plasma Protein A (PAPP-A) are popular in the prediction of preeclampsia. Research papers published by workers at the Fetal Medicine Foundation of UK helped in popularizing these markers a big way2. It has been consistently found that a combination of tests is more accurate in predicting preeclampsia rather than a stand-alone test3. While there are innumerable tests including ours to identify high-risk subjects for preeclampsia4, there are very few tests that can identify low-risk subjects for preeclampsia. Some studies did use clinical parameters and complex statistical analysis to identify low-risk subjects5. But, they remain in realms of research with limited clinical applicability. In this original study, we have tried to identify low-risk subjects for preeclampsia. For this, we have studied two doable Doppler parameters, PI≤1 and absence of Diastolic Notch (DN) in I-trimester uterine artery scan.

MATERIALS AND METHODS:
In this prospective longitudinal study, subjects that were enrolled were followed-up from the first trimester to their obstetric outcome. The population catered to at this mid-level obstetric care unit, predominantly comprises of urban middle and upper-middle-class subjects. All singleton pregnancies irrespective of their past obstetric performance or clinical risk-factors for preeclampsia were enrolled for this study. Enrolment was done at 11-13+6 weeks USG scan. After the scan, the subjects were observed specifically for the development of preeclampsia before 34 weeks.

Color Doppler was done with GELOGIQ F8 ultrasound machine. For the study, only one first trimester scan between 11-13+6 weeks of pregnancy was required. All scans were performed by the author. It was done by the transvaginal route. Using Doppler ultrasound, the main branch of the uterine artery could be located at the cervicocorporeal junction. With the help of a real-time color imaging, Doppler velocimetry measurements were performed by a standard and well-established method6. Transvaginally, the probe was placed in the anterior fornix. A midsagittal section of the uterus was obtained and the cervical canal was identified. The probe was then moved laterally until the paracervical vascular plexus was seen. Color Doppler was then turned on and the uterine artery was identified as it turns cranially to make its ascent to the uterine body. Measurements were taken at this point before the uterine artery branched into the arcuate arteries. Uterine arteries of both sides were scanned.

PI or Pulsatility Index was calculated as Peak Systolic Velocity minus End Diastolic Velocity divided by Time-Averaged Velocity = (PSV - EDV) /TAV. These values were readily provided by the in-built software in the sonography machine itself. Both variables studied, PI and absence of DN are independent variables not related to or dependant on each other.
Subjects were then followed-up for development of preeclampsia remote from term. They were labeled as preeclamptic on development of hypertension after 20 weeks of gestation but before 34 weeks of pregnancy with previously normal BP and without proteinuria. Hypertension of preeclampsia was labeled following standard norms as a BP of 130 systolic and/or 90 diastolic in pregnancy taken on two consecutive readings six hours apart after adequate rest of at least half an hour. Proteinuria was detected through standard dipstick test.

Statistical Analysis
The data so obtained from the study was statistically diligently evaluated. Chi-square test was used to analyze the statistical significance. To make the statistical evaluation more rigorous, a second set of tools for statistical evaluation was employed. In this Sensitivity, Specificity, and Predictive values were calculated, analysed and conclusions reached by a professional and qualified data scientist. Statistical limitations of the results were also spelt out. The results so obtained were examined in light of available references to draw valid conclusions.

RESULTS:
510 subjects were longitudinally studied from enrolment to their obstetric outcome for this study. For reasons of accurate statistical analysis they were distributed into eight groups the distribution of which is shown in Table 1.

TABLE 1

It was found that there subjects with low PI and absent DN together had a significantly low-risk of developing preeclampsia. The Chi-square value was 338.8585 and the p-value was < 0.00001. This made the association highly significant statistically with the chance of probability being negligible.

This association was then subjected to a second tool of statistical analysis. It was found that these results had a sensitivity of 91.45% and a negative predictive value of 87.1%. The specificity of 10.4% and a positive predictive value was 16.4%. Very high sensitivity and a negative predictive value of this combination show the high efficiency of this tool in identifying low-risk subjects for developing preeclampsia.

ANALYSIS AND DISCUSSION

The principle finding of this study was that pregnant subjects with PI≤1 and DN absent in uterine arteries, bilaterally, at 11-13+6 weeks scan are at a significantly low-risk of developing preeclampsia remote from term.

Preeclampsia remote from term is as an obstetric vasculopathy. As is now well defined, obstetric vasculopathies are those conditions that have a placental vascular origin7. Color Doppler is the most discriminative for predicting obstetric vasculopathies like early preeclampsia and early preterm birth8. Uterine artery PI and presence or absence of DN are good indicators of the status of the second wave of trophoblastic invasion. It is very well-known for years now that preeclampsia is due to the failure of the second wave of trophoblastic invasion. Endovascular trophoblast invasion has been reported to occur in two waves; the first into the decidual segments of spiral arteries by 8 to 10 weeks of gestation and the second into myometrial segments by 16 to 18 weeks of gestation9. The second wave of trophoblastic invasion physiologically completes by the second trimester in normal pregnancies.

When the first-trimester scan is performed (11-13+6 weeks), the second wave of trophoblastic invasion is usually still incomplete and is seen as a Diastolic Notch (DN) in uterine artery color Doppler study. Consequently, by the end of first-trimester (11 to 13+6 weeks) in a USG scan, the presence of DN is an expected finding. But if in this first-trimester scan itself, one finds that the DN is absent and the uterine artery PI is low, it suggests that the second wave of trophoblastic invasion has got completed in this subject as early as the end of first-trimester. As a result, in clinical practice, such a subject is expected to be a low-risk for developing preeclampsia. With this explanation in the background, we studied the efficacy of PI≤1.0 and absence of DN in identifying low-risk subjects for developing preeclampsia and found this combination to be useful.
PI>1.7 is considered as having a good value for the prediction of high-risk subjects for preeclampsia10. Most of the tests for predicting preeclampsia are focused on identifying the high-risk subjects for developing preeclampsia. All studies in this line including one of ours identifies tests that will reveal high-risk subjects reasonably accurately4. Consequently, subjects are to be labelled low-risk by the convention of exclusion. This means that if a subject is not high-risk, she is at a low-risk for preeclampsia11, 12. In the present study, drawing such a consequential linear conclusion can be erroneous. Therefore the study does not stretch itself beyond its results. One recent study has evaluated predictive performance of the competing risk model in screening for preeclampsia. In the end the study recommends that prediction of preterm preeclampsia is beneficial because treatment of the high-risk group with aspirin is highly effective in the prevention of the disease13.

As an extension to the results of the present study, one can suggest that new research can be undertaken to study if the use of aspirin can be discontinued in scientifically identified low-risk subjects, when it has already been started on basis of clinical parameters from conception or even before.

Analytical comments from professional Data Scientist: Statistical analysis of the results in this paper brings forward both, the strengths and limitations of this study. On applying the Chi-square test it was found that the results were highly significant. This means that those subjects who on a uterine artery color Doppler reveal that the PI≤1.0 and DN being absent at 11-13+6 weeks scan have a significantly low-risk of developing preeclampsia. But the complexity of statistical analysis emerges when tools for testing specificity and the like are applied and are deeply analysed. While the test revealed a very high specificity, it also showed a very high negative predictive value. What does this mean in common parlance? It means that the test is very efficient in identifying low-risk subjects for preeclampsia.

But, the sensitivity and positive predictive values are not high enough. It shows a statistical limitation of this test. One has to be very careful and exercise due discretion and maturity in interpreting the results. It shows that in clinical practice if one finds PI≤1.0 and DN absent in the uterine arteries that subject is at a low-risk of developing preeclampsia. But, the reverse may not be true. If one does not find these two findings in any subject it does not necessarily mean that such a subject is at a high risk of developing preeclampsia. Thus this test has a very well defined focused range of identifying low-risk subjects for preeclampsia. But, its absence is not in a position to tell that the subject is at a high-risk for the same. This statistical limitation of this study has to be accepted.

CONCLUSION:
From this study one can conclude that pregnant subjects with PI≤1.0 and absent DN at 11-13+6 weeks uterine artery color Doppler scan are at a significantly low-risk of developing preeclampsia. But this study cannot say that subjects with PI>1.0 and/or DN present at 11-13+6 weeks scan are at a high-risk for developing preeclampsia.

REFERENCES:

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4. Pankaj Desai: Notch depth index alone and in combination with PI in prediction of preeclampsia at or before 34 weeks of pregnancy: Pregnancy Hypertension: 16, 2019, 11-15

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7. Pankaj Desai: Obstetric Vasculopathies: Delhi, Jaypee Publishers:, 2013, Pg. 2

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9. Pijnenborg R, Bland JM, Robertson WB, Brosens I: Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta 1983, 4:397-414.

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13. Wright D, Tan MY, O'Gorman N, et al. Predictive performance of the competing risk model in screening for preeclampsia [published correction appears in Am J Obstet Gynecol. 2019 Apr 24;:]. Am J Obstet Gynecol. 2019; 220(2):199.e1–199.e13. doi:10.1016/j.ajog.2018.11.1087