European Journal of Cardiovascular Medicine

The placenta itself is where the issue in preeclampsia and IUGR starts. The chorionic villi's cytotrophoblastic cells typically invade the decidua basal, which then invades the spiral arterioles and superficial myometrium. This causes the vessels to gradually dilate, which lowers the uterine artery resistance and keeps the placenta and fetus perfused. This invasion/vascular remodeling changes the high-resistance vessel prior to pregnancy to a low-resistance blood flow known as normal placental sufficiency.  Placental insufficiency and IUGR, two primary causes of placental morbidity and mortality globally, are caused by this critical vascular remodelling that does not occur in pre-eclampsia. Early pharmacological management may be beneficial because PE is predicted by the first trimester uterine artery Doppler examination in conjunction with other biomarkers and medical history.  Two of the leading causes of maternal perinatal morbidity and mortality are intrauterine growth restriction (IUGR) and pre-eclampsia (PE) [1].  It's becoming more widely acknowledged that early-onset and late-onset PE are distinct types of the illness.  IUGR, aberrant uterine and umbilical artery Doppler assessment, and poor maternal and newborn outcomes are frequently linked to early-onset PE [2].  On the other hand, perinatal outcomes are often positive for late-onset PE, which is mostly linked to mild maternal illness and a low prevalence of fetal involvement. For the past 20 years, predicting PE and/or IUGR has been a significant clinical and research concern [3].  With reported sensitivities for PE and IUGR ranging from 30 to 80%, uterine artery Doppler examination is now the best test for predicting these disorders at 20–24 weeks of gestation.  It appears likely that sensitivity is significantly higher for early-onset variants, even though the majority of research has been on predicting PE or IUGR happening at any point during pregnancy.  According to recent data, angiogenic factors may play a role in the pathophysiology of PE, and evaluating them may help detect the illness early [4]. Placental growth factor (PlGF) is involved in the control of placental vascular development and is highly expressed by trophoblast cells.  The strong PlGF antagonist circulating soluble fms-like tyrosine kinase (sFlt1) stops PlGF from interacting with cell receptors.  PE3 and isolated IUGR have been shown to have elevated sFlt1 levels and lower circulating PlGF levels.

STUDY DESIGN: Prospective Cohort study

Setting:

This study was undertaken at DARBHANGA MEDICAL COLLEGE AND HOSPITAL. All women with singleton pregnancies between 10-14 weeks of gestation attending the DARBHANGA MEDICAL COLLEGE AND HOSPITAL obstetrics and gynecology OPD for routine Ante-natal care were included in the study.

DURATION OF THE STUDY: One year period from December 2021 to November 2022.

SAMPLING: 150 antenatal patients were included in the study done from December 2021 to November 2022. The age of the women varies between 19-33 years.

Inclusion Criteria:

•              All women with singleton pregnancies between 10-14 weeks of gestation attending the DARBHANGA MEDICAL COLLEGE AND HOSPITAL outpatient department for routine antenatal care between December 2021 to November 2022 who consent to participate in the study were included in the study.

Exclusion Criteria:

·         Women bearing fetuses with Sono-graphically detectable congenital abnormalities are not eligible.

·         People with a known congenital uterine abnormality identified in the results of the prior scans.

·         Those for whom there aren't any pregnancy outcome statistics

·         Women with history of renal disease, cardiovascular pathology, pre-existing diabetes mellitus.

Methodolgy

This study was conducted at the Department of Obstetrics and Gynecology, Darbhanga Medical College and Hospital. It included 150 women with singleton pregnancies, aged 19 to 33 years, who presented at 10 to 14 weeks of gestation and did not have any antenatal complications. These women provided consent to participate in the study and were followed up until delivery.

The patients' information, including age, parity, registration number, and socioeconomic position, were recorded after gaining informed consent.

Based on the last menstrual cycle, pregnancy dates were established, and at 10-14 weeks, measures of the crown-rump length (CRL) by 36 ultrasonography were used to confirm the pregnancy. Blood pressure readings and general physical findings were also recorded.

The hospital's ethical review board granted its approval, and patients signed informed permission was obtained. Real-time pulsed wave color flow Doppler ultrasound examination All participants underwent Doppler between 10 and 14 weeks. For each subject, the same examiner administered the test. At the point where the uterine arteries crossed the external iliac artery, color Doppler was used to pinpoint their location. Both uterine arteries were evaluated for resistance index (RI), pulsatility index (PI), and the presence or absence of diastolic notch.

At 24 to 28 weeks and again between 32 and 36 weeks, all patients were requested to follow up. Using a sphygmomanometer, their blood pressure was checked during these visits, and urine albumin levels were reported. Clinical evaluation of the progression of IUGR was performed using the interval growth rate and amniotic fluid index. Several factors were taken into account at delivery, including the gestational age, mode of delivery, birth weight, APGAR score, fetal outcome, admission to the NICU, and requirement for ventilator support. The gathered data were imported into Microsoft Excel, and SPSS was used to do the necessary statistical analysis.

Statistical Analysis:

For statistical analysis, data were initially entered into a Microsoft Excel spreadsheet and then analyzed using SPSS (version 27.0; SPSS Inc., Chicago, IL, USA) and GraphPad Prism (version 5). Numerical variables were summarized using means and standard deviations, while categorical variables were described with counts and percentages. Two-sample t-tests, which compare the means of independent or unpaired samples, were used to assess differences between groups. Paired t-tests, which account for the correlation between paired observations, offer greater power than unpaired tests. Chi-square tests (χ² tests) were employed to evaluate hypotheses where the sampling distribution of the test statistic follows a chi-squared distribution under the null hypothesis; Pearson's chi-squared test is often referred to simply as the chi-squared test. For comparisons of unpaired proportions, either the chi-square test or Fisher’s exact test was used, depending on the context. To perform t-tests, the relevant formulae for test statistics, which either exactly follow or closely approximate a t-distribution under the null hypothesis, were applied, with specific degrees of freedom indicated for each test. P-values were determined from Student's t-distribution tables. A p-value ≤ 0.05 was considered statistically significant, leading to the rejection of the null hypothesis in favour of the alternative hypothesis.

Table 1: Distribution of Pre-eclampsia

Table 2: Distribution of Diastolic notch

Table 3: Distribution of Comparison of Parity with Pre-eclampsia

Table 4: Distribution of Mean RI comparison with Parity of the mother

In our study, pre-eclampsia was observed in 31 patients, accounting for 20.7% of the total sample. This association was statistically significant, with a p-value of < .00001.In our study, diastolic notch was present in both uterine arteries in 81 patients (54.0%), present in one artery in 28 patients (18.7%), and absent in both arteries in 41 patients (27.3%). This distribution was statistically significant, with a p-value of < .00001.In our study, 66 patients (44.0%) were primi Parity, while 84 (56.0%) were multi Parity. This distribution showed a statistically significant association with the outcome variable, with a p-value of 0.03752.In our study, the mean RI was 0.6655 ± 0.10588 in primi Parity and 0.6926 ± 0.10938 in multi Parity participants, with no statistically significant difference observed (p = 0.1288).

This study included 150 women who were deemed representative of the local pregnant population, and it had a 100% follow-up rate.  This time window was selected for the uterine artery RI (Resistivity Index) since the research cohort was already scheduled for routine scans for nuchal translucency and early morphological assessment during this gestational phase.  Both the current study and previous research have shown a strong correlation between intrauterine growth restriction (IUGR) and pre-eclampsia. According to the current study, the IUGR detection sensitivity and positive predictive value (PPV) for patients with pre-eclampsia were 70% and 67.74%, respectively.  These results point to IUGR, which is known to have early defective placentation, and pre-eclampsia as having a similar pathogenesis.  Pre-eclampsia and IUGR later in pregnancy were found to be significantly correlated with a higher uterine artery resistivity index in the first trimester.  Previous research has examined the connection between IUGR, pre-eclampsia, and first trimester uterine artery RI. Pre-eclampsia and IUGR were found to be 2.4 and 3.8 times more prevalent in women with high uterine artery impedance (RI 0.85-0.95), respectively, by Van Den Elzen et al. [5]. Martin et al. found that the onset of pre-eclampsia and IUGR were both associated with a high RI index.  [6]  Research conducted by Harrington et al. on patients whose uterine artery impedance was evaluated between 12 and 16 weeks of pregnancy revealed similar outcomes.  The uterine artery RI 5th, 75th, and 95th centiles are, respectively, 0.53, 0.71, and 0.85, per B. Hollis et al. [7].  They also observed that individuals with high uterine artery mean resistance scores (75th percentile = 0.71) had a 5.5-fold higher prevalence of IUGR. Dug off et al. [8] chose mean RI cutoffs at the 75th centile (0.731) and the 95th centile (0.81) for their study.  At the 75th percentile, the sensitivity and specificity of IUGR and pre-eclampsia identification were, respectively, 72.3% and 66.7% and 84% and 75%.  However, the sensitivity for identifying these diseases was comparatively poor at 95th centile or higher.  Other researchers have employed the best RI (95th centile) and the mean RI (average of two uterine artery RIs) as indicators of abnormalities.  These investigations demonstrated that the best RI was less successful in predicting problems in the low-risk population, and because of its low sensitivity and high specificity, it was not recommended for use as a screening tool.  Like Dugoff et al. [8], this study's sensitivity was rather low at the 75th centile (=0.85), at 10% and 16%, respectively, with 42% and 37% specificity for IUGR and pre-eclampsia.  The Receiver-operating characteristics (ROC) curve was used in this study to calculate the mean RI cut-off, which came out to be 0.7175.  With an 83% sensitivity and a 30% false positive rate, it was found that it could identify 45% of pre-eclampsia patients based on this cut-off. Additionally, with a 73% sensitivity and a 26% false positive rate, the test was able to identify 38% of IUGR cases.  The results of the study indicated that uterine artery resistivity indices were lower in pregnancies with normal outcomes than in complicated cases. This suggests that the absence of normal uteroplacental circulation at this early stage of pregnancy may help predict the later development of some pregnancy complications.

Even though a large number of severe difficulties were not detected, the data from this inquiry were comparable to those from other investigations. The mean RI cut-off for the single patient in the current study who had an abruption while using an IUD at 29+3 weeks of gestation was 0.79, which was nearly in the 90th percentile.  Since the ladies in our study population were low-risk and frequented the DMCH outpatient department, no significant issues were found.  The overlap between pregnancies with normal and poor outcomes in terms of the first trimester uterine artery mean RI cut-off could be explained by a variety of reasons.

1.       The test may be correct, although there may be differences in uteroplacental resistance between healthy and unhealthy pregnancies.

2.       Variability may exist in the measured values.  These errors would rise with the number of observers.  However, the same observer made the first observation for this investigation.  It is currently uncertain if any other index would be more effective, since RI can only be used to make a rudimentary evaluation of the waveform.

3.       It's possible that these studies' classification of results used inadequate definitions.  Numerous factors actually contribute to the perceived outcomes.  For example, not all cases of pregnancy-related hypertension are caused by pre-eclampsia, and not all cases of antepartum hemorrhage (APH) are caused by placental abruption.

4.       In cases of early-onset pre-eclampsia, false negative results could be the result of an undetected kidney disease.  The term "small for dates" also describes a variety of illnesses, including placental or uterine insufficiency.

5.       Biological variance, such as daily variations, circadian changes, or food and exercise patterns, can lead test findings to be mistakenly positive or completely negative.  Depending on the waves of trophoblastic invasion, the timing of which is unpredictable, abnormal uterine waveforms may occasionally show up later in pregnancy, beyond the screening tests.

6.       A restricted uterine blood flow may be circumvented by compensating mechanisms in both the mother and the fetus.  Because the placenta has a functional reserve capacity, the loss of a portion of the villous parenchyma may not always affect the growth and development of the fetus.  The existence of a 30% false positive rate for pre-eclampsia and a 26.8% false positive rate for IUGR could be attributed to these compensatory mechanisms..

At this gestational stage, waveforms reflecting normal and aberrant flow velocity may overlap more than they would later in pregnancy.

Recent research indicates that the underlying cause of severe early-onset hypertension issues is more likely to be placental ischemia followed by improper placentation.  However, this correlation does not hold true for the less severe variations that appear immediately.

The latter group appears to be unrelated to increased uteroplacental resistance and to be influenced by maternal risk factors.  Therefore, from the very start of pregnancy, uterine artery Doppler RI can be a useful method for detecting conditions characterized by a high level of placental abnormalities.  This could also explain the higher documented rate of false negatives.

Twenty percent of the cases in this study needed to be delivered before 35 weeks of pregnancy due to the severity of the condition.  Six percent of these patients had IUGR alone, 3% had pre-eclampsia with IUGR as their sole problem, and around 14% had pre-eclampsia with IUGR as their only consequence.

One significant finding of the study was that 8% of the newborns needed NICU treatment because of issues with IUGR, respiratory distress, and premature birth.  Higher mean RI values were found to be statistically significantly correlated with the need for NICU care, with the mean RI cut-off for all of these moms being 0.7175 or higher.  This study demonstrated no correlation between primiparity and pre-eclampsia, despite the fact that it is commonly known that primiparous women (5–15%) had a higher incidence of pre-eclampsia than multiparous women (5%).  This lack of correlation may be due to the small sample size, which may not have provided sufficient statistical power to differentiate this issue.

There haven't been many research that have looked at low-risk patients to investigate whether the diastolic notch and negative pregnancy outcomes are associated.  Indicators of pre-eclampsia and poor fetal outcomes include the continuance of the notch, an increased resistance index, and a pulsatility index, which all indicate rising vascular resistance.  There is ongoing discussion on the exact moment the notch disappeared.

Studies evaluating low-risk patients to determine if the diastolic notch is associated with worse pregnancy outcomes are scarce.  Indicators of pre-eclampsia and poor fetal outcomes include the continuance of the notch, an increased resistance index, and a pulsatility index, which all indicate rising vascular resistance.  There is ongoing discussion on the exact moment the notch disappeared.  The widely accepted idea states that the notch disappears after the second wave of trophoblastic invasion, which occurs between weeks 19 and 21 of pregnancy.

Nevertheless, several studies have produced conflicting results. The presence of a diastolic notch in the first trimester has a sensitivity of 33%, specificity of 90%, positive predictive value of 36%, and negative predictive value of 89% for predicting subsequent pre-eclampsia, according to J.M. Herman Hertel et al. [9].  These conflicting findings suggest that the connection between diastolic notching and adverse pregnancy outcomes is still up for debate.  Further research is needed to clarify the relevance of notching as a predictive marker for issues like IUGR and pre-eclampsia.

Diastolic notches were found in both uterine arteries in 81 (54%) of the study individuals.  Furthermore, of the patients without a diastolic notch, 8 patients (19.5%) had IUGR and 7 patients (22.6%) had pre-eclampsia.  According to statistical analysis, there is no significant correlation between diastolic notch in the first trimester and pre-eclampsia or IUGR.  In order to predict future IUGR and pre-eclampsia, this study also evaluated the mean PI (Pulsatility Index).  The mean Pl for the first trimester was found to have no statistically significant relationship with the identification of pre-eclampsia and IUGR.

Indeed, studies such as those conducted by Gomez et al. [10] have demonstrated that uterine artery impedance is lower in pregnancies with a normal result than in complicated instances.  This suggests that certain pregnancy issues may manifest later in life if there is abnormal uteroplacental circulation during the first trimester of pregnancy.

The information that is now available indicates that in approximately 25% of pregnant women, a higher uterine artery flow impedance can predict pre-eclampsia.

The study found a statistically significant correlation between the mean RI cut-off and one-minute APGAR scores, birth weight, and gestational age at birth.  On the other hand, the mother's age, parity, and occupation did not differ significantly.  This implies that mothers of babies born with IUGR and pre-eclampsia had a mean RI cut-off of at least 0.7175.

First-trimester uterine artery Doppler resistance index (RI) is a valuable predictive tool for identifying pregnancies at risk for intrauterine growth restriction (IUGR) and pre-eclampsia. Elevated RI values are significantly associated with impaired placental perfusion, which contributes to these adverse outcomes. Early identification through Doppler screening enables closer surveillance and timely interventions, potentially improving maternal and fetal outcomes. Incorporating uterine artery Doppler assessment into routine first-trimester screening can enhance risk stratification and guide clinical management. However, further large-scale studies are recommended to validate its predictive accuracy and optimize its use in diverse populations and clinical settings.

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