European Journal of Cardiovascular Medicine

Out of all the obstetric complications, hypertension in pregnancy is the most common cause and a leading cause of maternal and perinatal mortality. Not only maternal deaths, hypertensive disorders are also responsible for substantial morbidity for the pregnant women. Pre-eclampsia is a multi system disorder specific to peurperium and pregnancy.It is manifested by onset of hypertension and proteinuria after 20 weeks of gestation and resolves by 12 weeks after postpartum ¹.

Pre-eclampsia has a  strong  association with several fetal complications like low birth weight, fetal growth restriction, spontaneous or iatrogenic preterm delivery, respiratory distress syndrome, admission to NICU. The incidence of hypertensive disorders during pregnancy is between 5-10%^1. Out of all the hypertensive disorders, pre-eclampsia affects 1-5 in 100 pregnant women. 5-8% of all pregnancies are found to be complicated by pre-eclampsia ². While the incidence of pre-eclampsia is 10% in nulliparous , the incidence of nulliparous range from 2-5%. In order to plan appropriate therapy, monitor the management and reduce the complications, pre-eclampsia must be diagnosed early in pregnancy, like any other obstetric emergency. For identifying the high risk pregnant women that may develop pre-eclampsia, accurate prediction models must developed ³.

This allows increased surveillance of those at high risk of disease and more appropriate prophylaxis can be given. Inability to identify the high risk pregnant women results in poor antenatal care and increased mortality and morbidity. With the early identification of these high risk patients, intensive maternal and fetal surveillance can be done which helps in the prevention of major complications such as placental abruption, eclamspia, fetal growth restriction ⁴.

The various risk factors of pre-eclampsia are older age, nullliparity , obesity , diabetes and chronic hypertension , HELLP or pre-eclampsia syndrome in previous Following implanation, trophoblasts differentiate into villous and extravillous trophoblasts. But the trophoblastic invasion is incomplete in pre-eclampsia cases. As a result the blood vessels are half in diameter to that of corresponding vessels in normal placenta. Thus it would probably be informative to assess the blood flow in the uterus, the intervillous space and the placenta ⁵.

But the methods for placental accessibility are invasive and limited. So the uterine artery blood flow velocity measured sonographicallly can be used to determine resistance to uteroplacental blood flow. Not much research has been done on he use of Doppler ultrasonography in predicting pre-eclampsia. Uterine artery doppler waveforms analysis has been extremely studied in the second trimester of pregnancy as a predictive marke rfor the development of pre-eclampsia. The purpose of this study was to ascertain wheter Doppler ultrasonography might be use dto predict pre-eclampsia in women at high risk ⁶.

AIM OF STUDY:

To determine the role of uterine artery Doppler in predicting pre- eclampsia in high-risk pregnant women.

OBJECTIVES OF STUDY:

1. To reduce maternal mortality and morbidity
2. To reduce perinatal mortality and morbidity
3. To stabilise hypertension and to prevent its progression to pre-eclampsia amd eclampsia.

BACK GROUND:

PREECLAMPSIA:

Definition: It is a multisystem disorder of unknown etiology characterized by development of hypertension to the extent of 140/90 mm Hg or more with proteinuria after 20^th week in a previously normotensive and nonproteinuric woman.

Pregnancy-induced hypertension (PIH) is defined as the hypertension that develops as a direct result of the gravida state. It includes gestational hypertension, pre-eclampsia, and eclampsia.

Diagnostic criteria:

Hypertension: 140/90 mmHg

Edema: Pitting edema over ankles after 12 hours of bedrest or weight gain of >1 lb.

Proteinuria: > 0.3 grams of total protein in 24 hours urine.

ETIOPATHOGENESIS:

Risk Factors:

1. Chronic high blood pressure or kidney disease before pregnancy
2. High blood pressure or preeclampsia in an earlier pregnancy
3. Women with overweight or obesity are also more likely to have preeclampsia in more than one pregnancy.
4. Women older than 40 are at higher risk.
5. Multiple gestation (being pregnant with more than one fetus)
6. Family history of preeclampsia

ETIOLOGY

Proposed mechanisms to explain the cause of preeclampsia are many. Important ones are

1. Placental implantation with abnormal trophoblastic invasion of uterine vessels.
2. Immunological maladaptive tolerance between maternal, placental and fetal tissues.
3. Maternal maladaptation to cardiovascular or inflammatory changes of normal pregnancy.
4. Genetic factors including inherited predisposing genes and epigenetic influences.

Abnormal Trophoblastic Invasion

Normal implantation is characterized by extensive remodeling of spiral arterioles within decidua basalis. Endovascular trophoblasts replace the vascular endothelial and muscular linings to enlarge vessel diameter. In cases of preeclampsia, trophoblastic invasion may be incomplete resulting in narrower diameter of vessels. Reduced mean diameter of vessels leads to decreased perfusion and hypoxic environment which gradually leads to release of placental debris. These changes incite a systemic inflammatory response which is stage II of preeclampsia syndrome.

Immunological Factors

Maternal immune tolerance is important to paternally derived placental and fetal antigens in normal pregnancy. Loss of this tolerance is another cited theory for preeclampsia. Histological changes at maternal, placental are suggestive of acute graft rejection. In women destined to be preeclamptic, extravillous trophoblasts early in pregnancy express decreased amounts of immunosuppressive nonclassic human leucocyte antigen G (HLA G). Normal type 2 bias seen in normal pregnancy is reversed in preeclampsia where T-helper 1 action is amplified leading to increased inflammatory cytokine secretion.

Endothelial Cell Activation

Cytokines like tumor necrosis factor-alpha (TNF-alpha) and the interleukins contribute  to the systemic oxidative stress found in association with preeclampsia.

Reactive oxygen species and free radicals are produced and resulting in self-propagating lipid peroxides. These peroxides inturn produce highly toxic radicals that damage systemic vascular endothelial cells, modify nitric oxide production by these cells and disturb the prostaglandins balance.

Genetic Factors

Preeclampsia seems to be a multifactorial, polygenic disorder. Some of the genes responsible are MTHFR, F5 (Leiden), AGT(M235T), HLA, NOS3, F2, ACE, CTLA4, LPL, SERPINE 1, GNA Promoter.

PATHOGENESIS

Vasospasm

Systemic endothelial activation causes vasospasm that elevates resistance to produce subsequent hypertension. Systemic endothelial cell injury promotes interstitial leakage which leads to platelet and fibrinogen deposition sub endothelially. With vasospasm and interstitial leakage, ischaemia of surrounding tissues can result in necrosis, hemorrhage and even other end organ damage which are characteristically seen in syndrome ⁶.

Endothelial cell injury

Systemic endothelial cell injury is now a centerpiece of preeclampsia pathogenesis. Endothelial cell injury leads to secretion of protein factors likely placental into maternal circulation that leads to activation and dysfunction of systemic vascular endothelium. Intact endothelium has anticoagulant properties. Injured and activated endothelial cells produce less nitric oxide, prostacyclin and may secrete substances that promote coagulation and greater sensitivity to vasopressors^[a],[b],[c].The activation , dysfunction and damage of endothelial cells is an important mechanism in pathophysiology of PIH as studied by J.Heimrath⁴ et al in 2007.

Increased pressor responses

Pregnant women normally develop refractoriness to infused vasopressors. Conversely women with pre-eclampsia have enhanced vascular reactivity to infused norepinephrine and angiotensin-2. Compared to normal pregnancy endothelial prostacyclin (PGI2) production is lower in pre-eclampsia. Also thromboxaneA2 production by platelets will be elevated and the prostacyclin: thromboxaneA2 ratio decreases. The net result favors greater sensitivity to infused angiotensin-2 and ultimately vasoconstriction. These changes are seen as early as 22 weeks of gestation. Pre-eclampsia is also related with reduced Nitric oxide synthase expression in endothelium resulting in lower nitric oxide activity (potent vasodilator). Endothelins are potent vasoconstrictors. Endothelin-1 concentration is increased in preeclampsia. Increase in endothelin-1 is mostly proposed due to systemic endothelial cell activation ⁷.

Angiogenic and antiangiogenic proteins

Pro and antiangiogenic substances are involved in placental vascular development among which families of VEGF and angiopoietin are important. Angiogenic imbalance characterized by excessive anti-angiogenic factors is found in preeclampsia. Soluble fms like tyrosine kinase 1 (sFlt-1) is a receptor for VEGF. Elevated maternal sFlt-1 levels inactivate and reduce circulating free placental growth factor (PLGF) and VEGF concentrations leading to endothelial dysfunction. Increased levels of sFlt-1 cause reduction of placental growth factor (PLGF) and vascular endothelial growth factor (VEGF) Soluble endoglin inhibits various Transforming growth factor beta (TGF – beta) isoforms from binding to endothelial receptors. Decreased binding to endoglin diminishes endothelial NO dependent vasodilation ⁸.

PATHOPHYSIOLOGY OF PREGNANCY INDUCED HYPERTENSION

In 1939 Ernest introduced the famous concept that pathophysiology of pregnancy induced hypertension is decreased perfusion of the placenta. According to Oxford Group in 1991 and supported by Roberts there are two stages in the development of pregnancy induced hypertension. First stage is decreased placental perfusion and the second stage is maternal endothelial cell activation. In normal pregnancy cytotrophoblast cells invade the decidua and myometrium. These cytotrophoblast cells replace the endothelium and media of the spiral arteries and as a result low resistance large diameter arterioles are formed. They become resistant to vasopressor agents and the perfusion of the placenta is increased ⁹.

Hyperdynamic circulation is caused by increase in maternal cardiac output. The systemic vascular resistance is altered compared to pregnant women with normal pressures in pre-eclampsia and there is hyperdynamic left ventricular function. Intravascular volume during normal pregnancy is increased instead in PIH there is minimal increase or no increase in intravascular volume. This is due to generalized constriction of the venules ¹⁰.

Signs and symptoms:

Mild preeclampsia: high blood pressure, water retention, and protein in the urine.

Severe preeclampsia: headaches, blurred vision, inability to tolerate bright light, fatigue, nausea/vomiting, urinating small amounts, pain in the upper right abdomen, shortness of breath, and tendency to bruise easily.

Other signs and symptoms of pre-eclampsia include:

• Excess protein in your urine (proteinuria) or additional signs of kidney problems
• Severe headaches
• Changes in vision, including temporary loss of vision, blurred vision or light sensitivity
• Upper abdominal pain, usually under your ribs on the right side
• Nausea or vomiting
• Decreased urine output
• Decreased levels of platelets in your blood (thrombocytopenia)
• Impaired liver function
• Shortness of breath, caused by fluid in your lungs

 .

Complications:

Central nervous system

Eclampsia (seizures)

Cerebral hemorrhage (stroke)

Cerebral oedema

Cortical blindness

Retinal oedema

Retinal blindness

Renal system

• Renal cortical necrosis
• Renal tubular necrosis

Respiratory system

• Pulmonary oedema
• Laryngeal oedema

Liver

• Jaundice
• HELLP syndrome (hemolysis, elevated liver enzymes, and lowered platelets)
• Hepatic rupture

Coagulation system

• Disseminated intravascular coagulation
• Microangiopathic haemolysis

Placenta

• Placental infarction
• Placental abruption

Foetus

• Death
• Preterm birth
• Intrauterine growth restriction

BASIC PRINCIPLES:

Whether it's colour flow or spectral Doppler, ultrasound images of flow are essentially produced by measuring movement. To find blood mobility, ultrasonic scanners send out a sequence of pulses. From one pulse to the next, stationary tissue echoes are identical. The time it takes for a signal to return to the receiver in moving scatterer echoes varies slightly (Figure 2). These variations can typically be expressed in terms of a phase shift, which yields the "Doppler frequency," or as a straight time difference (Figure 3). After that, they undergo processing to create a Doppler sonogram or a colour flow display ¹¹.

Color flow imaging:

Colour harmony A colour-coded map of Doppler shifts placed onto a B-mode ultrasound image is the result of Doppler ultrasonography (Colour Flow Maps). While colour flow imaging also makes use of pulsed wave ultrasound, its processing is not the same as that of a Doppler sonogram. It might be necessary for colour flow imaging to generate thousands of colour flow points for every frame overlay on the B-mode image. Colour flow imaging provides a mean frequency shift and a variance at each small area of measurement by applying fewer, shorter pulses along each colour scan line of the image. The frequency shift is shown as a pixel of colour. The colour image is then superimposed onto the B-mode image after the scanner performs this process multiple times to build it up. Rapid switching between B-mode and colour flow imaging is employed by the transducer elements to provide the illusion of a merged simultaneous image. A proportional loss of axial resolution results from the pulses used for colour flow imaging being three to four times longer than those used for the B-mode image ¹².

Colour is typically assigned to frequency shifts based on magnitude (various colour hues or lighter saturation for higher frequency shifts) and direction (red for Doppler shifts towards the ultrasound beam and blue for changes away from it). A favourable beam/flow angle is one of the general Doppler parameters that affects the colour Doppler image. Depending on how the arteries and veins are orientated, curvilinear and phased array transducers' ultrasonic beams can provide complicated colour flow pictures. In actuality, the skilled operator modifies the scanning strategy to acquire favourable insonation angles and provide clear flow images ¹³.

UMBILICAL ARTERY FLOW

The first foetal vascular to be assessed with Doppler velocimetry was the umbilical artery. The typical sawtooth look of arterial flow in one direction and continuous umbilical venous blood flow in the other is seen in the flow velocity waveforms from the umbilical cord. Doppler evaluation of the umbilical artery using continuous wave is easy. In order to obtain the distinctive waveforms from the umbilical artery and vein, the transducer—typically a pencil-shaped probe—is placed on the mother's abdomen covering the foetus and carefully adjusted. An ultrasound scan is performed initially, a free-floating section of the cord is located, and the Doppler sample volume is put over an artery and a vein using a pulsed wave Doppler device

When a pregnancy has normal umbilical arterial Doppler waveforms, there are no notable daily or diurnal variations. Foetal inspiration causes the foetal abdominal wall to move inside, while expiration causes the wall to move outward, resulting in a decrease in umbilical venous blood flow. Additionally, there is a breathing-related modulation of arterial pulsatility, hence during foetal breathing, umbilical artery Doppler tests should be avoided. While mild to moderate exercise has little effect on the umbilical artery's flow impedance, it may raise the foetal heart rate. Foetal behavioural states (sleep or alertness) have no effect on umbilical arterial flow waveforms. Foetal blood viscosity is elevated in several pregnancy illnesses (pre-eclampsia, for example), yet viscosity has a negligible effect on the increased impedance in the umbilical artery when compared to the underlying placental pathology. Therefore, while interpreting the umbilical Doppler indices, the viscosity of the foetal blood need not be taken into account ¹⁴.

Umbilical artery Doppler waveforms show a progressive increase in end-diastolic velocity and a drop in impedance indices as gestation progresses (Figure 5). End-diastolic frequencies can be detected as early as 10 weeks into a pregnancy when the high-pass filter is either turned off or set to the lowest setting. In a typical pregnancy, end-diastolic frequencies are always present starting at 15 weeks. Studies on human placentas have shown that the fetoplacental vascular system continues to grow during pregnancy. Additionally, as the pregnancy gets closer to term, the villous vascular system changes, causing sinusoidal dilatation to occur in the terminal villous capillaries, and more than 50% of the stromal volume may be vascularised. The different indicators exhibit intra- and interobserver variances of around 5% and 10%, respectively ¹⁵.

This is a Prospective observational study and it was conducted at Department of obstetrics and gynecology, GMH, TIRUPATI

Study Design: A Prospective observational study

Study Period:One Year from the date of ethical committee approval

Study Setting: Department of obstetrics and gynecology, GMH, TIRUPATI which is Affiliated to Dr. YSRUHS

Ethical considerations:

1. Prior approval from the Institutional Ethics Committee has been obtained.
2. All the participants in this study are Voluntarily involved
3. Informed consent took from every participant.
4. Participant confidentiality will be maintained.
5. Participants were not subjected to any potential harm.

Study Subjects: Antenatal women of age group 18-38 years attended Antenatal OPD to Department of Obstetrics and Gynecology.

Inclusion Criteria:

• Teenage primigravida
• Elderly primigravida
• Hypertensive patients
• Obese patients with BMI >35kg/m2
• Diabetic patients
• History of pre - eclampsia or eclampsia in previous pregnancy
• Multifetal gestation
• Prior placental abruption
• Family history
• Patients who are willing to give written informed consent.

Exclusion criteria:

• Patients with congenital anomalies of fetus
• Patients with unreliable LMP details and not confirmed by early ultrasound.

Sample Size:

Formula used for sample size calculation is a study done in Karachi by Nadia Shahid et al. has found that among 75 high risk pregnancies (pre-eclampsia) 54 were found abnormal Doppler (75.0%). Based on this estimate (79%), the sample size was estimated at 95% confidence interval with an alpha error of 0.05 and Beta or of 0.20(with a power of 80%) using the below formula

N = Z α2 PQ/L2

Where N is the required sample size.

By substituting the values, we get,

N= (1.96)2 x 75 x 25/10 X 10 = 3.84 x 75 X 25 /10 X 10= 3.84 X 1875/ 100

7200/100 = 72

Applying a design effect of 1.2 for the sampling method, the required the required sample size is calculated as 72X1.2 = 86.4 (rounded off to 87).

87 patients were included in the study.

Sampling Technique: Simple Random Sampling

Study Tools:

• Complete Blood Count
• Renal Function Tests
• Liver Function tests
• Urine routine
• Antenatal Scan
• Thyroid Function Tests

Operational Definitions:

The selected cases of preeclampsia for study were further subdivided into mild and severe preeclampsia

1. Mild preeclampsia:

• Patient having systolic blood pressure between 140-160 mmHg
• Diastolic bloodpressure between 90-110 mmHg
• Proteinuria upto 1+ (dipstick method).

1. Severe preeclampsia:

• Patient having systolic blood pressure between >160 mmHg,
• Diastolic blood pressure >110 mmHg
• Plus, one or more of the following criteria:

                              Proteinuria >1+,

                              Headache,

                              Visual Disturbance,

                              Upper Abdominal Pain,

                              Oliguria (<400 ml/24 Hours),

                              Serum Creatinine Elevated >1.2 Mg/Dl,

                              Marked Elevation of Serum Transaminase AST or ALT

                              Fetal Growth Restriction and Pulmonary Edema.

All the subjects will undergo necessary blood investigations using venous blood and sample will be processed as soon as possible (Within 1 hr of sample collection) maintaining at room temperature

Procedure of Data Collection:

The patients' informed consent was obtained before their data were gathered. The study included a total of 100 pregnant women based on the inclusion and exclusion criteria. The mothers' complete medical history was recorded, including their age, height, weight, body mass index (BMI), and any prior obstetrical or medial conditions. Using data from an earlier scan or the most recent menstrual cycle, gestational age was determined. Comprehensive systemic and general physical examinations were performed. Comprehensive blood counts, blood grouping, detailed urine reports, random blood sugar (RBS), and two clean captures of midstream urine were obtained on reagent strips more than four hours apart, and those with more than two proteinuria were noted. After 20 weeks of pregnancy, if a woman experienced proteinuria along with hypertension (BP >140/90), she was diagnosed with PE. A Toshiba Nemio 30 colour Doppler (Canon Medical Systems Corporation, Ōtawara, Japan) was the equipment used for the Doppler U/S. With a transducer laced on the left and right lower quadrants of the mother's abdominal wall, the mothers were placed in a semi-recumbent position for the Doppler U/S scan. This allowed for the visualisation of the external iliac artery and the identification of the flow velocity waveforms of the uterine artery. The resistance index (RI) and diastolic notch presence were then determined using them. The risk factors for PE, such as blood pressure, proteinuria, and symptoms, were recorded at every prenatal visit. Recorded data were all on pre-made proformas ¹⁶.

Statistical Analysis:

Patients’ data was collected in predesigned proforma. Data shall be analyzed using SPSS 23.0 was used for the analysis and evaluation of the data, and Microsoft Word and MS Excel have been used to generate graphs, tables, etc. For quantitative data, mean and standard deviation (SD) were calculated for qualitative data percentages calculated. A chi-square test was used for comparing differences between categorical variables. For comparison between the means, Wilcoxson matched test was used, and the students t-test used. For interpretation of results, significance shall be adopted at p-value < 0.05 at a 95% confidence interval.

This is a Prospective observational study and it was conducted at Department of obstetrics and gynecology, SVRRGGH, TIRUPATI for a period of 1 year from January 2023 to December 2023. A total of 87 individuals were included in the study of which 15 were developed pre-eclampsia.

Table 1: Age Category of antenatal women developed pre-eclampsia

Minimum age= 18, Maximum age= 35

Among 15 who developed pre-eclampsia, the majority (33.3%) are under 20 years old, indicating a significant presence of younger individuals in the group. The age ranges of 21-25, 26-30, and over 35 each constitute 13.3% of the sample, showing a balanced distribution among these age groups. Meanwhile, individuals aged 31-35 make up 26.7%, the second-largest group. The mean age of the sample is 26.95 years with a standard deviation of 5.12.

Table 2: Previous obstetric history

The majority, 60%, reported no previous obstetric complications, indicating a generally healthy obstetric history for most of the sample. Among those with complications, 26.7% had a history of pre-eclampsia, which is the most common complication noted. Both bad obstetric history and antepartum hemorrhage were reported by 6.7% of the individuals.

Table 3: Body Mass Index (BMI) distribution

A majority, 53.3%, have a BMI greater than 30, indicating that over half of the sample is classified as obese. Meanwhile, 26.7% of the individuals have a BMI within the 25-30 range, categorizing them as overweight. The remaining 20% have a BMI under 25, falling within the normal weight range. This distribution shows that a significant portion of the sample is dealing with overweight or obesity issues, which could have implications for their overall health and risk of associated conditions.

Table 4: Medical history of the population in the study

Gestational age, weeks (mean ±SD) = 24.78 ± 1.75

Table 5: Family History of the population in the study

The data examines the relationship between family history and the development of pre-eclampsia in a sample of 87 individuals. Among those with a family history of pre-eclampsia (24 individuals), only 1 (4.2%) developed the condition, while 23 (95.8%) did not. Conversely, among those without a family history (63 individuals), 14 (22.2%) developed pre-eclampsia, and 49 (77.8%) did not. Overall, 15 individuals (17.2%) in the sample developed pre-eclampsia, while 72 (82.8%) did not.

Table 6: Doppler flow of the uterine arteries in the study

The data summarizes the outcomes of a study involving 87 individuals. A significant majority, 81.61%, had normal study results, indicating that most participants did not show any abnormalities. In contrast, 18.39% of the participants had abnormal study results.

Table 7: Doppler ultrasound findings

Among the participants, 33.3% had a unilateral resistance index (RI) greater than 0.58, making it the most common finding. Bilateral RI greater than 0.58 was observed in 20.0% of the individuals. Similarly, 20.0% had a unilateral uterine artery notch. Bilateral uterine artery notches were less common, found in 13.3% of the participants. Additionally, 26.7% had both RI greater than 0.58 and a uterine artery notch. This data indicates a diverse range of arterial abnormalities within the group, with unilateral RI >0.58 being the most prevalent finding.

Table 8: comparison of doppler changes and development of preeclampsia

Table 9: Statics

The sensitivity of the test is 80.00%, indicating that it correctly identifies 80% of patients with pre-eclampsia, with a confidence interval (CI) ranging from 51.91% to 95.67%. The specificity is high at 94.44%, meaning that 94.44% of patients without the condition are correctly identified, with a CI of 86.38% to 98.47%. The positive likelihood ratio of 14.40 suggests strong evidence for the diagnosis when the test is positive, while the negative likelihood ratio of 0.21 indicates that a negative test result is helpful in ruling out the disease. The prevalence of the disease in the studied population is 17.24%, with a CI of 9.98% to 26.84%. The positive predictive value is 75.00%, indicating that 75% of positive test results truly reflect the presence of pre-eclampsia, while the negative predictive value is 95.77%, suggesting that a high percentage of negative results are accurate. Overall, the test shows an accuracy of 91.95%, highlighting its reliability in clinical practice.

Hypertensive disorders are the most common medical complications of pregnancy affecting nearly 7 - 15 % of all gestations and account for approximately a quarter of all antenatal admissions. According to WHO , a systemic review on maternal mortality worldwide , hypertension alone remains a leading cause of direct maternal mortality ¹⁸.

Different studies have reported varying frequencies of  pre-eclampsia and related findings on Doppler ultrasound . A study has observed high impedance flow in the  uterine artery in about 40 % of pregnant mothers, who subsequently developed pre-eclampsia. In another study it has been reported that after a positive ultrasound scan on notching or impedance to flow of uterine arteries , the  possibility of developing pre-eclampsia increases by two folds ¹⁹.

Another study has reported a pre-eclampsia frequency of 11.5% in which RI was >0.58 and the mothers were in between 18-24 weeks of gestation. In yet another study , 6 % of mothers were found to have pre-eclampsia in between 20- 24 weeks of gestation and an RI >0.58. However in this study , a much higher rate of 56.25%  was observed in terms of pre-eclampsia . Similar to this study , one research has reported a pre-eclampsia rate of 55% in pregnant women who had uterine artery notch bilaterally at 24 weeks of gestation, which later  increased to 81% at the time of delivery , with all such patients  giving birth prior to 35 weeks of gestation ²⁰.

Since pre eclampsia is regarded as the most common cause of maternal mortality and morbidity, an accurate identification of pre-eclampsia, especially in high risk pregnant women, is important for providing timely intervention , which proves to be crucial in improving maternal and fetal outcomes. So this study is chosen with an aim to determine the role of uterine artery Doppler in predicting pre-eclampsia in high-risk pregnant women ^{21, 22}.

This was a prospective observational study conducted at the Department of Obstetrics and Gynecology of Government Maternity Hospital , Tirupati for a period of one year from the date of ethical committee approval. All the women were initially screened for risk factors for pre-eclampsia such as previous obstetric history of pre-eclampsia, family history of hypertension / diabetes, h/o chronic hypertension. Among them, 87 women with high risk factors were included in the study ^{23, 24}.

 The uterine artery Doppler is performed on those high risk patients to evaluate  the  uterine artery’s flow velocity waveforms. They were then used to calculate the resistance index and the presence of presence of diastolic notch ²⁵.

Once the abnormal dopplers were found, the patients were closely followed up during every antenatal visit for the development of pre- eclampsia. All cases were followed up irrespective of normal Doppler values.In the further antenatal visits the risk factors for pre-eclampsia such as BP, proteinuria and signs and symptoms were noted. Women were labelled to have pre-eclampsia if they developed hypertension (BP >140/90 mmHg) after 20 weeks of gestation in combination with proteinuria ²⁶.

In my study population out of 87 patients studied,<20 years were 10 %,  41% were between 21 – 25 yrs of age,and 31% were between 26 – 30 yrs of age ,4% were 31-35 yrs of age, 3.4 % were > 35 yrs of age ²⁷.

Table 10:  showing various studies related to association of eldery gravida and pre-eclampsia

In this study the common age group is 21-25 years , 41 cases belonging to this age group with incidence of 47 % , >= 35 years is 3.4% which was comparable to the study by Nawsherwan et al ( 2020),  i.e  3.6 % and Mengting Sun (2023) I.e 3.5 % ^{28, 29}.

A study by Nawsherwan et al ( 2020)  concludes that pre-eclampsia  shows an association between advanced maternal age and adverse pregnancy outcomes.Present  study also shows that women aged 30 - 34 years and >=35 years had higher prevalence of pre-eclampsia. Increased maternal age is an independent risk factor for pre-eclampsia. Compared to young women, those with age more than 35 years were found to have greater incidence of pre-eclampsia.For every additional year after 34 years, the risk of pre -eclampsia increases by 30%.  (Ian donald) ^{30, 31}.

Table 11 showing association of Parity and pre-eclampsia

A study done by Fiza Amin et al has established nulliparity as a risk factor for pre eclampsia. In the present study also pre-eclampsia that is developed in cases of abnormal uterine artery Doppler  is more common in primigravida than multigravida. Pre-eclampsia has been believed to be a disease most common in primigravida and it is a disease of present pregnancy. The incidence of pre eclampsia is three times more compared to that in multiparous women. There is also increased risk of pre-eclampsia if the inter pregnancy interval is more than 10 years¹⁸. The risk is reduced in case of a previous abortion or a previous healthy pregnancy.  In present study population maximum women i.e59% are primigravida .Youngest primi being 17 years and eldest primi is 36 years old. 41%are multigravida, youngest multigravidais 21yearsand eldest multigravidais 35yearsold. Incidence of pre- eclampsia in patients with abnormal uterine artery Doppler with family history of pre- eclampsia ³².

Table 12:

In the present study the incidence of pre-eclampsia with a positive family history is 4%.This is comparable to other studies  has concluded that a maternal history of pre-eclampsia is a strong risk factor for pre-eclampsia in Taiwan and the same pattern was also observed in gestational hypertension ³³.

Heather A. Boyd  et al . study has established that a  maternal family history of pre eclampsia was associated with 2.15 times the risk of pre-eclampsia compared with pregnancies in women with no family history..Women whose mothers had pre-eclampsia had 3.38 (95% CI 2.89, 3.96) higher odds than those who did not have pre- eclampsia. Endeshaw M et al study has concluded that Family history of pre-eclampsia is found to be a dominant risk factor for pre-eclampsia in a pregnant women .So the wmen with positive family history should be encouraged to have a health seeking behaviour during pregnancy which would give a chance to diagnose pre-eclampsia as early as possible ³⁴.

9. ⁹. has mentioned that the familial nature of the disease was described as early as 1873 in a case series by Elliot which was included in a review by Chesley in 1968. Elliot reported a patient that died of eclampsia.Her mother had a similar end, and four of her sisters had eclampsia which proved to be fatal in three of them . Women having pre-eclampsia are more likely to have female relatives with similar condition than with those women with normal blood pressure. The genetic risk of pre-eclampsia may be contributed by both the mother and father. Women born of a pre-eclamptic pregnancy inherit susceptibility genes from their mother, and also pass the same genes to their fetuses, which are capable of triggering pre-eclampsia.Therefore , daughters of women who had pre-eclampsia have twice the risk of having pre eclampsia in their own pregnancy ³⁵.

Table 13 - Complications in previous pregnancy

Singh G et al study was a prospective study done over  a period of 3 years which was carried out in 79 pregnancies having bad obstetric history.In this study, 5.3 % was found statistically significant factor for pre-eclampsia.  A study by Bramham K et al , five hundred women with previous pre-eclampsia were followed prospectively. Pre-eclampsia reoccured in 117 women ( 23%). This study confirms that women who had previous history of pre-eclampsia and were delivered early are at high risk of development of pre-eclampsia . This study emphasizes on identification of risk factors for recurrence and illustrates that women wit previous pre-eclampsia are at  greater risk of developing adverse noenatal outcome ³⁶.

A study by Hernández-Díaz S, et al concluded that having pre-eclampsia in one pregnancy is a poor predictor for the subsequent pregnancy but it is a strong predictor for recurrence of pre-eclampsia in the future gestations. The risk of pre-eclampsia was 4.1 % in the first pregnancy and 1.7% in later pregnancies overall. However , the risk was 14.7% in the second pregnancy for women who had pre- eclampsia in the  first pregnancy and 31.9% who had pre-eclampsia in the previous two pregnancies ³⁷.

A case control study by Bhattacharya S, et al has shown in their results that inter pregnancy interval of 6 years or more were associated with increased incidence of pre-eclampsia (19.4%) .  The risk of developing pre-eclampsia is 5 times higher in those with a history of pre-eclampsia.  A previous second trimester pregnancy loss was associated with a 4 times higher risk , compared to a term delivery.The risk of pre-eclampsia was higher with a previous live birth , I.e after adjusting for pre-eclampsia in the first pregnancy than in the women with a previous history of fetal death after 20 weeks.

In the present study, the risk of developing pre-eclampsia with a previous history of pre-eclampsia is found to be 26.7%.This is done by screening out the patients with a history of pre-eclampsia in the previous pregnancy among all the cases attending the antenatal opd and doing a uterine artery Doppler and then following up for development of hypertension or proteinuria. This is similar to various other studies which show that history of pre-eclampsia in the previous pregnancy is a major risk factor for developing pre-eclampsia in the present pregnancy. In the present study there is only one case with a history of abruptio placenta in the previous pregnancy that developed pre-eclampsia accounting for 6 %. A study by Rakshith Nagaraj et al in which  there were total of 14027 deliveries and out of which 63 (0.44%) were  cases of placental abruption that developed PIH.The study concluded that with a  history of abruption coupled with pre-eclampsia , the risk of pre-eclampsia is increased to approximately 16 fold, which was higher than  expected. Hence , from the present study also it can be concluded that there is some association between pre- eclampsia and history of abruption as hypertension is and the pathology of hypertension in pregnancy is common for both the conditions.

In the present study,out of all the 15 cases that developed pre-eclampsia, 20 % of cases have BMI < 25 , 26 % of case have BMI 25-30, 53.3% have a BMI > 30 . Hence from this study it is observed that pre-eclampsia is more common in women with incresed BMI (obese > 30Kg/m²). According to a study by Robert JM et al in 2011 concluded that the prevalence of pre-eclampsia increased with increasing pre pregnancy BMI. According to a study by Abraham et al in 2022, elevated BMI that is observed in over weight and obese women represents a major risk factor for pre- eclampsia. The study confirmed the strong association between obesity and pre eclampsia as obese and over weight women presented higher risk of pre-eclampsia.

.A similar study Dantas EM¹⁶ et al in Brazil was done in 2013. Out of the initial 212 women recruited for the study, 30 suffered pre-eclampsia ( approximately 14 %). On average, these women had higher BMI values than the normal weight, normotensive controls. Dhanusha Nekkanti²⁷ et al, according to this study 27.9 % of cases are over weight, 12.1 % cases were obese. In 39.3 % cases mild pre-eclampsia and 60.7% of cases severe pre-eclampsia was reported and finally this study concluded that pre pregnancy weight gain and gestational weight gain were associated with high risk of pre-eclampsia.

Table - 14  Association of Pre pregnancy BMI and pre-eclampsia

A study by Siddiqui S²⁸ et al (2022)

There were three obese pre-eclampsia patients (23-24.9 BMI) , eight pre-eclampsia patients with pre- pregnancy BMIs of 25 or higher and including three over weight patients. No pre-eclampsia was seen in underweight or normal pre pregnacy BMI patients. This study concluded that there is a positive relationship between pre-eclampsia and a high pre-pregnancy BMI and also it is an independent risk factor for developing pre-eclampsia. With each 5-7Kg/m²  increase in pre pregnancy body mass index (BMI)²⁹ , the risk of pre-eclampsia almost doubles.

Table 15-  Studies related to GDM  and pre-eclampsia‌

A study by Ashok Kumar et al (2023)  out of 2050 of the study population, 316 had GDM were included  in the study , out of which 96 women ( 30.3%) developed pre-eclampsia. This study concluded with the above findings that pregnant women with diabetes is at high risk for pre-eclampsia. A study by Bharadwaj et al in 2016, a prospective observational study was carried out on 1059 pregnant women and among them , 129 were met with the IADPSG criteria and were diagnosed with GDM and rest were included in normoglycemic group . Women with gestational hypertension and pre-eclampsia were included in the pregnancy associated hypertension group Normoglycemic women had lower rate of pregnancy associated hypertension (5.4%) compared to women with GDM( 7.8%). The study concluded that GDM is  associated with a higher incidence of pregnancy associated hypertension. The beta cells are predisposed to dysfunction of beta cells which is unmasked by the progressive insulin resistance of pregnancy and this explains common pathopysiology postulated with both GDM and the hypertension in pregnancy.

In the present study  out of the 15 cases of pre-eclampsia , 4 cases are of GDM  that developed pre-eclampsia accounting for 26%. So the women with GDM  require early diagnosis and intensive monitoring for the development of pregnancy associated hypertension.

So appropriate optimization of the comorbididties and the prenatal counselling is critical for women who are planning pregnancy.So all the screening tests   like DIPSI , BP etc should be done to all the antenatal women attending the OPD and should be educated about the pregnancy complications especially to the high risk pregnant women. The other comorbidities in this study which later developed pre-eclampsia were hypothyroidism and chronic hypertension.

According to an article by Abhinaya M.C ³² et al (2023) in which 380 patients had attended antenatal OPD and emergency labour room of Assam medical college and hospital , Dibrugarh .Among them patients with pre-eclampsia and eclampsia were selected for the study . Based on their clinical findings, laboratory tests and other relevant history they were further evaluated for any other associated comorbidities. The results of this study in which , the eventful maternal (44.1%) and fetal (50.92%) outcome was found to be more in eclampsia and pre-eclampsia patients with comorbidities than those in the patients without any comorbodities which is statistically significant.

In the present study , out of the 15 cases that developed pre-eclampsia, 9 cases are belonging to lower socioeconomic status (60%) and 6 cases are belonging to upper socioeconomic status (40%). Hence it can be said that the development of pre-eclampsia is more common in lower socioeconomic group than the upper socioeconomic group.  Similar studies by Padhan SC³³ et al in which a total of 2879 participants were included but there was no strong evidence of association between individual level socioeconomic factors and the neonatal or pregnancy outcomes in high income settings. Another study Siama Ejaz³⁴ et al which was a case control of 74 normal pregnant and 76 of already diagnosed pre-eclamptic women. Their socioeconomic status was assessed through the standard of living index( SLI). Based on their groups , it appeared that the large percentage of pre-eclamptic females are belonging to the lower socioeconomic group (43.3%) and thus concluded living facilities are indications of socio economic status and they are strong risk factors of pre-eclampsia.

In the present study , abnormal uterine artery doppler indices( RI > 0.58 ,  persistent uterine artery notching) are used for screening in the high risk pregnant women i.e teenage primigravida, elderly primigravida, hypertensive patients, obese patients with high BMI , diabetic patients, history of pre eclampsia or eclampsia in previous pregnancy , multifetal gestation, prior placental abruption, family history. The cases are folowed up for development of any adverse pregnancy outcome such as devlopment of hypertension, pre-eclampsia .

In the study conducted by Rekha NA³⁵ et al   , in which an institutional study was conducted among 100 pregnant women. The uterine atrtery doppler was done in early second trimester during the antenatal visits. Along with the doppler BP was recorded , urine analysis , complete blood work is done in every antenatal visit and were followed up till their delivery .The authors analyzed the data and considered it significant . They reported that pre-eclampsia was developed in 31.25% of the pregnant women with bilateral uterine artery notching at 13-16 weeks of gestational age . The study is found to be having a sensitivity of 71.4% and specificity of 74.41% , positive predictive value of 31.25% and negative predictive value of 94.11% in the prediction of pre-eclampsia in  pregnant women. The study is concluded by saying that the uterine artery Doppler should be made a routine test to all the pregnant women as risk factors can be identified at an early stage and timely intervention can be done to reduce the maternal and noenatal complications. According to a study Sun M³⁶ et al which is a prospective cohort study of 100 singleton pregnancies. The uterine artery Doppler was done on the study population at 18-22 weeks of gestation and the Doppler indices of pulsatility index( PI) , resistance index (RI) and persistence of diastolic notch were taken as cut off and the outcome of pre-eclampsia was studied . 14 women developed pre-eclampsia out of 100 women in which the resistance index showed a sensitivity of 21.4% , specificity of 91.8 % .Diastolic notch had a sensitivity of 35.7% , specificity of 98.8%.

The study concluded that as the uterine artery Doppler being non-invasive can be included during the routine sonography to identify patients who are at the risk of developing pre-eclampsia. According to a study by Adekanmi²⁷ et al which is a longitudinal cohort study that had uterine artery and umbilical artery Doppler sonography at 22-24 weeks and 32-34 weeks gestation followed up by documentation of their delivery outcomes. Among the 98 high risk pregnant women 62.2% developed pre-eclampsia and 32.8% developed pre-eclampsia. The combination of umbilical and uterine artery Doppler was able to predict 80.3% of severe pre-eclampsia. The uterine artery PI is the best predictor of Pre-eclampsia among the high risk pregnant women in NIgeria.

According a study by Barati³⁷ et al in which 379 pregnant women without any risk factors randomly underwent the uterine artery Doppler between 16-22 weeks of gestation .Those who had a mean pulsatility index of > 1.45 were considered to be having an abnormal result and then followed up for development   of pre-eclampsia or fetal growth restriction. There were 17 cases of abnormal uterine artery Doppler results and 15 of them (88.2%)  develped pre-eclampsia . For this prediction , the mean uterine artery PI had to be > 1.45 and had to have a sensitivity of 79% and a specificity of 95.5%. This study concluded that the uterine artery Doppler evaluation at 16-22 weeeks of gestation is an appropriate tool in the identification of pregnancies that may be at an increased risk for development of pre-eclampsia and small for gestational age ³⁶.

This study is similar to the present study with a sensitivity of 80% and specificity of 94.4%.

Other parameters such as family history, previous obstetric history, medical history were also investigated   in my study population. These parameters are considered in my study populations reference to the following study - Plasencia et al,³⁸examined how well maternal factors such body mass index, age, ethnic origin, smoking, medical and obstetric history, and uterine artery PI in the first trimester were used to screen for PE. They came to the conclusion that in unaffected people, fetal crown-rump length, body mass index, maternal ethnic origin, and prior history of PE all had an impact on log MoM PI. Body mass index, ethnic origin, log MoM PI, and prior and family history of PE all made substantial contributions to the prediction of PE. The anticipated detection rate of PE necessitating delivery before 34 weeks was 82% for a false-positive rate of 10%, they noted. This was in contrast to 31% for late PE, 12% for gestational hypertension, and 18% for small for gestational age ³⁷.

The test's sensitivity in our study is 80.00%, meaning that 80% of patients with pre-eclampsia are accurately identified, with a confidence interval (CI) that spans from 51.91% to 95.67%. With a confidence interval (CI) of 86.38% to 98.47%, the specificity is excellent at 94.44%, indicating that 94.44% of patients without the condition are properly recognized. When a test is positive, the positive likelihood ratio of 14.40 indicates strong evidence for the diagnosis, and when the test is negative, the negative likelihood ratio of 0.21 indicates that the disease can be ruled out.

Conde - Aguelo et al, for the benefit of WHO evaluated the predictive value of biophysical, biochemical, and clinical testing for preeclampsia. The authors came to the conclusion that neither a high-risk nor a low-risk population could benefit from a clinically meaningful screening test to anticipate the onset of preeclampsia. While the pre-test probability increased minimally when the results were positive, they did note that among women at low-risk of developing this disorder, bilateral diastolic notching at Doppler ultrasonography, anticardiolipin antibodies, and urine kallikrein have a moderate predictive accuracy. Regarding the studies that evaluated the Doppler ultrasonography accuracy, 42 of them—or 42,261 cases—met the reviewers' requirements. .

The test was often performed in the second trimester of pregnancy. Based on the definition of the abnormal uterine artery flow velocimetry waveform, studies were categorized into four groups: There were four types of flow waveform ratios that were used: (1) those that used resistance index, pulsatility index, systolic/diastolic ratio, and diastolic/systolic ratio; (2) those that used the presence or absence of any diastolic notch; (3) those that used bilateral diastolic notches; and (4) those that combined the use of diastolic notches and flow waveform ratios. Only studies that employed a resistance index higher than 0.58, higher than the 90–95th percentile, or the presence of bilateral or any diastolic notches to signify abnormal test results were eligible for meta-analyses.

Regardless of the criterion, the overall degree of prediction of preeclampsia was mild to moderate in both high-risk and low-risk populations.  Papageorgiou⁴⁰ et al, contacted a second reviewer regarding the results of 15 Doppler studies on second trimester screening in an unselected sample including 20,000 women in all. The likelihood ratio (LR) for the later development of preeclampsia in women with greater resistance to flow was 6 in the pooled data from all investigations, while the likelihood ratio was approximately 0.5 in those with normal Doppler. The fact that uterine artery Doppler is more accurate in predicting severe disease than mild disease was a key finding of both reviews.

Steel et al,⁴¹ in their study show that the sensitivity of increased impedance in the uterine arteries was 39% for gestational hypertension and 63% for pre-eclampsia. Papageorgiou et al, According to the study's findings, pre-eclampsia with fetal growth restriction (FGR) had a sensitivity of 69%, while pre-eclampsia without FGR had a sensitivity of 24%. The gestational age at which delivery is attempted is an additional indicator of illness severity that has been observed in certain studies. According to research by Harrington et al., bilateral notching at 24 weeks indicated 55% of women who would go on to develop pre-eclampsia; this number increased to 81% in cases of pre-eclampsia that required delivery before 34 weeks.

Similarly, Albaiges et al demonstrated that the sensitivity for predicting preeclampsia based on elevated PI or bilateral notches in the second trimester was 45%, whereas the sensitivity for preeclampsia necessitating delivery before 34 weeks was 90%.demonstrated that the sensitivity for predicting preeclampsia based on elevated PI or bilateral notches in the second trimester was 45%, whereas the sensitivity for preeclampsia necessitating delivery before 34 weeks was 90%.

Finally Papageorgiou et al, demonstrated that the corresponding sensitivity rates for pre-eclampsia necessitating delivery before 36, 34, and 32 weeks were 70%, 81%, and 90%.

Hafner et al, discovered that the uterine artery Doppler in the second trimester and the value of the 3D placental volume in the first trimester had comparable sensitivity for the prediction of preeclampsia and fetal growth limitation. More recently, Toal et al, investigated the value of a placental profile in the second trimester (including placental morphology, uterine artery Doppler, and maternal blood screening) in high-risk pregnancies and discovered that a normal profile considerably lowered the odds ratio for a poor perinatal outcome.¹⁸ Certain risk factors related to the mother's past may also increase the uterine artery Doppler's sensitivity.

It was found that the patient's specific risk of developing preeclampsia could be estimated by combining uterine artery Doppler with risk factors from the mother's past, including race, smoking habit, essential hypertension, prior preeclampsia, family history, body mass index, and parity.Yu et al.'s study of 32,157 pregnant women who were not chosen for further testing revealed that the Doppler reading of the uterine arteries in the second trimester combined with risk variables such ethnicity, history of pre-eclampsia, previous term birth, and smoking habit ³⁸.

Hypertensive disorders in pregnancy are a major cause of maternal and perinatal morbidity and mortality, especially in developing countries. Early identification of high-risk women is essential for timely intervention and prevention of complications. In this study conducted at GMH Tirupati from January to December 2023, 87 high-risk antenatal women were screened using uterine artery Doppler. Among 16 women with abnormal Doppler findings, 12 developed pre-eclampsia, while 3 cases occurred despite normal Doppler results, giving a sensitivity of 80%. Uterine artery Doppler parameters such as RI > 0.58 and persistent notching showed good predictive value. As a non-invasive tool, uterine artery Doppler effectively assesses uteroplacental hemodynamics and helps in early prediction of pre-eclampsia when used alongside clinical features. Its use in tertiary care settings can improve maternal and neonatal outcomes, though further research is recommended.

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