Preeclampsia is a multi-system syndrome of pregnancy characterised by hypertension and is a significant cause of maternal and perinatal morbidity and mortality globally, and usually occurs after 20 weeks of gestation. It is defined as the sudden onset of hypertension that is accompanied by proteinuria and/or signs of dysfunction of maternal organs. Clinically, hypertension can be mild or severe, and can result in neurological, renal, hepatic, hematological, and cardiopulmonary complications. The pathophysiology is related to abnormal placental growth, inadequate uteroplacental flow, oxidative stress, activation of inflammation and generalized endothelial dysfunction in the mother. These changes can affect the flow of blood to and from the mother, and can lead to fetal growth restriction, preterm labor, placental abruption, and other issues in the mother's pregnancy. Timely diagnosis and intervention are thus critical for proper surveillance, early intervention and prevention of potentially life-threatening complications, as well as early recognition of disease progression (1-3).

Biochemical markers are becoming the focus of attention as an additional tool for the evaluation of the severity and progression of preeclampsia. Serum uric acid is involved in purine metabolism and renal excretory functions and is related to oxidative stress, and lactate dehydrogenase (LDH) is an intracellular enzyme, which is released into blood after cellular injury. Elevated levels of these markers could be indicative of metabolic disturbance, tissue damage, and maternal organ involvement. The mechanisms for hyperuricemia in preeclampsia include decreased renal clearance, increased placental oxidative stress, and metabolic changes. Elevated LDH levels can also be a sign of cell damage due to endothelial injury, hepatic dysfunction and hemolysis. They are relatively easily obtained and are not costly, but their diagnostic and prognostic value may be different on the basis of gestational age, severity of disease and co-occurring maternal conditions. Therefore, they could be used together with the clinical and laboratory markers to get a fuller picture of the disease status of the mother (4-6).

Another significant mechanism in preeclampsia development and progression is angiogenic imbalance. Soluble fms-like tyrosine kinase-1 (sFlt-1) is an antiangiogenic protein that binds to vascular endothelial growth factor and placental growth factor (PlGF) to prevent their roles in normal vascular and endothelial function. High levels of sFlt-1 and low levels of PlGF are linked with endothelial dysfunction, an increase in vascular resistance and poor placental blood flow. As a result the sFlt-1/ PlGF ratio has become a potential tool to measure the level of placental dysfunction and to aid in the diagnosis of suspected preeclampsia. Angiogenic biomarkers could also serve as a source of additional information about the risk of progression of disease and adverse pregnancy outcome, especially when disease is present at a preterm stage. However their interpretation differs depending on gestational age, analytical methods and clinical presentation and should not be used instead of established diagnostic criteria or thorough assessment of the mother (7, 8)

Management of preeclampsia requires careful evaluation of maternal and fetal conditions, effective control of severe hypertension, prevention of eclamptic seizures, and appropriate timing of delivery. Magnesium sulphate is widely used for seizure prophylaxis in women with preeclampsia with severe features and for treatment of eclampsia. Despite its established anticonvulsant effectiveness, maternal complications may occur because of progressive disease, delayed presentation, or underlying organ dysfunction. Biochemical and angiogenic markers may help characterize the severity of maternal illness, although their ability to predict seizure-related outcomes following magnesium sulphate administration remains insufficiently established. The combined evaluation of conventional biochemical markers and angiogenic parameters may therefore provide additional information for clinical risk assessment. However, uncertainty remains regarding their relative associations with severe preeclampsia and treatment-related outcomes, particularly in hospital-based clinical populations. The present study was therefore conducted to determine the association of serum uric acid, LDH, sFlt-1, PlGF, and the sFlt-1/PlGF ratio with preeclampsia severity and clinical outcomes following magnesium sulphate treatment among pregnant women attending the Department of Gynecology and Obstetrics, Liaqat Memorial Hospital / KMU-Institute of Medical Sciences, Kohat (9, 10).

Study Design and Setting

This hospital-based analytical observational study was conducted in the Department of Gynecology and Obstetrics, Liaqat Memorial Hospital / KMU-Institute of Medical Sciences, Kohat, over six months, from January 2025 to June 2025. The study aimed to determine the association of serum uric acid, lactate dehydrogenase (LDH), and angiogenic biomarkers, including soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), with the clinical severity of preeclampsia. The relationship between baseline biomarker concentrations and clinical outcomes following magnesium sulphate administration was also evaluated. An observational approach was selected to examine biochemical changes in relation to maternal disease severity and treatment-associated outcomes without altering standard obstetric management.

Sample Size and Sampling Technique

There were 78 women with preeclampsia and pregnancy in this study. The patients who were eligible and came to the Department of Gynecology and Obstetrics during the study period were selected by non-probability consecutive sampling technique. Recruitment continued until the sample size was obtained. Patients were classified as having preeclampsia without severe features and preeclampsia with severe features based on accepted clinical criteria for diagnosis.

Inclusion and Exclusion Criteria

The eligible population consisted of pregnant women (18-45 years of age) who had been diagnosed with preeclampsia from gestational age of 20 weeks and above. Preeclampsia was classified as new-onset hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) after 20 weeks of gestation and with presence of a proteinuria of ≥0.3 g/g or maternal organ dysfunction. In order to permit the comparison of the biochemical and angiogenic parameters according to disease severity, women with non-severe and severe clinical presentations were included. Patients who had previously diagnosed chronic renal disease, chronic hepatic disease, and/or active systemic infection, medical conditions known to cause significant changes in uric acid or LDH levels, or pre-existing chronic hypertension were excluded. Women who did not have all the biochemical tests or biomarker measurements for the angiogenic markers were also not included in the respective analysis. These criteria were designed to identify conditions of minimal possible confounding that relate to preeclampsia.

Clinical Assessment and Classification of Preeclampsia

All the registered women who gave birth were clinically evaluated and documented maternal age, BMI, gravidity, parity, gestational age, previous clinical history and any risk factors were noted. Blood pressure, clinical symptoms, urinary protein and laboratory investigation were noted. Severity of preeclampsia was determined by obstetric criteria. The criteria for preeclampsia with severe features were: women with a systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg, thrombocytopenia, severe renal impairment, hepatic dysfunction, pulmonary edema, persistent severe headache, or visual disturbances. Preeclampsia with no of the above would be considered preeclampsia without severe features. No attempts were made to classify severity according to concentration of such serum markers as uric acid, LDH and/or markers of angiogenesis.

Biochemical and Angiogenic Biomarker Assessment

Serum uric acid, LDH, sFlt-1 and PlGF levels were measured in maternal blood sampled at the initial assessment. For analyses of associations with subsequent treatment-related outcomes, baseline measures were preferred prior to administration of magnesium sulphate. The uric acid levels in the serum were expressed in mg/dL and the LDH activity was expressed in U/L. The markers were evaluated as markers of metabolic disturbance and cellular injury associated with preeclampsia. Both serum sFlt-1 and PlGF levels were quantified as pg/mL and the ratio of sFlt-1/PlGF was calculated by dividing the level of sFlt-1 by the level of PlGF. Other laboratory tests performed were complete blood count, platelet count, serum creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and urinary protein status. Concentrations of biochemical and angiogenic markers were compared between the two severity groups to verify if there were any differences in the concentrations of these markers depending on the clinical presentation of the mother.

Magnesium Sulphate Administration and Assessment of Treatment Outcomes

The treatment of magnesium sulphate was decided according to the patient's condition and institutional management practice by the obstetric doctors. Treatment was mainly recommended for seizure prophylaxis in women with severe preeclampsia and eclamptic seizures (if present). Treatment records were used to document the regimen, loading dose, maintenance dose, duration of treatment and interruption or discontinuation of treatment. Patients receiving magnesium sulphate were closely followed for clinical seizure activity and any adverse effects from the treatment. Parameters monitored were respiratory rate, deep tendon reflexes, urinary output, and overall neurological status. The presence of eclamptic seizures after treatment was started, subsequent seizures, need for another anti-epileptic drug, suspected magnesium toxicity, and stopping the treatment because of side effects were documented. The outcomes were assessed based in the occurrence of seizures and safety parameters, since the main function of magnesium sulphate is the anticonvulsant protection. The blood levels of these biochemical and angiogenic biomarkers were correlated with the outcome of seizures when the number of events observed allows for meaningful statistical analysis. The treatment allocation was not randomized and the associations were assessed after taking into account the differences in the baseline disease status.

Assessment of Maternal and Neonatal Outcomes

Maternal outcomes were assessed during the hospital stay, and included eclampsia, HELLP syndrome, acute kidney injury, placental abruption, pulmonary edema, intensive care unit admission and maternal mortality. Obstetric outcomes evaluated included gestational age at delivery, mode of delivery and preterm birth. Neonatal outcomes included birth weight, fetal growth restriction, five minute APGAR score, admission to neonatal intensive care unit (NICU) and perinatal mortality. These outcomes were analysed by preeclampsia severity and looked for any associations with the baseline concentrations of biochemical and angiogenic biomarkers.

Data Collection Procedure

Data were collected on a data collection proforma and included clinical and laboratory information. Demographic data, obstetric history, presenting symptoms, blood pressure readings, laboratory investigations, concentrations of angiogenic biomarkers, and information on the treatment with magnesium sulphate during the hospital stay and on maternal and neonatal outcomes were obtained from patient assessments and hospital records. Study identification codes were given to each participant to ensure confidentiality. Data from the analytical dataset that identified patients were removed. Records were checked for completeness and consistency prior to the analysis of data. To minimize inconsistencies in classification and measurement, the same operational definitions were used throughout the study.

Statistical Analysis

IBM SPSS Statistics version 26 was used for analysis of data. The data were summarised as mean ± SD values for variables that were approximately normally distributed, and median and interquartile range values for variables that were skewed. Categorical variables were reported as numbers and percentages. The distribution of continuous variables was assessed by the Shapiro–Wilk test and graphically. The independent-samples t-test was used for normally distributed continuous variables between the women with and without severe features, and the Mann–Whitney U test was used for non-normally distributed continuous variables. The chi-square test or Fisher's exact test was used to compare categorical variables if applicable. Pearson or Spearman correlation coefficients were used to analyze the correlation between serum uric acid, LDH, sFlt-1, PlGF and continuous clinical parameters, depending on the data distribution. Based on receiver operating characteristic (ROC) curve analysis, the discriminatory performance of each of these biomarkers and the sFlt-1/PlGF ratio was to be evaluated for the diagnosis of preeclampsia with severe features. Where estimable, areas under the curve (AUCs) and 95% confidence intervals were reported. To determine independent association of selected biomarkers with the presence of severe features, multivariable logistic regression was considered. Due to the limited number of events in the outcome, the number of predictors was limited and stability of the model was considered. The associations with post-treatment seizures were examined descriptively or by appropriate inferential analysis based on the frequency of their occurrence. A p value of < 0.05 (two-sided) was regarded as statistically significant.

Out of 78 women, of these, 32 (41.0%) women developed preeclampsia without severe features and 46 (59.0%) had severe features. The average age of mothers was 28.8 years old ± 5.3 years and the average age of gestation was around 34 weeks at diagnosis. There were a significant number of primigravida women in the study. Of those with severe features, women had a higher prevalence of maternal organ dysfunction and negative pregnancy outcomes.

Table 1. Demographic and Obstetric Characteristics of Women with Preeclampsia (n = 78)

Women with severe features had increased SBP, DBP, impaired renal function, elevated hepatic enzymes and decreased platelet counts than women without severe features. The greatest clinical differences were seen in blood pressure and markers of organ dysfunction in the mother.

Table 2. Clinical and Laboratory Characteristics According to Severity of Preeclampsia

Substantial increase in biochemical evaluation of serum uric acid and lactate dehydrogenase was found in the severe-feature group. Angiogenic imbalance was also more evident with increased sFlt-1 levels, decreased PlGF levels, and increased sFlt-1/PlGF ratio. These data support the predicted association between endothelial dysfunction and placental angiogenic imbalance and the severity of maternal disease.

Table 3. Comparison of Serum Uric Acid, LDH, and Angiogenic Biomarkers According to Severity of Preeclampsia

Magnesium sulphate was administered to 46 women with severe features in this cohort. Most completed the prescribed regimen without major adverse effects. Although seizures after treatment initiation were uncommon, their absence in most patients cannot by itself establish treatment efficacy or individual response.

Table 4. Magnesium Sulphate Treatment and Clinical Outcomes (n = 78)

Women with severe features were at higher risk of adverse maternal and neonatal outcomes. Maternal complications were HELLP, acute kidney injury and intensive care unit admission. Likewise, the severe-feature group had a higher rate of preterm delivery, fetal growth restriction, and admission to the neonatal intensive care unit.

Table 5. Maternal and Neonatal Outcomes According to Preeclampsia Severity

Figure 1. Comparison of Serum Uric Acid, Lactate Dehydrogenase (LDH), sFlt-1, PlGF, and sFlt-1/PlGF Ratio According to Preeclampsia Severity.

Preeclampsia remains an important cause of maternal and perinatal morbidity because of its complex pathophysiology, unpredictable clinical progression, and involvement of multiple organ systems. The condition is characterized by abnormal placentation, systemic endothelial dysfunction, inflammatory activation, and disturbances in maternal vascular regulation. These pathological mechanisms contribute to hypertension, renal impairment, hepatic dysfunction, and hematological abnormalities, particularly in women presenting with severe features. Serum uric acid and lactate dehydrogenase (LDH) have considerable clinical relevance because they reflect different aspects of the underlying disease process. Elevated serum uric acid may result from impaired renal excretion, altered purine metabolism, and oxidative stress, whereas increased LDH activity indicates cellular injury and tissue damage. Higher concentrations of these biochemical markers may therefore accompany more advanced disease and greater maternal organ involvement. However, neither marker is sufficiently specific to establish preeclampsia severity independently, and their interpretation should remain integrated with maternal symptoms, blood pressure measurements, renal function, hepatic enzymes, and platelet counts (11-13).

Angiogenic imbalance is a significant biological pathway involved in placental dysfunction and preeclampsia. Soluble fms-like tyrosine kinase-1 (sFlt-1) functions as an antiangiogenic factor that decreases the biological activity of both vascular endothelial growth factor and placental growth factor (PlGF), thus inhibiting normal endothelial function. Having a higher concentration of sFlt-1 in the blood and a lower level of PlGF leads to a higher sFlt-1/PlGF ratio, which could be indicative of placental dysfunction and a higher risk of developing complications in the mother.

The assessment of these biomarkers offers information on disease mechanisms which can't be fully captured using conventional measures of BP or proteinuria. Their joint assessment could help to enhance clinical risk stratification in cases of uncertain clinical presentation or in cases where progression to severe disease is suspected. However, factors such as gestational age, assay characteristics, and other pregnancy-related factors affect levels of angiogenic biomarkers. Thus, these investigations should be used in addition to, rather than in lieu of, the currently accepted clinical and laboratory markers to determine the severity of preeclampsia (14-16).

Because of its known anticonvulsant properties, magnesium sulphate is a key part of the treatment of preeclampsia with severe features and eclampsia. It is used primarily for the prevention and treatment of eclamptic seizures, but not for directly lowering hypertension or the underlying placental disease. The effectiveness of magnesium sulphate treatment can be influenced by a variety of factors such as the severity of the mother's illness, when treatment is started, renal function, the magnesium sulphate administration protocol and monitoring.

Close monitoring of respiratory rate, deep tendon reflexes, urine output and neurological function are important to detect signs of toxicity and ensure safe administration. While traditional biochemical and angiogenic markers may be used to determine the severity of preeclampsia, their independent predictive value of seizures after magnesium sulfate treatment is not clear. In addition, women with more advanced biochemical abnormalities may have higher inherent clinical risk, which can make it hard to separate disease-related complications from variance in the responses to treatment. Hence, biomarker testing should be seen as a possible part of a wider maternal risk assessment and not as an alternative to the current guidelines for magnesium sulphate treatment and monitoring (17, 18).

The clinical value of combining biochemical and angiogenic markers goes beyond disease classification of the mother to the ability to recognize pregnancies with a higher risk of poor maternal and fetal outcomes. Endothelial dysfunction and defective placental perfusion can lead to foetal growth restriction, preterm delivery, abruption of the placenta, dysfunction of maternal organs and an increased need for neonatal intensive care. The uric acid-LDH-sFlt-1-PlGF-sFlt1/PlGF ratio could provide a more comprehensive picture of maternal and placental involvement than any other single biomarker. This would help the clinicians to recognise high risk pregnancies that may need more monitoring and intervention by a specialist, as well as plan a particular delivery.

Gestational age, maternal coexisting diseases, analytical variability, and clinical status, however, all need to be taken into consideration when evaluating biomarkers. Observational investigations conducted in a hospital setting may also be small in size and subject to selection bias, residual confounding, and a lack of numbers of rare maternal complications. Further multicenter prospective trials extending biomarker assessments over time, with standardized magnesium sulphate protocols and with sufficient maternal and neonatal outcome data are necessary to elucidate the added clinical information obtained from these markers and to define their role in individual clinical management (19, 20).

Serum uric acid, LDH, sFlt-1, PlGF, and the sFlt-1/PlGF ratio represent potentially useful biochemical indicators for assessing the severity of preeclampsia. Elevated uric acid and LDH concentrations may reflect maternal organ dysfunction, while increased sFlt-1 and reduced PlGF levels indicate an underlying angiogenic imbalance associated with placental disease.

Combined biomarker assessment may improve clinical risk stratification and support the early identification of women requiring intensive maternal and fetal surveillance. Magnesium sulphate remains essential for preventing and treating eclamptic seizures, although the value of these biomarkers in predicting individual treatment-related outcomes requires further investigation. Integration of biomarker testing with established clinical assessment may support more comprehensive management of preeclampsia and contribute to improved maternal and neonatal care.

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