Role of low molecular weight of heparin in preventing severe preeclampsia

INTRODUCTION

Preeclampsia is life threating multisystem vascular disorder with prevalence ranges from 5 to 8 % of pregnancies. It is the most common reason of perinatal and maternal morbidity and mortality affecting 8.5 million pregnancies worldwide, accounting for over 70 000 maternal deaths and 500 000 infant deaths annually. ¹

According to studies the complement system has major role in the preeclampsia pathogenesis, as complement system over activation or deficient regulation increase circulating anaphylatoxins and deposition of complement factors in the placenta leads to dysfunction of placental. HELLP syndrome (increased liver enzymes, hemolysis, and low platelets), placental abruption, severe renal failure, and pulmonary edema are all consequences of preeclampsia that can lead to eclampsia .²

Heparins are the drug of choice in pregnant women because it doesn't pass through the placenta and has a favorable maternal safety profile with a low risk of

major bleeding, unfractionated heparin (UFH) and lowmolecular-weight heparin (LMWH) are major types of heparin. By binding anti thrombin, all heparins function as antithrombotic factors, preventing active coagulation factors from causing blood clotting (factors IIa, VIIa-TF, IXa, Xa, and XIa). In pregnant women, LMWH is the preferable. ³

LMWH is safe in pregnant women without maternal or fetal side effects or major bleeding episodes.⁴

LMWH's potential to prevent preeclampsia is unclear at this time. There is evidence to support the use of low-molecular-weight heparin (LMWH) as a maternal vasodilator and endothelial enhancer, as well as an anti-compartment effect (C5a).⁵

Low-molecular-weight heparin has been shown in earlier trials to lower the incidence of venous thromboembolism and placenta-mediated pregnancy problems in pregnant women with thrombophilia who are at high risk of difficulties.

The study's goal is to determine the function and effectiveness of low molecular weight heparin in avoiding severe preeclampsia.

PATIENTS AND METHODS

This study was a randomized interventional study carried out at El Hussein University Hospital and Sidi Salem central Hospital from November 2020 to November 2021 for 100 female patients with mild pre-eclampsia

Sample size: This study was based on McLaughlin et al study, .'s ⁶ Epi Info STATCALC was used to determine the sample size based on the following assumptions: - A power of 80percent and a two-sided confidence level of 95%. The computed odds ratio is 1.115, with a 5percent margin of error. From the Epi- Info output, the ultimate maximum sample size was 96. To account for any drop-out instances during follow-up, the sample size was expanded to 100 cases.

Inclusion Criteria for study group: Pregnant patients ≥ 21 years old, more than 28 weeks gestation up to 36 weeks gestation (as documented by ultrasound) with mild pre-eclampsia.                                                                                                   

Exclusion Criteria for groups: Patient less than 21 years old or greater than 40 years old, patients with severe pre-eclampsia, allergy to heparins, history of gastrointestinal or genitourinary bleeding and thrombocytopenia related to heparin use.

Methods: cases were exposed to:

Complete history was taking: Personal history like: name, age, marital state, address, menstrual history especially last menstrual period, present history: of chronic diseases and medication, past history of HTN, DM, family history of similar condition or diabetes, history of allergy to any medication and surgical history of operation, laparoscopic interference.

Examination:

General examination: Monitoring of the body's vital signs (blood pressure, temperature, heart rate, respiratory rate), Signs of (Pallor, Cyanosis, Jaundice, and Lymph node enlargement) and weight, Height, BMI and lower limb edema.

Abdominal and local clinical examination: Abdominal inspection: For detection of: Scars, abdominal distension, caput medusa, striae (stretch marks), abnormal masses indicating hernia according to the location and ecchymosis indicating internal hemorrhage. Abdominal palpation: Light palpation of the abdomen: For detection of: Tenderness, rebound tenderness and guarding. Deep palpation of the abdomen for detection of deeper masses. Abdominal percussion: Percussion was used to assess the size of the liver by applying percussion downward from the lung to the liver, and then the bowel. Abdominal auscultation

Vulvar Examination: Fundamental examinations of the vulvar area include the assessment of basic development, symmetry, and hair quality and growth distribution, as well as the detection of skin abnormalities, swelling, ulcerations, and the presence of growths such as external genital warts (EGW). Vaginal Examination: The urethral aperture, the Skene glands, any discharge, soreness, or erythema, as well as any eversion or prolapse of the meatus, are all checked during the urethral examination. Bimanual Examination:   was to define the size and nature of the uterus and the presence or absence of adnexal masses.

Laboratory study: Complete blood picture (CBC): hemoglobin concentration (Hb %), red blood cells (RBCs), white blood cells (WBCs), platelet count. Renal function test:  serum creatinine, blood urea and urine analysis.Liver Test Profile: Serum aspirtate and alanene amino transferases (AST and ALT), serum albumen, serum biliruben, serum gamma-glutamyl transferase (GGT), (SGOT), (SGPT), prothrombin time and international normalized ratio (INR). Protein in urine, uric acid and 24h albumin in urine.

Ultrasound: To exclude cases of oligohydramnios and any other abnormalities and to assess gestational age, Doppler studies and biophysical profile.

Procedure: All 100 patients were undergone expectant management of mild preeclampsia which include: Bed rest, anti HTN drugs and fluid or not

Patients were divided into 2 groups: Study group: 50 cases received low molecular Weight heparin clexane 40mg once a day (Manufactured by Sanofi India Ltd) in addition to usual regimen. Control group: 50 cases received usual regimen.

Antenatal follow up:

Maternal: Daily follow up: Blood pressure: Temperature: We used mercury thermometer under septic condition to obtain temperature. Pulse: Assess pulse rate, rhythm, volume, equality. Detection the degree of Lower limb edema. Detection of fits and chest pulmonary edema

Weekly follow up:  complete blood count: Hb, hematocrit: increased, RBCs count, MCV, MCH, MCHC : microcytic hemolytic anemia and platelets: thrombocytopenia in severe cases. Renal function test:  serum creatinine, blood urea and urine analysis.Liver Test Profile, Protein in urine, uric acid and 24h albumin in urine and body mass index

Fundus examination: by palpation at the midpoint between the umbilicus and the pubic symphysis for detection of the fundal height which correlate to the gestation age. Weekly observation and documentation of Weight gain. Ultrasound and Doppler ultrasound: to assess fetal gross and fetal wellbeing. Observation of development of fits. Asking for symptoms of severe preeclampsia: Headache, nausea, epigastric pain and blurred vision

Outcome: 1ry outcome: Period of treatment, severity of pre-eclampsia, and number of patients proceeded to severe preeclampsia and termination of pregnancy. 2ry outcome: Apgar score, entering ICU and mortality and morbidity of the mother

Ethical Consideration: Study protocol had been submitted for approval by Institutional Review Board, Al-Azhar University. Informed verbal consent had been obtained from each participant sharing in the study.

Statistical Analysis: Using IBM SPSS software package version 20.0, we examined the collected data. (IBM Corp., Armonk, New York,) (2) Numbers and percentages were used to describe qualitative data. Kolmogorov-Smirnov tests were employed to determine whether or not the distribution of data was normal. We used range (lowest and highest values), mean, and standard deviation for describing our quantitative data. The significance of the findings was evaluated at a 5% level of significance. Tests performed included: Chi-square test: For categorical data, comparing two groups is done using the Chi-square test. In the case of typically quantifiable variables, the student t-test may be used to compare the results of two groups under investigation. Analyzing unusually quantifiable characteristics in order to compare two study groups

RESULTS

U: Mann-Whitney test

t: T-Student test

p: p-value for comparisons between the two groups investigated

*: Statistically important at P <0.05

Table 1: Comparison among two groups as regard to patient’s demographic data

According to the demographic characteristics of the patients, Table 1 revealed no statistically important change among groups.

U: Mann-Whitney test

t: T-Student test

p: p-value for comparisons among the two groups investigated

*: Statistically important at P <0.05

Table 2: Comparison among two groups as regard to patient’s laboratory investigations at start of study

Table (2) showed no statistically significant differences between groups according to patient’s laboratory investigations.

p: p-value for comparisons among the two groups investigated

*: Statistically important at P <0.05

Table 3: Comparison between two groups as regard to patient’s Outcome

Table (3) showed statistically significant differences between groups according to patients with severe preeclampsia.

p: p-value for comparisons among the two groups investigated

*: Statistically important at P <0.05

Table 4: Comparison between two groups as regard to patient’s Clinical improvement

Table (4) showed statistically significant differences between groups according to patients clinical improvement with more improvement in group (A) when it compare to group (B).

p: p-value for comparisons among the two groups investigated

*: Statistically important at P <0.05

Table 5: Comparison between two groups as regard to patient’s APGAR score

Table (5) showed statistically significant differences between groups according to patients APGAR score with more improvement in group (A) when it compare to group (B).

p: p-value for comparisons among the two groups investigated

*: Statistically important at P <0.05

Table 6: Comparison between two groups as regard to patient’s NICU admission

Table (6) showed statistically significant differences between groups according to patients NICU admission with more improvement in group (A) when it compares to group (B).

Fig. 1: Comparing two groups in terms of patient blood pressure

Figure (1) show statistically significant differences between groups according to patients blood pressure after treatment was stable in group (A) while in group (B) had to be worth when it compare to group (A).(Table (6); Figure (1))