A holistic evaluation of risks associated with the use of progestogen-based hormonal contraceptive among reproductive age women in Ilorin: Hematological and biochemical perspectives

 Corresponding author: Ibrahim Eleha Suleiman Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. A holistic evaluation of risks associated with the use of progestogen-based hormonal contraceptive among reproductive age women in Ilorin: Hematological and biochemical perspectives Kikelomo Olayemi Oyeleke 1, Fatimah Bolanle Salaudeen 2, Borisade Motolani Susan 1, Lateefat Remilekun Abdulsalam-Mudi 3, Ben-Anefo Toochukwu Charity 1 and Ibrahim Eleha Suleiman 4, 5, * 1 Department of Medical laboratory science, Ladoke Akintola University of Technology, Ogbomosho, Oyo State, Nigeria. 2 Department of Laboratory Services, Civil Services Hospital, Ilorin, Kwara State, Nigeria. 3 Department of Hematology and Blood group serology, University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria 4Department of Chemical Pathology, Ladoke Akintola University of Technology, Ogbomosho. Oyo State, Nigeria 5 Department of Chemical Pathology and Immunology, University of Ilorin Teaching Hospital, Ilorin, Kwara State, Nigeria. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 175-189 Publication history: Received on 11 January 2025; revised on 24 February 2025; accepted on 27 February 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.21.3.0219 Abstract Background: Despite the effectiveness of hormonal contraceptives (HCs) in birth control, many women remain hesitant to adopt it, while some are abandoning it due to concerns about potential side effects. These fears are often driven by conflicting reports in the existing literatures regarding the risks associated with their use, particularly concerning longterm health impacts on critical organs and systems. In view of this background, this study evaluated likely progestogenbased hormonal contraceptives (PHCs) associated risk among the inhabitants of Ilorin metropolis. Methods: A total of 325 participants comprises of 220 PHC users and 105 non-users were recruited for the study, their socio-demographic were obtained using questionnaire. Comprehensive hematology and coagulatory parameters as well as various organ’s specific biomarkers and anthropometric data were evaluated among the two groups using standard methods and procedures. Quantitative and qualitative variables were expressed in mean ± SD and percentage respectively. Student’ test and descriptive analysis was used for the comparisons. Logistic regression was used to assess the independent effect of PHCs on coagulation factor alteration, controlling for potential confounders. SPSS version 26.1 was used for the statistical analysis, and p<0.05 was considered statistically significant. Result: The outcome revealed higher frequency of abnormalities in both the rate and the duration of menstrual blood flow in PHC users than non-users. The result also showed that mean RBC count was significantly higher among PHCs users (p=0,010), while both aPTT and Protein-S were significantly reduced in the PHC users than that of non-users (p = 0.002) and (p = 0.004) respectively. Conclusion: This finding concludes that both short and long-term usages of PHC is not associated with anemia, inflammation, renal, and cardiac. However, it’s resulted in mild thrombotic and hepatic injury. Keywords: Contraception; Progestogen; Hormonal contraceptives; Progestogen-based HC 1. Introduction Hormonal contraceptives (HCs) are widely used by women of reproductive age as a reliable method of family planning and birth control [1]. Despite their effectiveness, many women remain hesitant to adopt HCs due to concerns about World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 175-189 176 potential side effects [2]. These fears are often driven by conflicting reports in the existing literatures regarding the risks associated with their use, particularly concerning long-term health impacts on critical organs and systems. For instance, in respect to the level of red blood cell counts (RBC) among HCs users, elevated level was reported by [3]. On the contrary, both [4] and [5] reported lower RBC counts among HCs users. To compound the issue, [6] observed insignificant differences between the users and non-users. Aside from hematological abnormality, other common concerns among potential users include risks of renal, cardiac, hepatic injuries, as well as the possibility of inflammatory and thrombotic events. Progestogen-based contraceptives (PHCs), as name imply consist of only progesterone analogue as the active ingredient, and exist in various forms [7]. Virtually all synthetic progesterone analogues, such as levonorgestrel and norethindrone, are synthesized from testosterone [8]. Factors that determine effectiveness of progestin-only contraceptives are; dosage, potency, and half-life of the progestin. More so, user-dependent factors, such as compliance to the prescription schedule can as well influences the efficiency of PHCs [9]. Based on their duration of action, PHCs can be categorized into short acting, intermediate acting, and long acting formulations. In respect to the concentration of progestogen, PHCs can be grouped into low dose, intermediate dose and high dose [10]. The low dose PHCs inconsistently inhibit ovulation in about 50% of cycles [11]. The intermediate dose allow some follicular development but much more consistently inhibit ovulation in roughly 97–99% of cycles [7]. While, high dose PHCs completely hinder follicular development and ovulation [12]. In addition to the above mechanism of the action, the three forms shared the ability to thicken the cervical mucus, thus reducing sperm viability and penetration [13]. This study provides a holistic evaluation of the likely associated risks with progestogen use among reproductive-age women in Ilorin. We conducted a comparative analysis of renal, cardiac, hepatic, inflammatory, anemic, and thrombotic risks between different forms of progestrogen users and non-users to provide a clearer understanding of the health implications of PHCs. By addressing these specific areas of concern, we aim to contribute to the ongoing debate surrounding HC safety and offer evidence-based guidance for women and healthcare professionals in the region. 2. Material and methods 2.1. Study area and design A comparative cross-sectional study was conducted in Ilorin metropolis at four family planning clinics under Kwara State government. Ilorin is located on longitude 8.5373oN and latitude 4.5444o E, in north-central, Nigeria. The family planning clinic delivers services such as antenatal care, post-natal care, and contraceptive services. This study was conducted between March to September, 2024 2.2. Data collection Questionnaire and direct interview was used to gather socio-demographic data such as age, gender, marital status, family type, history and duration of contraceptive usage. Anthropometric data were as well measured, while laboratory investigation also obtained for further analysis. Laboratory tests included hematological parameters, clotting profile, fibrinolytic profile, and their ratios, as well as renal, cardiac and hepatic related biomarkers. 2.3. Inclusion/ exclusion criteria Every female from age 15 to 40 years with positive history of any form of PHCs (injectable, Implant, or vaginal rings) for at least six months prior to March, 2024. For the control group, women between the ages 15 to 40 years who visited the family planning clinic and have never taken any contraceptive in the last one year. Individual with pre-existing coagulation disorders or other major medical conditions affecting hemostasis were excluded from the study. Those below 15 or above 40 years of age, those who were unwilling to provide informed consent for study participation, lactating and pregnant women, individuals with history of chronic illnesses like diabetes mellitus, hypertension, kidney disease, cardiac disease, human immunodeficiency virus (HIV), hepatitis, or critically ill were as well excluded. 2.4. Operational definition Hormonal contraceptive: woman using any form of progestogen (a progesterone analogue), in any of the form listed below; • 2-months-injectible: any participant using an intramuscular or subcutaneous injectable contraceptive at 2 month interval for at least six months, it contains 150mg/ml of levonorgesrel and norethindrone. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 175-189 177 • 3-months-injectible: any participant using an intramuscular or subcutaneous injectable contraceptive at 3 month interval for at least six months, it contains 150mg/ml of levonorgesrel and norethindrone. • Implant: any participant having plastic rod impregnated with 68 mg of levonorgesrel and norethindrone placed under the skin of her upper arm for at least six months. • Vaginal ring: any participant having non-biodegradable material impregnated with levonorgesrel and norethindrone habitually inserted inside her vagina. • Non-user: any participants who did not use any form of PHCs in the last one year. 2.5. Statistical analysis Statistical analysis was carried out using the IBM SPSS version 20 for window software (SPSS Inc. Chicago, IL USA). Descriptive analysis, and Student’s test was used for the comparisons of data. Quantitative variables are presented as mean ± SEM and qualitative variables as percent. P-values < 0.05 were considered significant. Logistic regression was used to assess the independent effects of PHCs use on hematological and clotting profile alterations, controlling for potential confounding factors. 3. Results 3.1. Socio-demographic data As shown in Table 1, a total of 220 reproductive-age women who were attending family planning clinics under the Kwara State government hospitals from March to September, 2024 were included in the study. Based on the form of HC adopted, more than half of the participant were 3-months injectable users (54%), implant users (30.5%), 2-months injectable users (10.5%) and vaginal ring users (5%). The mean age of the subjects was (28.0 ± 9.26) years. Of the participants, 196 (89.1%) were married and 129 (58.6%) were artisans and merchants. Regarding their educational status, 87 (36.3%) were attended college and above. 3.2. Comparison of the duration in days of menstrual flow between PHCs users and non-users Figure 1 show the percentages of irregularities in the number of menstrual days. 37.7% and 12.4% were recorded in users and non-users respectively. Those who experienced reduced number of days were 33.6% and 9.5% respectively in the users and non-users. While 22.3% reported prolonged days of flow in the users, the incident was 7.6% among non-users. Notably, 70.5% of non-users had were predictable and regular number of days, whereas only 6.4% of PHC users reported such. 3.3. Comparison of the rate of menstrual flow between PHCs users and non-users Figure 2 show the percentages of those with irregular menstrual blood flow. 29.1% was recorded in PHC users against 10.5% in non-users. While 21.4% reported normal volume of blood flow in PHC users, the percentage was 56.2% in non-users. The percentages of those who reported reduced and larger volume/blood flow among the PHC users were 41.4% and 8.2% respectively. Whereas, their percentages in non-users were19% and 14% respectively. 3.4. Comparison of hematology and coagulatory parameters between PHCs users and non-users Table 2 shows the comparative analysis of hematology and coagulatory parameters between PHC users and non-users control. While significant elevation was observed in the mean level of RBC count, reduction were observed in concentration of Protein-S, with reduced aPTT duration in HCs users in relation to non-users. However, no significant differences were observed in the level of the remaining parameters between the two groups. 3.5. Comparison of biochemical parameters between PHCs users and non-users Table 3 shows the comparison of concentration of biochemical analytes between PHC users and non-users control. While ALT activity was higher in PHC users, LDL was reduced, though, no significant differences were observed in the level of the entire parameters between the two groups. 3.6. Logistic regression analysis The mean ± SD value for the D-dimer to platelet ratio (DPR) was higher in PHCs users with reduced aPTT time than those with normal aPTT (34.2±37.6) vs. (16.2±25.5). In the univariate analyses, the duration of PHC’s uses, D-dimer, platelet count, Protein-S and PT values showed statistically significant associations with hypo-coagulable state. After adjusting for these variables, only protein-S showed an association with reduced aPTT. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 175-189 178 Table 1 Demographic characteristics and drug history of studied participants Characteristics PHCs users None-PHCs users Number (Percentages) 220 (100%) 105 (100%) Mean age (years) 28.0 ± 9.26 29.1 ± 8.69 Age range (years) 15 – 25 38 (17.3) 34 (32.4) 26 – 40 182 (82.7) 71 (67.6) BMI (kg/m2) Normal 183 (83.2) 82 (78.1) Overweigh 37 (16.8) 23 (21.9) Marital status Married 196 (89.1) 94 (89.5) Single 24 (10.9) 11 (10.5) Duration of HCs usage < 1 year 77 (35) NA 1 – 5 years 81 (36.8) NA 5 -10 years 62 (28.2) NA Forms of HCs adopted Implant 67 (30.5) NA Vaginal ring 11 (5.0) NA 2-months-Inj 23 (10.5) NA 3-months-Inj 119 (54.0) NA Occupation Student 17 (7.7) 8 (7.6) Civil servant 56 (25.5) 30 (28.6) Artisan/ merchant 129 (58.6) 53 (50.5) House wife 18 (8.2) 14 (13.3) Values are presented as mean ± standard deviation or number (%), HCs = hormonal contraceptives, BMI = body mass index, NA = not applicable. Figure 1 Bar chart comparing the rate of flow of menstrual blood between PHC’s users and non-users in Ilorin World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 175-189 179 Figure 2 Bar chart comparing the period of flow of menstrual blood between PHC’s users and non-users in Ilorin Table 2 Comparison of hematological and coagulatory parameters between hormonal contraceptives users and nonusers control Parameters PHCs users Non-PHCs users P-value WBC counts (x 109/L) 5.14 ± 1.44 5.52 ± 1.62 0.386 Lymphocytes (%) 48.7 ± 9.05 47.8 ± 7.59 0.664 Granulocytes (%) 41.3 ± 9.85 41.8 ± 8.34 0.830 MID (%) 9.99 ± 3.16 10.41 ± 2.78 0.556 RBC counts (x 1012/L) 4.30 ± 0.41 3.98 ± 0.43 0.010* Hemoglobin (g/dL) 12.3 ± 1.09 11.9 ± 0.94 0.144 Hematocrit (%) 36.98 ± 3.44 34.98 ± 3.64 0.169 MCV (fL) 86.2 ± 6.64 88.3 ± 7.49 0.276 MCH (Pg) 24.29 ± 2.23 25.12 ± 2.33 0.190 MHCH (g/dL) 28.17 ± 1.06 28.44 ± 0.97 0.314 RDW-CV 15.25 ± 1.15 14.93 ± 0.83 0.209 RDW-SD 44.80 ± 3.23 45.14 ± 3.19 0.609 Platelet counts (x 109/L) 226.13 ± 55.49 207.11 ± 98.07 0.269 MPV (fL) 7.76 ± 0.89 9.79 ± 0.76 0.097 PDW (%) 11.38 ± 1.83 11.77 ± 1.73 0.387 PCT (%) 0.22 ± 0.49 0.22 ± 0.81 0.962 World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 175-189 180 P-LCR (%) 25.37 ± 6.56 25.62 ± 5.89 0.876 PLCC 55.53 ± 14.04 54.44 ± 16.34 0.800 Fibrinogen (g/L) 2.64 ± 1.33 2.74 ± 1.96 0.747 D-Dimer (g/dL) 491.09 ± 373.1 438.68 ± 376.1 0.094 Protein S (fL) 18.77 ± 2.57 24.33 ± 1.56 0.002* Prothrombin Time (sec) 12.79 ± 4.31 14.94 ± 2.11 0.256 aPTT (sec) 25.18 ± 3.75 33.83 ± 8.78 0.004* The values are mean ± standard deviation, Student t-test was used to compare the means at p = 0.005, RDW = red cell distribution width, MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, MCV = mean corpuscular volume, MPV = mean platelet volume, P-LCR = platelet-large cell ratio, PCT = plateletcrit, aPTT = activated partial thromboplastin time. Table 3 Evaluation of other risks between HCs users and non-HCs users Characteristics PHCs users Non-PHCs users p-value WHR 0.95 ± 0.25 0.97 ± 0.90 0.268 BMI (Kg/m2) 23.20 ± 2.75 22.01 ± 4.37 0.165 Total cholesterol (mmol/L) 3.40 ± 0.47 4.55 ± 0.78 0.262 Triglyceride (mmol/L) 1.03 ± 0.15 1.10 ± 0.14 0.659 LDL (mmol/L) 2.13 ± 0.25 3.65 ± 0.64 0.059 TC/HDL 4.43 ± 0.19 7.43 ± 2.49 0.052 Troponin I (ng/mL) 0.21 ± 0.04 0.19 ± 0.07 0.974 sNGAL (ng/mL) 89.7 ± 11.4 91.1 ± 18.6 0.659 Creatinine (µmol/L) 63.67 ± 8.57 64.5 ± 3.87 0.891 Urea (mmol/L) 3.04 ± 1.43 4.25 ± 0.19 0.662 eGFR (mL/min/1.73) 125.67 ± 16.3 128.00 ± 7.1 0.841 UCR 0.032 ± 0.01 0.035 ± 0.09 0.823 Phosphate (mmol/L) 0.91 ± 0.43 1.03 ± 0.34 0.783 Albumin (g/L) 42.00 ± 3.64 41.54 ± 2.12 0.832 ALT (IU/mL) 9.6 ± 5.21 5.3 ± 1.39 0.117 hsCRP (µg/L) 3.06 ± 1.64 3.16 ± 0.38 0.962 CAR 0.07 ± 0.04 0.07 ± 0.03 0.951 DFR 124.39 ± 28.5 158.86 ± 32.7 0.605 DPR 0.90 ± 0.38 1.09 ± 0.65 0.007* PLR 4.85 ± 1.68 4.96 ± 2.35 0.104 GLR 0.92 ± 0.40 0.93 ± 0.35 0.513 The values are mean ± standard deviation, Student t-test was used to compare the means and p = 0.005, BMI = Body mass index, WHP = Waist to hip ratio, sNGAL = serum neutrophil gelatinase-associated lipocalin, UCR = Urea to Creatinine ratio, ALT = Alanine aminotransferase, HsCRP = high sensitive C-reactive protein, CAR = HsCRP to Albumin ratio, DFR = D-dimer to fibrinogen ratio, DPR = D-dimer to platelet ratio, PLR = Platelet to lymphocytes ratio, GLR = Granulocytes to lymphocytes ratio. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 175-189 181 Table 4 Odd ratios for aPTT abnormality according to as DPR a continuous variable Univariate Multivariate OR 95% CI P-value OR 95% CI P-value Age (year) 0.964 0.945 – 1.023 0.523 - - -- BMI (Kg/m2) 0.552 0.233 – 1.306 0.176 - - -- HCs form 0.562 0.243 – 1.307 0.187 - - -- Duration 0.364 0.144 – 0.921 0.033* 0.564 0.386 – 1.106 0.109 D-dimer 0.388 0.274 – 0.748 0.001* - - -- Fibrinogen 1.477 0.587 – 3.768 0.452 - - -- Protein-S 3.873 2.648 -7.310 0.009* 2.538 1.873 – 5.834 0.042* PT (sec) 0.864 0.787 – 0.949 0.009* 0.972 0.866 – 1.091 0.630 PLT 0.332 0.142 – 0.864 0.004* - - -- Hemoglobin 0.894 0.865 – 1.123 0.904 - - -- RBC count 0.897 0.795 – 1.087 0.867 - - -- DFR 1.365 0.786 – 2.654 0.254 - - -- D = Duration of PHCs uses, PT = Prothrombin time, PLT = Platelet, DFR = D-dimer to fibrinogen ratio, DPR = D-dimer to platelet ratio, PLR = Platelet to lymphocytes ratio, 4. Discussion Ilorin, a rapidly growing city in Nigeria, mirrors global patterns of HC use, with many women avoiding or discontinuing these contraceptives due to perceived health risks. Though, considerable number of the inhabitants’ practices one form of the natural method contraceptive or the other [2]. The lack of consensus in the scientific community on the magnitude and nature of these risks further compounds the uncertainty, leaving women and healthcare providers alike uncertain about the safety of prolonged HC use [13]. Our preliminary finding among the inhabitants of Ilorin revealed majority of non-users exhibits exaggerated fear against HCs generally. We aimed to identify association between PHCs uses and different health risks. This is the First population-based study to evaluate comprehensive hematological and biochemical parameters in this part of world. A total of 220 reproductive age women using various forms of PHCs were recruited, along with 105 age-matched nonuser control (Table 1). Comprehensive hematological and biochemical parameters were analyzed as an inexpensive and easily accessible tools for PHCs safety evaluation. Multiple biomarkers can improve sensitivity and specificity of diagnostic test [14]. Both multiple and single parameters was adopted in the evaluation of the following risks; obesity, anemia, thromboembolism, systemic inflammation, cardiovascular injury, renal injury and hepatic function among others. A quota consecutive method was adopted, given the large sample size requirements and strict exclusion criteria. Though a non-probability method, but allows easier sample selection and is advantageous when dealing with large sample sizes, as it enables working with multiple samples at lower relative cost and time compared to probability sampling methods [15]. 4.1. The evaluation common menstrual abnormality The current study evaluated menstrual irregularities such as variations in the number of days of blood flow, and the rate of flow among PHC users in relation to non-users. As presented in Figure 1, irregularities in the number of menstrual days were significantly higher among PHC users than non-users. Specifically, 37.7% of PHC users reported unpredictable number of their days since they started using contraceptives, compared to 12.4% reported among non-users. The figure also revealed that 33.6% and 22.3% reported reduced and prolonged number of menstrual days respectively among the PHC users. Whereas, the corresponding percentages among non-users were 9.5% and 7.9%. Notably, 70.5% of non-users reported predictable and regular World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 175-189 182 number of days, whereas only 6.4% of PHC’s users reported normal duration of flowing PHC use. These findings align with previous studies by [16] and [17]. Figure 2 revealed patterns of responses from the participants in relation to the rate of their menstrual flow in the last six months and from the inception of PHC uses. 21.4% reported having a normal flow among PHC users, in contrast the percentage was 56.2% in non-users. The percentages of those with light, heavy and inconsistent rate of flow were 41.4%, 8.2% and 29.1% respectively among the users. The corresponding percentages in non-users were 19%, 14.3% and 10.5% respectively. The higher incidence of reduced blood flow among PHC users, as observed in this study, may be considered a positive outcome. Because anemia is a common consequence of prolonged and heavy bleeding, with significant adverse effects on health and economic well-being [18]. Overall, these findings indicate that PHC use may influence menstrual patterns, highlighting the need for further investigation into the implications of these changes on women's health. On the other hand, our data also revealed that apart from PHC, other unidentified factors might responsible menstrual irregularities as data from non-PHC user’s shows. More so, rather than generalizing it that it increases menstrual bleeding, the extent or percentage is more appropriate. 4.2. Obesity and metabolic disorder assessment Both BMI and WHR were used for the evaluation of obesity and metabolic risk in our study. BMI is one of the widely used parameter for classifying individuals based on weight relative to height [19]. On the other hand, the WHR is an indicator of fat distribution, with higher ratios often associated with central (or visceral) obesity, which carries a greater risk for metabolic diseases [20]. As revealed in table 2, the absence of significant differences in BMI and WHR in this study supports the notion that PHC use does not necessarily lead to weight gain or obesity. Many studies have shown similar findings; [21] conducted a systematic review and found that most users of modern HCs do not experience significant weight gain, particularly those using combined oral contraceptives (COCs). Also, [22] showed that WHR remains stable among PHC users, particularly for those on low-dose PHCs, which have been shown to have minimal effect on abdominal fat distribution. Moreover, [23] concluded that initial increases in weight for some HC users are often temporary or are within the range of natural weight fluctuations. Thus, this finding are reassuring, suggesting that PHC use does not contribute to central obesity or lead to weight gain in a way that would increase metabolic risk. 4.3. Anemia risk Anemia was defined as HBG level <11g/dl for both males and females based on the WHO cutoff value. Reduced level of hemoglobin is associated with reduced oxygen-carrying capacity [24]. On the other hand, hematocrit, is one the vital parameters for evaluating anemia, and it is the proportion of blood volume occupied by RBCs [25]. Three hematological parameters were reviewed between the PHC’s users and non-users, namely hematocrit, hemoglobin level and RBC count. A moderately higher but insignificant level of HBG and hematocrit were recorded in PHC users in relation to non-users (Table, 2). The lack of significant differences in both parameters further supports the finding that not all HC uses lead to an increased risk of anemia [26]. This could be attributed to lighten of menstrual bleeding, which helps conserve iron and prevents anemia. In fact, some studies have found that COCs, may even help to stabilize or increase Hb levels due to reduced menstrual blood loss [27, 28]. The RBC count is another important marker of anemia, with low counts indicating potential deficiencies in RBC production or increased its loss [29]. The significant elevation in RBC counts observed in PHC’s users in this study (p = 0.010), suggest that PHC does not compromise RBC production, it rather enhances erythropoiesis or inhibit the rate of hemolysis. This aligns with findings by [26], which showed that COC users had stable or slightly higher RBC counts compared to non-users. These effects could be attributed to the influence estrogen, which may prevent excessive blood loss and help maintain stable RBC levels [28]. 4.4. Thromboembolic risk assessment There was no homogeneity in the pattern of thrombotic parameters evaluated in this study. While there were no significant differences in the values of parameters such as; fibrinogen, D-dimer, DFR, PLR and PT between the PHC users and non-users, the differences in aPTT, Protein-S and DPR were significant (Table 2 and 3). The unchanged fibrinogen, D-dimer, DFR, PLR and PT values align with previous findings such by [29], suggesting coagulatory biomarkers often shown variable responses to HCs depending on the specific type and dosage of hormones used. In fact, D-dimer levels is more directly influenced by active clot formation and breakdown and may not necessarily increase with HC use [30]. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(03), 175-189 183 The stability in these parameters could indicate that, for many women, modern PHCs may not cause substantial changes in baseline coagulation markers that are typically associated with thromboembolic risk. These finding revealed that all coagulation markers are not equally affected by PHC use. Nonetheless, the observed significant decrease in aPTT (p = 0.004), Protein S (p = 0.02), and DPR (p = 0.007) in PHC users is noteworthy and indicates potential changes in the coagulation pathway that could predispose PHC users to thromboembolic events. A shortened aPTT suggests a faster intrinsic pathway coagulation, which could indicate a hyper-coagulable state [31]. Also, reduced levels of Protein S, an anticoagulant protein, are particularly significant because it plays a crucial role in inhibiting clot formation by enhancing the anticoagulant effects of Protein C [32]. A range of studies supports the notion that HCs, especially those containing estrogen, can influence coagulation markers such as Protein S and aPTT, thereby contributing to an increased risk of thromboembolism [33, 34, 35]. The DPR is a valuable predictor of pulmonary embolism, which enhance the specificity of D-dimer and improve its accuracy [36]. The significant lower DPR in PHC’s users reflects the imbalance between clot formation and platelet activity that favors thrombosis. While studies evaluating DPR in HC users are limited. It has been confirmed that altered protein-S and aPTT potentiate thrombotic risk, particularly in women with additional risk factors [37]. 4.5. Assessment of systemic inflammation Inflammation is an integrated immune response and a key defensive apparatus against the disturbance of homeostasis in infectious and injurious conditions [38]. Studies have shown that inflammation plays an important role in several disease conditions such as atherosclerosis, acute kidney injury and cardiovascular disease among others [39]. The parameters adopted for evaluating systemic inflammation in this study are; hsCRP, Albumin, CAR, NLR and fibrinogen; [40]. NLR reflects the balance between neutrophils and lymphocytes and is commonly used as a biomarker for cardiovascular and inflammatory conditions [41]. The CAR is a highly specific marker of low-grade inflammation and is often elevated in cases of cardiovascular risk or systemic inflammation [42]. As revealed in Table 3 and 4, there were absence of significant differences in the entire above mentioned parameters between the HC users and non-users. Our finding on NLR was aligned with [43], while report on Albumin was in consonant with that of [44]. There is paucity of information on impact of HC uses on CAR in the available literatures. Though, finding by [45] NL, noted that certain COC may mildly elevate hsCRP levels. Nonetheless these changes are often small and not necessarily indicative of a clinically significant inflammatory response. These findings suggest that PHCs, especially modern low-dose formulations, do not trigger inflammatory responses sufficient to alter the plasma level of those parameters. This stability may be due to advancements in PHC formulations, which now often include lower doses of estrogen, known to reduce the risk of systemic inflammatory effects [46]. Fibrinogen also serves as an inflammatory biomarker that increase in response to inflammation or tissue damage [47]. In this study, fibrinogen levels were similar between PHC users and non-users, which aligns with findings of [48]. Thus, suggesting that PHC use alone may not elevate inflammatory biomarkers or promote systemic inflammation without underline cardiovascular risk factors. 4.6. Cardiovascular injury and diseases assessment Cardiovascular disease (CVD) is one the major global health challenge and the leading cause of death worldwide [49]. In order to evaluate cardiovascular risk in our study, lipid profile and anthropometric data were compared between the HC users and non-users. Lipid profile offers supplementary insights in evaluating the risk of CVD, and epidemiology study has revealed association between the profile and CVD and death [50]. Our observation of lack of significant differences in BMI, WHR, TG, and TC between HC users and non-users aligns with that of [51] and suggesting that PHCs do not consistently influence these parameters substantially. Though, [52] reported that some estrogen-progestin containing HC may slightly elevate TG due to the estrogen component; though, this effect is generally mild and varies by HC formulation and individual response [13]. Furthermore, the same author observed a modest improvement in both highand low-density lipoproteins (HDL and LDL) levels respectively. Interestingly, we observed moderately lower LDL and TC/HDL ratio values among HC users in this study. The finding is in line with that of [53] and [54] that HC may lead to an increase in HDL, while keeping LDL relatively stable, depending on the dosage and specific formulation, thus mitigating the risk factors associated with lipid profiles. An elevation in LDL level and TC/HDL ratio are strongly associated with risk of atherosclerosis and CVD due to their role in promoting plaque formation in the arteries [55]. The TC/HDL ratio is particularly predictive of CV outcomes, as it reflects the balance between atherogenic and protective lipoproteins [56]. For the BMI and WHR, previous research has indicated that HC use does not necessarily result in weight gain or increased BMI [57], as commonly perceived; any changes tend to be minimal or vary depending on the individual and the specific type of contraceptive used.