Preeclampsia is a multisystem disorder of pregnancy that presents with new-onset hypertension after 20 weeks of gestation and proteinuria, or any other sign of maternal organ dysfunction.[1] It is still one of the most significant reasons for maternal and perinatal morbidity and mortality globally.[2] The pathogenesis remains not fully understood and complex, but abnormal placentation, impaired uteroplacental perfusion, endothelial dysfunction, inflammation, and alterations in the balance between angiogenic and antiangiogenic pathways are thought to be key mechanisms.[3] Preeclampsia occurs in around 2-8% of pregnancies worldwide, and the disease disproportionately affects low- and middle-income countries, where late diagnosis and less access to specialist obstetric services can lead to greater maternal and fetal morbidity.[4]

High blood pressure is only one of the clinical complications of preeclampsia. Severe disease can include eclampsia,[5] It is important to note that the hypertensive disorders of pregnancy, such as preeclampsia, continue to be one of the most common causes of maternal mortality worldwide.[6] This risk is especially high in women who have had a previous high-risk condition, including pregestational diabetes, chronic hypertension, renal disease, autoimmune disease, previous preeclampsia, and multifetal pregnancy.[7]

Low-dose aspirin is now a proven prevention strategy in women with a risk factor for preeclampsia.[8] Aspirin may have beneficial effects on the prostacyclin-thromboxane balance, platelet aggregation, and placental vascular function by inhibiting the prostaglandin-forming enzymatic activity of cyclooxygenase and thromboxane A2 in platelets.[9] The American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the U.S. Preventive Services Task Force recommend low-dose aspirin (81 mg/day) in women at high risk of preeclampsia, starting after 12 weeks of gestation and preferably before 16 weeks.[10] The USPSTF found evidence suggesting that aspirin prophylaxis decreases the risk of preeclampsia and associated adverse events, but does not significantly increase serious maternal or fetal complications.[11]

Little evidence has been available to date to assess the combined effects of aspirin and calcium for prevention, and the incremental benefits are less apparent. The question is very relevant in resource-limited settings where nutrition-related risk factors may also be present, and where low-cost preventive interventions might have significant public health impact, due to a high prevalence of obstetric risk factors. Thus, the present study was designed to compare the effectiveness of low-dose aspirin alone versus aspirin and calcium supplementation in the prevention of preeclampsia in high-risk pregnancies, to assess if aspirin with calcium supplementation is more effective in providing preeclampsia prevention, and to evaluate if combined prophylaxis is more effective in reducing maternal and perinatal complications of preeclampsia.

A prospective, comparative interventional study was conducted in the Department of Obstetrics and Gynecology at District Headquarters Hospital DHQ Wana for six months, from 1 December 2025 to 31 May 2026. The sample size was calculated using the OpenEpi sample-size calculator for comparison of two proportions, with a two-sided confidence level of 95%, statistical power of 80%, and a 1:1 allocation ratio. The comparative groups were assumed to have 73.1% and 52.2% incidence of preeclampsia, respectively, based on the previous randomized trial of Souza et al., which studied the use of aspirin plus calcium supplementation among high-risk women with chronic hypertension and abnormal uterine artery Doppler findings.[12] The number of women calculated for each group was about 83 and the total number of women in all groups was 166. After allowing for approximately 10% attrition or loss to follow-up, the final required sample was 182 participants, with 91 women allocated to each group. A non-probability consecutive sampling technique was used. Women who were 18-40 years old, had a viable singleton pregnancy, had at least one of the known risk factors for preeclampsia, and were at 12-20 weeks’ gestation were eligible. Previous preeclampsia, chronic hypertension, pregestational diabetes mellitus, chronic kidney disease, autoimmune disease e.g systemic lupus erythematosus or antiphospholipid syndrome and multifetal gestation were considered high-risk factors. Women were enrolled if they were available for the use of a prophylactic treatment, adhered to fixed follow-up during the antenatal period, and gave written informed consent. Women were excluded if they had a history of preeclampsia or hypertension at enrollment, had major fetal congenital anomalies, had a fetal death, had a known allergy or contraindication to aspirin or calcium, had a history of gastrointestinal bleeding or bleeding disorders, had severe hepatic disease, hypercalcemia, significant renal calculi, or were taking therapeutic-dose aspirin or calcium at enrollment. Women who were not likely to return for follow-up or those who had a planned delivery outside the study hospital or who refused to participate were also excluded. After obtaining ethical approval from the institutional review committee, eligible women were approached during their antenatal visits, and the study objectives and procedures were explained. Informed written consent was obtained prior to enrolment. Baseline data was obtained on a structured data collection proforma that inquired about the mother's age, parity, gestational age, body mass index, socioeconomic status, obstetric history, previous preeclampsia, chronic hypertension, diabetes mellitus, renal disease, autoimmune disease, and other medical conditions. Blood pressure was recorded at the time of enrollment by taking an adequate rest and using a calibrated sphygmomanometer, and relevant laboratory investigations were documented. A urinary protein assessment was done if clinically indicated to rule out pre-existing preeclampsia. Aspirin participants were given low-dose aspirin (150 mg per day), and calcium participants were given low-dose aspirin (150 mg per day) and calcium supplementation (1.5-2 g elemental calcium per day) according to the institutional supplementation protocol. Continuation of treatment was done as clinically indicated while pregnant. Participants were given counseling on taking the medications and reviewed at frequent prenatal appointments. Blood pressure, symptoms suggestive of pre-eclampsia, medication adherence, and adverse effects were measured at each follow-up. They performed relevant laboratory investigations as necessary, such as urine protein evaluation, platelet count, serum creatinine, and liver function tests. The main outcome was the development of preeclampsia, defined as usual clinical criteria after 20 weeks of gestation. Secondary outcomes included gestation at birth, preterm birth, fetal growth restriction, mode of delivery, birth weight, and maternal or fetal adverse outcomes. Patient history and medication records were used to determine treatment adherence. Data were entered, cleaned and analyzed in SPSS Statistics version 26 by IBM. Continuous variables like maternal age, gestational age, BMI and birth weight were tested for normality using the Shapiro-Wilk test. Data of normally distributed variables were expressed as mean ± SD, while the data of non-normally distributed variables were expressed as median (interquartile range). The categorical variables were reported as frequencies and percentages. The independent-samples t-test was used for continuous variables with normal distribution, and the Mann-Whitney U test for continuous variables with non-normal distribution, to compare baseline characteristics between the aspirin-only and aspirin-plus-calcium groups. The chi-square test and Fisher's exact test was used for categorical variables. The chi-square test was used to compare the incidence of preeclampsia between the two groups, and the relative risk and 95% confidence interval were used to quantify the effect of combined supplementation. Multivariable binary logistic regression was performed to identify independent factors associated with development of preeclampsia after adjusting for clinically relevant potential confounders such as maternal age, parity, BMI, previous preeclampsia, chronic hypertension, diabetes, and gestational age at initiation of prophylaxis. A two-sided p-value <0.05 was considered statistically significant.

A total of 182 high-risk pregnant women were enrolled in the study, and 91 women were assigned to each treatment group. The two groups differed from each other at baseline only in terms of their weight gain and fetal growth, and not in blood pressure, major risk factors for preeclampsia, or other known baseline factors such as maternal age, gestational age at enrollment, BMI, parity, socioeconomic status, chronic hypertension, pregestational diabetes, chronic kidney disease, or autoimmune disease. There were no statistically significant differences between groups at baseline (Table 1).

There were no significant differences in the distribution of the primary risk factors between the two groups. Medication adherence was noted in over 90% of participants of both groups. Gastrointestinal events and treatment discontinuation for adverse events were rare, and no significant differences were seen between the groups in terms of treatment-related adverse events (Table 2).

Preeclampsia developed in 34 (37.4%) women receiving aspirin alone compared with 22 (24.2%) receiving aspirin plus calcium, representing a significantly lower risk with combined prophylaxis (p=0.048). The mean gestational age at diagnosis was also significantly later for the combination group. There were no significant differences in the occurrence of severe preeclampsia, hospitalization, eclampsia, or HELLP syndrome with combined supplementation, though this was numerically less common (Table 3).

Women receiving aspirin plus calcium had a higher mean gestational age at delivery than those receiving aspirin alone (p=0.012). Combination group experienced less but non-significant preterm delivery rate. There was no difference in cesarean delivery, placental abruption, PPH, admission to an ICU, or maternal death (Table 4).

The mean birth weight was significantly higher in neonates receiving aspirin plus calcium compared with those receiving aspirin alone (p=0.049). Low birth weight, small-for-gestational-age status, NICU admission, stillbirth, and early neonatal death were less frequent with combined supplementation, but these differences were not statistically significant. Median 5-minute Apgar scores were comparable between the groups (Table 5).

There was an independent association between aspirin plus calcium supplementation and reduced odds of preeclampsia versus aspirin alone on multivariable logistic regression (p=0.043). There was an independent increased risk of developing preeclampsia with previous preeclampsia and chronic hypertension. Maternal age ≥35 years, BMI ≥30 kg/m², pregestational diabetes, chronic kidney disease, autoimmune disease, and good medication adherence were not independently significant predictors in the adjusted model (Table 6).

Table 1. Baseline demographic and clinical characteristics of participants

Table 2. High-risk factors, medication adherence, and treatment-related adverse effects

Table 3. Development of preeclampsia and severity of disease

Table 4. Maternal pregnancy and delivery outcomes

Table 5. Neonatal Outcomes of the Study Participants

Table 6. Multivariable logistic regression for factors associated with development of preeclampsia

In the present study, it has been found that the addition of calcium supplementation to low-dose aspirin was associated with a significant reduction in the incidence of preeclampsia in high-risk pregnancies. The relative risk for women receiving aspirin plus calcium was 0.65, as 24.2% developed preeclampsia, compared with 37.4% for women receiving aspirin alone. The adjusted analysis also showed a protective link between combined therapy (aspirin plus calcium): women taking aspirin plus calcium had about 44% reduced odds of preeclampsia compared to women taking aspirin alone. This discovery suggests that calcium may offer a further preventive benefit along with antiplatelet prophylaxis. The results of benefit from combined prophylaxis are biologically plausible since aspirin and calcium exert their effects in different pathways related to preeclampsia. Recent clinical studies have indicated that aspirin's efficacy may vary by dosage and timing of initiation. In a randomized trial from China, Huai et al. found that aspirin led to significantly reduced incidence of preeclampsia and preterm delivery in high-risk women with stage 1 hypertension, especially when used at or before 16 weeks gestation.[13] The same applies for the use of 100mg aspirin, Lin et al. in a large randomized trial of 898 high-risk Chinese women, did not show any overall effect of aspirin in reducing preeclampsia, though there may be some inter-population variation in the effectiveness of aspirin due to differences in population characteristics and baseline risk.[14] This relatively additional benefit seen in the present study is therefore due to the effect of calcium, and not necessarily only to aspirin. The current results also apply to trials testing the effectiveness of aspirin in high-risk patients. In a double-blind randomized trial, Diguisto et al. examined the effect of low-dose aspirin on the composite endpoint of preeclampsia or birth weight less than the 5th percentile in nulliparous women determined to be high risk with uterine artery Doppler, and determined that low-dose aspirin failed to significantly lower the composite outcome.[15] In contrast, among women with high risk, those taking 150 mg aspirin had significantly fewer cases of preeclampsia than those taking 75 mg (8.77% vs. 33.92%, p=0.001).[16] The differing results indicate that variation in patient selection, baseline risk, aspirin dosage and timing of treatment may be responsible for differences in preventive efficacy. To reduce the variance in aspirin dosage, all subjects in the present study were given 150 mg aspirin. In particular, the reduced risk of preeclampsia seen with aspirin plus calcium is noteworthy, since calcium supplementation is biologically plausible during pregnancy. The large randomized trials from Dwarkanath et al. in India and Tanzania compared calcium supplementation at 500 mg/day to 1500 mg/day in 22,000 nulliparous women, and found that calcium at 500 mg/day was noninferior to 1500 mg/day for the prevention of preeclampsia.[17] While the trials did not directly compare the effects of aspirin plus calcium to aspirin alone, they do offer contemporary evidence that calcium supplementation can be an important part of preventive measures, especially in populations that do not consume sufficient amounts of calcium in their diet. In the current results, this concept is broadened by the suggestion of the safety of calcium in the prevention of dementia in women already deemed to be at high risk of developing it. The current findings are inconsistent with the direct investigation of the use of aspirin in a population in which all participants were given calcium supplementation by the 2025 CASPER trial conducted by Ngwira et al. In that double blind cluster randomized trial of 306 women, the preeclamptic women were 19.3% of those who took 150 mg aspirin plus calcium and 12.2% of those who took calcium and placebo, but the difference was not statistically significant (p=0.781).[18] There are several reasons why this might be. The CASPER was conducted in Malawi, with 266 participants available for final analysis, and adherence was around 69% compared with adherence in the present study of > 90%. The apparent combined-prophylaxis effect might be significantly altered by differences in dietary calcium intake, baseline disease burden, treatment duration, access to healthcare, and treatment adherence. Importantly, CASPER included a component of calcium alone, while the present study included a component of aspirin plus calcium, meaning that the two studies answer slightly different clinically relevant questions. The amount of aspirin used in the present study should be taken into account also. In a randomized trial in Karachi involving women at moderate and high risk of preeclampsia, Ashraf et al. reported an incidence of preeclampsia lower with 150 mg than 75 mg of aspirin, about 30% vs. 47%.[19] In the same way, Sinha et al. reported that there was significant decrease in preeclampsia with 150 mg of aspirin versus 75 mg of aspirin.[16] The results of these studies justify the use of 150 mg in this study and show that the difference between the treatment groups does not necessarily mean that calcium is an effective substitute for aspirin. Instead, results indicate that calcium could be used as a supplement to an effective aspirin program. More recent evidence has raised doubts about whether higher doses of aspirin are clinically significant. Amro et al. compared 162 mg and 81 mg aspirin in high-risk obese pregnant women in ASPREO, and reported preeclampsia with severe features in 35% and 40%, respectively, with a posterior relative risk of 0.88 (posterior credible interval of 0.74 to 1.02).[20] Recently, Khander et al. randomized 400 high-risk pregnant women to 162 mg of aspirin compared to 81 mg and did not show a statistically significant difference between the two groups for preterm preeclampsia or preeclampsia with severe features (p=0.40).[21] The results suggest that there is not always a dose response benefit to aspirin treatment and support the need for further research into alternative preventive treatments, such as calcium supplements. One of the most significant results of the present study was the delayed onset of preeclampsia and the higher mean gestational age at delivery for those who had combined prophylaxis. The mean gestational age at diagnosis was 36.2 weeks vs. 35.1 weeks in the aspirin-plus-calcium and aspirin groups, respectively, and the mean gestational age at delivery was 37.8 vs. 37.0 weeks, respectively. Combined treatment also resulted in a lower rate of preterm delivery, but this was not statistically significant. The results support previous findings of the possibility of effective preeclampsia prevention to postpone the onset of the disease and to lessen prematurity. In a randomized trial of 936 women at high risk for preterm preeclampsia, Mendoza et al. found that the careful selection of continuation and discontinuation strategies for aspirin may help guide prevention, but in doing so would not significantly affect pregnancy outcomes.[22] The present findings also lend some support to the hypothesis that changes in the therapeutic approach to prevention could affect disease onset and disease severity instead of merely disease prevention. Neonatal results also pointed to combined prophylaxis. Infants in the aspirin-plus-calcium group had a significantly greater mean birth weight than those in the aspirin group, although differences in low birth weight, small-for-gestational-age status, NICU admission, stillbirth, and early neonatal death did not reach statistical significance. This pattern is important clinically because there is a strong correlation between preeclampsia and impaired fetal growth and prematurity. However, the number of neonatal adverse events in the current study is relatively small, which reduces the power to detect differences in rare events. The same level of caution is advised when evaluating the lack of difference for severe preeclampsia, eclampsia, HELLP syndrome, placental abruption, and ICU admission. LIMITATIONS There were some limitations in the study. It was conducted at a single tertiary-care center, which may limit the generalizability of the findings to other populations and healthcare settings. The small number of participants may have limited statistical power for detecting differences in rare maternal and neonatal complications. Dietary calcium intake and baseline serum calcium levels were not assessed, although these factors may influence the effectiveness of calcium supplementation. Medication adherence was evaluated primarily by patient history and medication records, which may have been reported with bias. Also, the six-month study period did not allow for evaluation of long-term maternal and neonatal outcomes. Finally, although multivariable analysis was performed, residual confounding from unmeasured factors cannot be excluded.

The addition of calcium supplementation to low-dose aspirin was associated with a significantly lower incidence of preeclampsia among high-risk pregnant women compared with aspirin alone. There was also no significant increase in treatment-related adverse effects, but combined prophylaxis was associated with later diagnosis of preeclampsia, higher gestational age at delivery, and higher birth weight of neonates. Previous preeclampsia and chronic hypertension remained important independent predictors of preeclampsia. More multicenter randomized controlled trials with dietary calcium evaluation are needed to establish the incremental preventive benefit of calcium plus aspirin.