Clinical Characteristics of Pregnant Women on the Use of Daily Low-dose Aspirin in Different Hypertensive Pregnancy Disorders: A Retrospective Comparative Study.

BACKGROUND: Hypertensive disorders represent major causes of maternal and fetal complications. It includes a range of conditions, most notably preeclampsia. Aspirin is a well-accepted therapy for the primary and secondary prevention of cardiovascular events. The indications for the use of aspirin during pregnancy are, however, the subject of much concern. This study aimed to assess the clinical characteristics from the benefits of daily low-dose aspirin administration alongside antihypertensive in pregnant women with different hypertensive disorders.
MATERIALS AND METHODS: A retrospective observational study was carried out on pregnant women during their routine visit to the obstetric clinic at Baghdad Teaching Hospital. Patients diagnosed during pregnancy with different hypertensive disorders on the prescription of antihypertensive medication with or without daily low-dose aspirin administration were selected. Data were collected to structure a detailed assessment regarding the patients' demographic, gestational, and medical records.
RESULTS: Methyldopa was the main antihypertensive agent (98%). Among pregnant women with daily aspirin use, 68% had gestational hypertension, 24% had preeclampsia alongside proteinuria (P = 0.0001), the frequency of daily dose intake of methyldopa (250 mg) tablet (two vs. three times) was significant (P = 0.0001). All pregnant women within the group of daily low-dose aspirin were safe from the incidence of eclampsia (P = 0.0001).
CONCLUSION: This study provides intriguing evidence for the benefits of daily low-dose aspirin use during pregnancy as it is considered as a simple protective measure from serious maternal complications of hypertensive disorders, where these complications continue to affect maternal health long after delivery.

INTRODUCTION

Hypertensive disorders represent one of the most common problems of pregnancy, which affect approximately 10% of all pregnant women worldwide.[1] They cover a spectrum of conditions, including chronic hypertension, gestational hypertension (GH), preeclampsia, and eclampsia, and are considered as an important cause of different cardiovascular (CV) conditions and leading cause of morbidity, long-term disability, and death among both mothers and babies.[23] The majority of the different CV conditions alongside deaths related to hypertensive disorders can be avoided by providing timely and effective care to pregnant women presented with such complications.[4]

It is thought that antiplatelet agents, such as low dose of aspirin, taken in early pregnancy may reduce pathological coagulation and vasoconstriction in the placental circulation and also promote placental growth, thereby reducing the incidence of CV conditions in pregnant women at moderate-to-high risk of preeclampsia by approximately 15%.[5]

The aim of this study was to assess the patterns and clinical characteristics elicited from the benefits of daily low-dose aspirin administration alongside antihypertensive medication in pregnant women with different hypertensive disorders in real clinical settings.

MATERIALS AND METHODS

Study design

The study was designed as a retrospective observational, single-center analysis and conducted at an obstetric clinic of Baghdad Teaching Hospital, Baghdad province, Iraq. Patients were surveyed from July through October 2017. The study was reviewed and approved by the ethics committee of College of Pharmacy, Mustansiriya University, Iraq.

Participants and data collection

Pregnant women visiting the obstetric clinic during the aforementioned period were recruited in this study. Pregnant women over the age of 18 years, those with any of the hypertensive disorders of pregnancy, recommended antihypertensive medication intake with or without low dose of daily aspirin administration (75 mg daily from 12 weeks of gestational age [GA]) were included and used to estimate the sample size of this study, whereas those missing enough obstetric and clinical data were excluded. Data regarding maternal, obstetric, clinical, and health records for each participant were screened and collected at the obstetric clinic during the routine visits. They were extracted and used to structure a detailed assessment for the patients. The data collected included maternal demographic-related information (age, education level, smoking habits), whereas obstetric-, clinical-, and health-related information included GA in weeks, gestational conditions, family history of medical disorders, medication history, surgical history, presence of medical conditions, type of hypertensive disorder, presence or absence of proteinuria, medications being used during the gestational period, and measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP).

Assessment of hypertensive disorders

Measurements of blood pressure (BP) were based on the International Society for the Study of Hypertension in Pregnancy criteria to determine women with chronic hypertension, GH, and those with preeclampsia. Measurements of BP were recorded at the corresponding GA using a mercury column sphygmomanometer after 5 min rest in correspondence to a schedule theme at the obstetric clinic. Participants’ visits usually occurred every 4 weeks until the 28th week of pregnancy, every 2 weeks from then until the 36th week, and then weekly until delivery. The mean values of SBP and DBP were recorded for each participant depending on the mentioned visiting schedule.

According to those criteria, chronic hypertension is defined as high BP that precedes pregnancy, diagnosed within the first 20 weeks of pregnancy, or does not resolve by the 12-week postpartum checkup. GH is a new onset of hypertension after 20 weeks of gestation. The diagnosis requires that the patient has elevated BP (SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg) with previously normal BP and no protein in the urine with any manifestations of preeclampsia and eclampsia. Preeclampsia is defined as an SBP ≥ 140 mm Hg or a DBP ≥ 90 mm Hg, measured on at least two occasions after 20 weeks of gestation, with proteinuria (>0.3 g/24 h) accompanied by severe headaches and epigastric pain.[6]

Pregnant women with different hypertensive disorders and managed with antihypertensive medication were divided into two groups following the inclusion criteria. Group A included pregnant women with daily low-dose aspirin administration and group B included those without daily low-dose aspirin. In both the groups, study outcomes included clinical characteristics regarding age, GA, presence of gestational diabetes mellitus (GDM), patterns of antihypertensive medication intake (medication type and dosage frequency), measurements of SBP and DBP, presence of proteinuria, and frequency of patients who progressed to preeclampsia and eclampsia.

Statistical analysis

The Statistical Package for the Social Sciences (SPSS) software for Windows (IBM Corp. Armonk, NY, USA), version 23, was used for statistical analysis. Descriptive analysis was used to describe the study population, and the results were expressed in numbers, percentages, mean values, and standard deviations. Comparison of mean between any two groups was carried out using independent sample t-test. Association between categorical variables was assessed using either chi-square or corrected chi-square test. The level of significance used for the statistical analysis was P < 0.05.

RESULTS

Table 1 presents the sociodemographic characteristics of the recruited study participants who met the inclusion criteria of this study. As 17 patients met the exclusion criteria, 100 pregnant women were enrolled and included in this study. The mean age was 30.86±6.57 years and the majority (48%) were between 31 and 50 years. All of the study participants reported no history of smoking before or during pregnancy and 48% had a secondary education level.

Table 1

Demographic data of study population

Variable	Patient number (N)	Percentage (%)
Demographic
Age (years)
<20	2	2
20–30	50	50
31–50	48	48
Education level
Primary	24	24
Secondary	48	48
University	28	28
Obstetric
GA (weeks)
1–13	4	4
14–24	10	10
25–37	86	86
Presence of GDM
Yes	22	22
No	78	78
Type of hypertensive disorders
Chronic hypertension	10	10
Gestational hypertension	48	48
Preeclampsia	42	42
Clinical health
Height (cm)	158.32 ± 6.2	-
Weight (kg)	69.36 ± 7.5	-
Body mass index (kg/m2)	27.7 ± 6.85	-
CV family history
Yes	5	5
No	95	95
Past surgical history
Yes	46	46
No	54	54
Medical conditions
Yes	10	10
No	90	90
Antihypertensive medication
Yes	98	98
No	2	2
Rh factor
Rh+	70	70
Rh-	30	30
Blood group phenotype
A	20	20
B	22	22
AB	14	14
O	44	44

Regarding the obstetric characteristics [Table 1], 86% of the study participants were diagnosed at 25–37 weeks, 10% at 14–24 weeks, and 4% at 1–13 weeks GA. From the study participants, 22% had GDM. For the types of hypertensive disorders diagnosed among the participants, 48% had GH, followed by 42% preeclampsia and 10% chronic hypertension.

In terms of the clinical and health characteristics, 98% reported intake of antihypertensive medication. For the maternal ABO blood group distribution, it was found that 70% of the study participants had Rh+ factor. Meanwhile, 44% patients were found to have O blood group phenotype. Other characteristics of the study participants are shown in Table 1.

Table 2 presents the clinical characteristics of pregnant women with and without daily low-dose aspirin administration. Among those, 50% was observed for pregnant women using daily low-dose aspirin versus those without aspirin usage. Accordingly, an equal incidence (48%) at the age range of 31–50 years was also observed in both groups A and B. The majority of the study participants within both groups A and B were at a GA between 25 and 37 weeks (84% vs. 88%, respectively). In this study, the prevalence of GDM among pregnant women within both groups A and B was insignificant (20% vs. 24%; P = 0.0870, respectively).

Table 2

Clinical characteristics of pregnant women with and without daily low-dose aspirin usage

Variable	Group A (with aspirin) (total = 50) N (%)	Group B (without aspirin) (total = 50) N (%)	P value
Age (years)			0.0896 * NS
<20	0	2 (4)
20–30	26 (52)	24 (48)
31–50	24 (48)	24 (48)
GA (weeks)			0.090 * NS
1–13	4 (8)	0
14–24	4 (8)	6 (12)
25–37	42 (84)	44 (88)
Presence of GDM			0.0870 * NS
Yes	10 (20)	12 (24)
No	40 (80)	38 (76)
Gestational medications methyldopa (250 mg tab.)			0.0894 * NS
Yes	48 (96)	50 (100)
No	2 (4)	0
Frequency of methyldopa (250 mg tab.)			0.0001**
2 times/day	42 (84)	16 (32)
3 times/day	8 (16)	34 (68)
SBP (mm Hg)	128.8 ± 9.6	144 ± 16.4	0.088 * NS
DBP (mm Hg)	84.4 ± 5.2	93.6 ± 13.1	0.0933 * NS
Presence of proteinuria			0.0001**
Yes	12 (24)	30 (60)
No	38 (76)	20 (40)
Preeclampsia incidence	12 (24)	30 (60)	0.0001**
Eclampsia incidence			0.0001**
Yes	0	10 (20)
No	50 (100)	40 (80)

*NS = nonsignificant

**P < 0.05 = significant

No significant difference was reported regarding the use of antihypertensive medication (methyldopa, 250 mg tablet) among the study participants of both groups A versus B, (96% vs. 100%; P = 0.0894, respectively). However, the frequency of daily dose intake of methyldopa (250 mg) tablet (two vs. three times daily) was significant (P = 0.0001) among pregnant women with group A (84% on 2 times/day vs. 16% on 3 times/day) compared to those within group B (32% on 2 times/day vs. 68% on 3 times/day) as shown in Table 2.

Although no significant changes were observed regarding BP measurements (SBP and DBP), the average SBP and DBP readings were comparable within both the groups (SBP: 128.8 ± 9.6 vs. 144 ± 16.4 mm Hg; P = 0.088) and (DBP: 84.4 ± 5.2 vs. 93.6 ± 13.1 mm Hg; P = 0.0933) as shown in Table 2.

A significant incidence of preeclampsia was observed among pregnant women within group B compared to those in group A (60% vs. 24%; P = 0.0001, respectively). In addition, only 24% of the pregnant women within group A had proteinuria versus 60% within group B; P = 0.0001. Furthermore, all pregnant women (100%) within group A were safe from the incidence of eclampsia in comparison to those within group B (20%; P = 0.0001) as shown in Table 2.

DISCUSSION

Treatment recommendation for hypertension in pregnancy is of high importance and widely considered. Although patients with hypertension have relatively good outcome, difficulty in differentiating various hypertensive conditions, inability to predict which patients are at highest risk, and variability in the progression of preeclampsia and possibly eclampsia make these disorders the greatest challenge of clinical medicine in obstetrics.

In this study, the majority of pregnant women diagnosed with different hypertensive disorders of pregnancy within both groups A and B were at a GA between 25 and 37 weeks (84% vs. 88%, respectively). Our results were in agreement with previous studies, which reported that in pregnancy, a substantial change in BP is observed. In early pregnancy, a decrease in BP is observed followed by a steep rise in the latter half of pregnancy.[78] There is also evidence that even women without preexisting hypertension or preeclampsia have an increased BP, where the maximum level is reached, which is associated with reduced fetal growth.[910]

In our study, despite no significant difference (P = 0.0870) was observed regarding the prevalence of GDM between patients of groups A and B (might be related to the small sample size), it is well known that coexisting gestational medical conditions, such as GDM, are associated with a high risk of other CV conditions such as preeclampsia in the second pregnancy. In this regard, the development of GDM or hyperglycemia during pregnancy represents a risk factor for future maternal complications and is linked to an increased risk of metabolic syndrome and adverse CV outcomes for the mother later in life.[1112] A retrospective study by Schneider et al.[13] found that preeclampsia increased among women with GDM (adjusted odds ratio, 1.29, 95% confidence interval, 1.19–1.41).

In clinical practice settings, methyldopa and labetalol are appropriate first-line agents for managing and controlling hypertensive disorders of pregnancy.[14] In this regard, methyldopa (250 mg) tablet was the principle antihypertensive medication recommended for pregnant women with hypertension within both groups of the study. However, the frequency of daily dose intake of this medication varied between groups and was significantly used in low frequency (two vs. three times daily; P = 0.0001) among pregnant women with hypertension within group A compared to those within group B as shown in Table 2. It could be concluded that the coadministration of antihypertensive medication (methyldopa) with low-dose aspirin (75 mg/day) has a synergistic beneficial effect in further lowering and controlling BP as well as impending pregnant women with hypertension to be in a more progressive phase (preeclampsia). In this study, the impact and response to this combination was manifested as a noticeable lowering of SBP and DBP for pregnant women within group A compared to those within group B (though it was an insignificant difference). Previous reviews and clinical trials suggested that low-dose aspirin lowers BP and could effectively be used for preventing hypertension and other CV events in patients with and without hypertension.[15] Similar results were obtained in another study by Hermida et al.[16] who found that BP was significantly lowered when low-dose aspirin (100 mg/day) was administered to pregnant women who are at higher risk for GH or preeclampsia.

In this study, the beneficial therapeutic effects of daily low-dose aspirin administration were observed in the form of a significant low incidence of preeclampsia (24%) within group A compared to group B (60%; P = 0.0001) [Table 2]. The aforementioned result was also associated with significantly low incidence of proteinuria within group A compared to group B (24% vs. 60%; P = 0.0001, respectively). Moreover, all pregnant women within group A were safe from the incidence of eclampsia in comparison to those within group B, which was attributed to the beneficial effect of coadministration of low-dose aspirin with antihypertensive medication as shown in Table 2.

Although the exact underlying cause of preeclampsia remains to be fully elucidated, literature reported that abnormalities involving angiogenesis, oxidative stress, and inflammation are implicated in which platelet TXA2/PGI2 imbalance is presented from 13 weeks of gestation in high-risk patients. TXA2 increases significantly, whereas prostacyclin (PGI2) drops sharply.[17] This imbalance can be reversed by 2 weeks of daily low-dose aspirin therapy, which inhibits TXA2 secretion, and thus platelet aggregation, without altering secretion of endothelial prostacyclin (PGI2).[1819]

Until recently, numerous clinical trials for the primary and secondary prevention of preeclampsia, using different supplements and medications, including calcium, or the antioxidants (vitamins C and E), have failed.[202122] Provided that there is no contraindication, guidelines suggest that women at high-to-moderate risk to hypertensive pregnancy disorders (such as chronic hypertension, DM, first pregnancy, family history of preeclampsia, and multiple pregnancy) may be advised to take daily aspirin (75 mg) administered from 12 weeks until the term.[23]

Bujold et al.[24] reported that administration of daily low-dose aspirin initiated at ≤16 weeks of gestation significantly decreases the risk of preeclampsia and other adverse maternal and neonatal outcomes.

A large review of 59 trials, conducted on 37,560 women, found that daily low-dose aspirin reduced the risk of preeclampsia by 17%, the risk of fetal or neonatal deaths by 14%, and the relative risk of preterm births by 8%.[5] A meta-analysis study found that daily low-dose aspirin was associated with a significant reduction in the overall risk ratio of preeclampsia regardless of the time to delivery.[25]

This is the first study that was conducted in Baghdad, Iraq, in a real-life setting, for better understanding of clinical characteristics elicited from the benefits of daily low-dose aspirin administration throughout the gestational period alongside antihypertensive medication in pregnant women with different hypertensive disorders. However, the study has some limitations that should be taken into consideration, resulting from hidden confounders and biases because of the retrospective nature of the study. Another limitation was the small sample size for the population that was recruited during this study and patients’ recruitment at the obstetric clinic of a single hospital. Finally, there was inability to identify adherence for medications being recommended for the patients, which might limit the ability to detect improvements in some outcomes.

CONCLUSION

Besides its well-known antithrombotic effect, it is now clear that aspirin exerts secondary protective effects alongside antihypertensive medication in pregnant women with different hypertensive disorders, particularly those at risk of preeclampsia. This could be associated with a reduced risk of preeclampsia, and in turn of eclampsia and other adverse maternal and neonatal outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.