When the factors that can influence the occurrence of WCH were investigated, it was found that nulliparous women had a much higher likelihood of developing the condition than multiparous women did. Moreover, an increase in the systolic blood pressure is more typical in the early stages of pregnancy, whereas an increase in the diastolic blood pressure is more typical in the late stages of pregnancy.^{[11, 12]} Hypertensive disorders during pregnancy (HDP), including the WCH, have also been found to be more common in pregnant women with pre-existing type 2 diabetes mellitus. According to our findings, an in-office BP of 135/85 mmHg was detected for the first time in early pregnancy in 14% of the women with pre-existing diabetes. Simultaneously, WCH was present in 84% of these women, which is 12% of the entire cohort. Chronic hypertension was detected in 14% of the cases, and normotension – in 74% of the cases. The women with WCH had a higher pre-pregnancy BMI and higher home-measured BP than normotensive individuals.^[13]

Gestational diabetes, obesity, multiple pregnancy, maternal age less than 20 or older than 35 years old, and thrombophilia are also among the factors that contribute to an increased risk of developing HDP.^[12] There is also an increase in the prevalence of impaired glucose tolerance and coronary artery disease among patients with WCH and hypertensive disorders compared with the normotensive group. Additionally, the highest prevalence of dyslipidemia was observed in the WCH group (41.6%), followed by the group of patients with stable hypertension (35.5%) and 19.6% in the normotensive group.^{[7, 14]}

Björklund et al.^[15] found that metabolic abnormalities (insulin sensitivity, elevated fasting blood glucose, impaired glucose tolerance, and elevated serum insulin levels) and tachycardia develop over time in patients with WCH and persistent hypertension.

WCH is accompanied by hyperlipidemia, which, along with disorders of carbohydrate metabolism and a tendency to be overweight, links WCH to a metabolic syndrome.^{[7, 16]}

Risk factors for WCH, previously attributed to the stress response, also include female sex, smoking, and daytime systolic BP variability.^[17] Vascular aging of the arteries is the dominant determinant of the ‘white coat’ effect. Patients with WCH have higher values of carotid-femoral pulse wave velocity, and augmentation index, which is an independent predictor of atherosclerotic lesions of carotid arteries, and an increase in the amplitude of the reflected pressure wave.^[18]

Although WCH is triggered by stress-related activation of the sympathetic nervous system, the response of blood pressure to increased cardiac contraction and peripheral vasoconstriction is markedly manifested in vascular arterial aging. This is manifested by an increase in arterial stiffness and reflection of pulse waves, which increases blood pressure. WCH is associated with an increased risk of cardiovascular disease (CVD) and a higher mortality rate from CVD because vascular aging, namely an increase in arterial stiffness and a decrease in vascular wall compliance, is a recognized major risk factor for cardiovascular diseases and target organ damage, as well as the main pathophysiological factor explaining the occurrence of WCH.^[19]

ISSHP recommends that women with an elevated office blood pressure of ≥140/90 mmHg diagnosed before 20 weeks of gestation should be examined with ABPM, which includes frequent automatic blood pressure measurements during wakefulness and sleep for 24 hours.^[1] This examination can help in the differential diagnosis of true hypertension in pregnancy from WCH.^[20–22] (Fig. 1).

Figure 1.

White coat hypertension diagnostic criteria and monitoring during pregnancy.

Home blood pressure monitoring (HBPM) is an acceptable alternative when ABPM is not available. HBPM should be performed twice a day, in the morning and in the evening, and then averaged over 7 days. Mean BP ≤130/80 mmHg while awake and/or ≤115/70 mmHg during sleep is considered normal. Presence of WCH is assessed based on the data obtained. If the waking blood pressure is 130/80 mmHg or the sleeping blood pressure is 115/70 mmHg, the diagnosis is chronic hypertension.

The gold standard for ruling out masked hypertension and WCH is ABPM.^{[1, 3, 8]} With the help of ABPM, the falling pattern is also evaluated, i.e. the ratio of systolic blood pressure (SBP) at night to SBP during the day.^[7] The falling pattern has an important predictive value regarding the risk of later cardiovascular disease.^[23] Patients with WCH are diagnosed with more variable circadian rhythm than normotensive patients, higher pulse pressure, and no dips. ABPM non-dipping status in patients with WCH is associated with decreased compliance of the vascular wall of the arteries.^[24] The unfavorable falling pattern in ABPM, which is an insufficient fall in SBP at night compared to daytime, even along with normotension, should be assessed as a clinically significant independent risk factor for developing preeclampsia (PE) and cardiovascular disease in the future.^[25–27]

The generally accepted upper limit of home blood pressure (135/85 mmHg) used in the differential diagnosis of WCH during pregnancy, has recently been called into question.^[28] Normal office values of blood pressure during the day in pregnant women are recognized as blood pressure values less than 130/77 mmHg at ≤22 weeks, 133/81 mmHg at 26–30 weeks, and 135/86 mmHg at 30 weeks. In late pregnancy, the upper reference limit is 140/91 mmHg for office blood pressure and 123/78 mmHg for home BP. The average difference between office BP and home BP in healthy pregnant women is 10 mmHg.^{[10, 29]} Daily fluctuations in blood pressure during pregnancy amount to a nighttime decrease in SBP and DBP by 12%-14% and 18%-19%, respectively. The nighttime decrease in blood pressure weakens before the onset of nephropathy against the background of gestational arterial hypertension.^[10]

According to the findings of a Japanese study of pregnant women, an increase in blood pressure of 10 mmHg according to ABPM increases the risk of giving birth to small-for-gestational-age newborns by 1.74 times.^[30]

Women diagnosed with WCH in early pregnancy are twice more likely to develop HDP compared to normotensive women.^{[13, 23]} According to various data, based on ABP monitoring in early pregnancy, 40% of women subsequently develop gestational hypertension.^{[6, 31]} Women who have WCH before 20 weeks of pregnancy are five times more likely than normotensive women to develop PE.^{[10, 26, 32]} However, the risk of developing PE was not significantly higher compared to normotensive women when WCH was diagnosed at any stage of pregnancy.^[8] According to the results of a retrospective cohort study, it was confirmed that WCH diagnosed in the first trimester of pregnancy is a risk factor for developing PE and gestational hypertension in late pregnancy.^[33]

HDP are a worldwide health problem for women and their infants.^[34–37] When WCH was detected at any stage of pregnancy, it increased the risk of premature birth and births of small-for-gestational-age infants by 2-3 times, according to most studies.^{[8, 32]} Simultaneously, these results may have limitations, given the recommendations of the International Society for the Study of Hypertension in Pregnant Women to include only women under 20 weeks of pregnancy in the diagnosis of WCH. Therefore, when managing women throughout pregnancy, it is necessary to diagnose WCH in a timely manner before the 20th week of pregnancy.^[8]

Generally, WCH diagnosed during pregnancy tends to have a better prognosis than gestational hypertension: the risk for PE, a birth of small-for-gestational-age newborns, and preterm birth is significantly lower in women with WCH than that of women with gestational hypertension. ^{[26, 29]} Delivery in women with WCH occurs about 1 week later compared with women with chronic hypertension.^[32]

Based on these findings, it is possible to conclude that WCH is associated with worse perinatal and maternal outcomes when compared to normotensive subjects, but better outcomes when compared to gestational hypertension and chronic hypertension, and thus occupies an intermediate risk for developing complications.^[38–40]

Recently, microribonucleic acids (microRNAs) have been targeted as potential biomarkers.^[41] MicroRNAs are not prone to rapid degradation, therefore, they can be measured both in tissues and in biological fluids. According to the update of the miRNAs database from 2018, 2654 mature miRNAs were discovered in humans.^{[42, 43]}

A study identified 9 microRNAs with reduced expression and 7 miRNAs with increased expression in the placenta of patients with developed severe PE compared to the control group of healthy pregnant women.^[44] Overexpression of microRNA-21 is positively correlated with elevated blood pressure. The direct target of microRNA-21 is mitochondrially encoded cytochrome B (mt-CytB), the stimulation of which increases the production of reactive oxygen species. As is well known, an increase in oxygen causes vascular wall remodeling due to the development of endothelial dysfunction, inflammation, and cell migration^[45] Moreover, miRNA-21 overexpression can trigger the development of the atherosclerotic process by targeting the endothelial nitric oxide synthase (eNOS).^[46]

The analysis of published data has shown the association of many types of microRNAs with the pathogenesis of various types of hypertensive disorders. This is explained by their pleiotropic properties, the ability to regulate the expression of numerous target genes, and their participation in complex regulatory networks. However, only 2 miRNA types, miRNA-21 and miRNA-130a, were expressed in essential hypertension and pulmonary arterial hypertension. Here, miRNA-21 demonstrates a particularly high degree of expression.^[47] Additionally, there is a direct correlation between increased expression of miRNA-21 levels and the development of white coat hypertension.^[48] Simultaneously, the role of microRNA-21 in the proliferation and apoptosis of vascular smooth muscle cells and cardiomyocytes and participation in the functions of cardiac fibroblasts is already well known.

Dysregulation of microRNA-21 expression can initiate the proliferative status of smooth muscle and endothelial cells of the pulmonary artery in the early phase of hypoxic exposure. Elevated levels of miRNA-21 and B-type natriuretic peptide have also been diagnosed in patients with pregnancy-induced hypertension.^[49]

The role of the increased miRNA-21 expression in the development of left ventricular concentric remodeling with an increase in the thickness of the interventricular septum according to echocardiography and a decrease in the number of functioning nephrons against the background of an increase in blood pressure was demonstrated by the study’s findings. Simultaneously, a feature of developing myocardial remodeling is the predominance of precisely hypertrophic changes in the myocardium over fibrosis. However, specific mechanisms of microRNA-21 involvement in the pathogenesis of myocardial remodeling require further research.^[50]