The chronobiology of blood pressure in pregnancy

Accepted Manuscript The Chronobiology of Blood Pressure in Pregnancy Suzanne Pears, Angela Makris, Annemarie Hennessy PII: DOI: Reference:

S2210-7789(17)30501-9 https://doi.org/10.1016/j.preghy.2018.04.002 PREGHY 417

To appear in:

Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health

Received Date: Revised Date: Accepted Date:

8 December 2017 29 March 2018 6 April 2018

Please cite this article as: Pears, S., Makris, A., Hennessy, A., The Chronobiology of Blood Pressure in Pregnancy, Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health (2018), doi: https://doi.org/ 10.1016/j.preghy.2018.04.002

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The Chronobiology of Blood Pressure in Pregnancy Suzanne Pears1, 2,4, Angela Makris 3,4,5, Annemarie Hennessy3, 4,6 1Royal

Prince Alfred Hospital of Sydney 3Western Sydney University 4Heart Research Institute 5Liverpool Hospital 6Campbelltown Hospital 2University

ABSTRACT This review summarizes the literature to date on the subject of the chronobiology of blood pressure in pregnancy, and more specifically, in the common disease state of high blood pressure in pregnancy or preeclampsia. While the guidelines for treating hypertension in pregnancy use absolute measures to start treatment, they do not take into account the important rhythms of hypertension including nighttime and daytime readings. These variations are likely to have strong impacts on pregnancy outcomes, risk and long-term hypertension risk. Keywords: chronobiology, circadian, blood pressure, pregnancy, hypertensive disorders pregnancy, preeclampsia This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. INTRODUCTION Chronobiology is the study of biological rhythms that examine cyclic, or periodic, phenomena in living organisms and their adaptation to solar and lunar related rhythms 1. Chronobiological studies can include comparative anatomy, physiology, genetics, molecular biology, behaviour, development, reproduction and evolution.1 Chronobiology is an interdisciplinary field of investigation and includes sleep medicine, endocrinology, psychiatry, sports medicine as well as space and travel medicine. Variations in the timing and length of biological activities is apparent with many essential biological processes including, but not limited to, eating, sleeping, mating, hibernating, migration and cellular regeneration.1 The most central rhythm in chronobiology is the circadian rhythm: a roughly 24-hour cycle that is demonstrated by rhythmic physiological processes approximating a day. 2 It is regulated by circadian clocks1 which are endogenous, and characterised by a molecular response, such as gene oscillations, to light. Apart from sleep and endocrine cycles in humans, most is known about blood pressure rhythms in humans. Recent work has implicated the circadian clock genes in the regulation of processes in the heart, kidney, vasculature, and the metabolic organs, which are all critical in the regulation of blood pressure.3 There is some evidence that suggests that disruption

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to circadian rhythms during pregnancy can increase the risk of hypertensive pregnancy complications.4 Blood pressure reflects endogenous internal rhythms, which have links to variation between heartbeats, respiratory cycle variation, immediate activity variation, diurnal variation (lightlinked) and stages of life variation including pregnancy. Blood pressure has been considered in the past as a definitive, constant, physiological characteristic 5 however it is now well recognised that blood pressure is a continuous variable, impossible to characterise accurately except by multiple or continuous readings under various conditions.6 Blood pressure is influenced by level of activity, exercise or rest, degree of wakefulness or sleep; environmental factors such as temperature, mood and a multitude of other emotional or psychological factors that reflect a person's response to the internal and external milieu7,8 many of which are related to circadian rhythms. This review will focus on the chronobiology of blood pressure in pregnancy, and more specifically, in the common disease state of high blood pressure in pregnancy or preeclampsia. BLOOD PRESSURE IN NORMAL PREGNANCY AND PREECLAMPSIA In normal pregnancy, the physiological changes to the cardiovascular system are significant. By eight weeks’ gestation, the cardiac output has already increased by 20%. 9 Peripheral vasodilation is increased and is mediated by endothelium-dependent factors, including nitric oxide synthesis, upregulation by oestradiol and possibly vasodilatory prostaglandins. 9 This peripheral vasodilation leads to a 25–30% fall in systemic vascular resistance, and to compensate for this, cardiac output increases by around 40% during the entire pregnancy, which is reflected in an increase in stroke volume and heart rate.9 Stroke volume declines towards term and the increase in maternal heart rate of between 10–20 bpm is maintained, sustaining the increased cardiac output.9 Arterial under-filling in pregnancy leads to the stimulation of arterial baroreceptors, activating the renin-angiotensin-aldosterone and the sympathetic nervous systems stimulating a release of antidiuretic hormone.10 These changes lead to sodium and water retention and create the hypervolaemic, hypo-osmolar state characteristic of pregnancy.10 Extracellular volume increases by 30–50% and plasma volume by 30–40% which plays a critical role in maintaining circulating blood volume, blood pressure and uteroplacental perfusion during pregnancy. 11 Given the unique nature of blood pressure in pregnancy, identifying unsustained or episodic high blood pressure can present a challenge, particularly in the context of office or one-off measurements over a short period of time. The International Society for the Study of Hypertension in Pregnancy (ISSHP) recommend a minimum of two blood pressure measurements to diagnose hypertension and preferably, for accurate diagnosis, that blood pressure remain elevated after overnight rest in hospital or in a day (time) assessment unit. 12 Hypertensive disorders of pregnancy (HDPs) occur in approximately 10% of first pregnancies and 8% of all pregnancies.13 Preeclampsia is defined as new onset of hypertension with

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proteinuria after 20 weeks' gestation (>140 mmHg systolic or >90 mmHg diastolic) and one or more of the following: proteinuria (>300mg/day), maternal organ dysfunction or fetal growth restriction.12 Preeclampsia is a leading cause of maternal and neonatal mortality worldwide. 14 Though maternal mortality from preeclampsia has fallen in developed countries, it remains a common cause of preterm delivery of low-birth-weight, growth restricted babies.15 Although the exact cause of preeclampsia remains unclear, the syndrome may be initiated by placental factors that enter the maternal circulation and cause endothelial dysfunction resulting in hypertension and proteinuria.14,16-18 Hermida et al (1997) found that in a study of 289 pregnant women (189 of these were uncomplicated pregnancies, 71 women went on to develop gestational hypertension and 29 developed preeclampsia), both systolic and diastolic blood pressure in uncomplicated pregnancies steadily deceased up to the 20 th week of pregnancy. Blood pressure subsequently increased until the day of delivery, with the final blood pressure values similar to what was found in early pregnancy.19 In contrast to this, women that went on to develop gestational hypertension and preeclampsia had blood pressure values that demonstrated significant linear increases throughout their pregnancies, with an even more pronounced elevation in the second half of pregnancy when compared to the women with uncomplicated pregnancies. 19 The authors point out the importance of noting that blood pressure measurements at the beginning of gestation in this group of women were similar for the complicated and uncomplicated pregnancies. By the 14th week of gestation (i.e. end of the first trimester), the blood pressure values for women that developed gestational hypertension and preeclampsia reached 115/68mmHg, whereas the women that went on to have uncomplicated, normotensive pregnancies had an average blood pressure of 102/59mmHg at the end of the first trimester. Further, these results show that differences between complicated and uncomplicated pregnancies can be observed long before the actual clinical diagnosis of gestation hypertension or preeclampsia is made.19 Additionally, Hermida et al. (2003) found that compared with uncomplicated pregnancies, a statistically significant elevation of the 24 hour mean of blood pressure is found in pregnancies with gestational hypertension or preeclampsia in all trimesters when compared with normotensive pregnancies.20 The trend of blood pressure increasing as gestational age advances during the second half of pregnancy has been found to be more significant for women who develop preeclampsia when compared to those who developed gestational hypertension.20 More specifically, this study documented first trimester differences of approximately 12 mm Hg in the 24 hour mean of systolic blood pressure (SBP) and approximately 7 mm Hg in diastolic blood pressure (DBP) in women that were diagnosed with gestational hypertension or preeclampsia later in the pregnancy as compared with normotensive pregnancies. In the second trimester, this study found differences between healthy and complicated pregnancies of approximately 13 mm

3

Hg in the 24 hour mean of SBP and 7mmHg in that of DBP. The documented differences in the 24 hour mean of BP between women with healthy and complicated pregnancies undergoing sampling during the third trimester are approximately 15 mm Hg for SBP and 9 mm Hg for DBP.20 THE BLOOD PRESSURE CYCLES AND CIRCADIAN RHYTHMS OF NORMAL PREGNANCY AND PREECLAMPSIA Continuous monitoring of blood pressure throughout the day and night has been performed in a number of studies, and demonstrates that the blood pressure values collected over a 24 hour period form a characteristic circadian pattern. The 24 hour diurnal circadian rhythm of blood pressure in pregnancy is similar to the non-pregnant state,21 with a nocturnal decrease, especially during sleep, of 10–20% followed by an increase early in the morning. 22 In women with normal pregnancies, significant decreases in systolic and diastolic pressures are noted at night, with minimum values typically occurring between midnight and 4:OO am these pressures increase during the waking hours, reaching a maximum by late evening.23-25 Brown et al. (1997) found that in a study of 276 women with uncomplicated pregnancies, the average upper limits of normal were 130/77, 132/79, 133/81, and 135/86 mm Hg. These measurements were taken between week 9-17, 18-22, 26-30, and >30 weeks’ gestation respectively. SBP fell by 12% to 14% and DBP by 18% to 19% during sleep at all stages of pregnancy. Awake ambulatory blood pressure monitoring (ABPM) systolic measurements were 11 to 12 mm Hg higher than clinic measurements and diastolic measurements were 5 to 11 mm Hg higher throughout pregnancy. Maximum blood pressure variability ranged from 8 to 13 mm Hg.21 Ambulatory, continuous blood pressure monitoring has also shown a circadian blood pressure variability over the course of pregnancy that characterises clinically healthy pregnant women as well as women who go on to develop gestational hypertension or preeclampsia. 20,26-28 Maternal cardiovascular adaptations to pregnancy involve considerable change throughout the trimesters as described earlier. In healthy pregnant women, the systolic and diastolic blood pressures begin to fall during the 1st trimester, continuing to decrease until halfway through pregnancy (an average of 5 to 10 mm Hg for SBP and 10 to 15 mm Hg for DBP) and then the gradually return to pre-pregnancy baseline levels by the end of the 9th month.27,29-32 One study of forty-eight normal pregnancies showed lowest blood pressure noted during the 1st trimester, a minimal increase noted during the 2nd trimester, and an incremental rise during the last trimester.33 Blood pressures were found to rise during the day and fall at night for each trimester of pregnancy with a recorded mean nocturnal decrease in arterial pressure averaging 15 % was noted in all participants during each trimester.33 In addition, a decrease in SBP of at least 10% was noted in all participants during each trimester.33

4

Similar pregnancy circadian rhythms are seen in animals. Pregnancy in baboons is characterised by lower systolic, diastolic, and mean blood pressures than in the non-pregnant state. As pregnancy progresses, diastolic and mean pressures tend to increase whereas systolic pressure remains low.34 Starka et al. (1999) found evidence that blood pressure of healthy pregnant baboons demonstrated diurnal variation, similar to the 24 hour circadian periodicity to humans.35 Haemodynamic adaptation in early rat pregnancy is characterised by a fall in blood pressure and total peripheral resistance, together with a rise in cardiac output and stroke volume – the same pattern as seen in human pregnancy.36 Melatonin influences rhythmic changes in blood pressure by affecting the master clock localised in the suprachiasmatic nucleus of the hypothalamus and subsequently the tone of sympathetic and parasympathetic nervous systems.37 The physiological nocturnal fall in BP is probably associated with the nocturnal decrease in adrenergic activity and the increase in parasympathetic activity.38 In addition, several investigators have shown that the nocturnal surge of endogenous melatonin may contribute directly to arterial vasodilation that leads in turn to nocturnal blood pressure fall in normotensives and dippers with essential hypertension 39-41. Furthermore, Brown et al. (2014) found that within a cohort of two hundred and forty-one pregnant women diagnosed with essential hypertension in early pregnancy, 32% of these women in fact had white-coat hypertension, supporting the notion that white-coat hypertension is a common phenomenon in pregnant women that appear to have essential hypertension according to routine blood pressure measurement in early pregnancy. 42 Allostasis is the ability to maintain stability and homeostasis during external changes. Allostatic load, which refers to the bodily compensations made in the pursuit of allostasis, causes physiological and pathophysiological changes.43 Major allostatic responses involve the sympathetic nerve system and the hypothalamus–pituitary–adrenal axis and when these systems are activated, catecholamines are released from the adrenal medulla and from the sympathetic nerves.43 This response normally ceases as soon as the stress has passed, with plasma catecholamine and cortisol levels returning to baseline.43 Overexposure to allostatic load can occur either because of hyperresponsiveness or delayed recovery, inducing a hyperactivity of the hypothalamus-pituitary axis and sympathetic nerves, and ultimately leading to cardiovascular disease on chronic phase.43 The link between allostatic load and circadian rhythm changes is demonstrated by associations between exposure to earthquakes (an allostatic model) and cardiovascular disease (for example, coronary artery disease). Such associations have been reported in Thessaloniki in 1978, Newcastle in 1991, Northridge in 1994 and in Hanshin-Awaji in 1995.44 Chen et al. (2009) showed that participants in the study following the Wenchuan earthquake demonstrated a non-

5

dipper diurnal blood pressure change.45 This finding is relevant because it means that overexposure to an allostatic load caused a significantly abnormal circadian rhythm.43 Further, a study by Higgins et al. (2002) found that the women in their study had higher mean daytime SBP and DBP as well as higher 24 hour systolic pressures compared with those not working. Their study also found that the rate of subsequent development of preeclampsia was significantly higher among those at work compared with those not working. 46 The explanation for the association between work and preeclampsia is unknown, but it has been suggested that the stress of work leads to an increased release of catecholamines and a daylong sympathetic response that increases blood pressure.47 Assessment of blood pressure in pregnant women has largely depended on measurements taken in the physician’s office; such measurements may be influenced by many factors, including but not limited to: emotional state, sleep-wake schedule, physical activity and diet.48-50 These casual measurements are not enough to predict dangerous, life threatening hypertensive episodes and these measurements are also not helpful in refining dose or timing of antihypertensive medications.51 Thus, conventional methods are neither sufficient nor precise enough for blood pressure monitoring in preeclampsia.51 Clinic blood pressure measurements have consistently been shown to be poor predictors of preeclampsia.52-54 A study of 82 pregnant women found that routine antenatal clinic values were not able to distinguish between the group of women that developed hypertension in late pregnancy and those that did not.31 Further, Shennan & Halligan (1998) describe a survey undertaken in the United Kingdom whereby a large proportion of women who suffered eclamptic fits were found to not have had any blood pressure readings that distinguished them from the pregnant population. This survey also found that a large number of first fits occurred in a hospital setting without markedly elevated blood pressure readings. These findings provide evidence that conventional techniques for measuring blood pressure in a clinic and hospital setting are inadequate.50 Penny et al. (1998) found ABPM to be a significantly better predictor of the development of severe hypertension in pregnancy (within 2 weeks of assessment) for both systolic and diastolic blood pressure when compared with conventional day unit assessment. 55 Hermida & Ayala (2004) also found that clinic blood pressure measurements were a less sensitive and specific measure for diagnosing hypertension in pregnancy than ABPM. 54 ABPM can however, identify differences between the circadian pattern of blood pressure in healthy and complicated pregnancies as early as the first trimester of pregnancy, before the actual clinical diagnosis of gestational hypertension or preeclampsia is made. It is important to

6

note however, that the use of the 24-hour blood pressure mean does not provide a proper approach for early diagnosis of hypertensive complications in pregnancy. 52 ABPM has the advantage of, in addition to the immediate presentation of repeated automatic measurements of blood pressure, data can readily be analysed to assess the circadian variation of blood pressure in pregnancy.51 SBP and DBP are not constant over a 24-hour period.56 They show the characteristic circadian pattern in most individuals, including non-pregnant and pregnant women in response to internal clock and mental, physical and social activity. 51 Preeclampsia is associated with increased maternal morbidity and mortality and there is increasing evidence that the negative health effects of preeclampsia may not be restricted to pregnancy.57 Women diagnosed with preeclampsia are also found to be at increased risk of future cardiovascular events in the future.57 Charlton et al. (2013) have demonstrated that the principal underlying abnormality, endothelial dysfunction, remains in women who have had preeclampsia and that it is this damage that increases the risk of developing cardiovascular disease in later life. The contributions of hypertension and dyslipidaemia before and during the pregnancy are also important and contribute to future risk.58 HOW

DO

BLOOD

PRESSURE

CYCLES

CHANGE

IN

PREGNANCY

HYPERTENSION/PREECLAMPSIA? Preeclampsia appears to interfere with the normal circadian decrease in blood pressure at night, sometimes resulting in no decrease or an increase. This phenomenon of nocturnal hypertension in preeclampsia has been observed in a number of studies. Redman et al. (1976) describe the nocturnal blood pressure trends in a group of pregnant women, including nine normotensive women, nine women with untreated chronic hypertension and seventeen women with severe preeclampsia. In these women, the mean nocturnal fall for the diastolic pressures of the normotensive and chronic hypertensive women at 28 weeks of gestation were similar (-4.8 mm Hg and -6.0 mm Hg, respectively). The systolic blood pressure profiles of the women with chronic hypertension, however, revealed a significantly greater fall, -16.3 mm Hg compared with -11.7 mm Hg in the normotensive women. Comparatively, of the women with severe preeclampsia, ten demonstrated a marked reversal of the normal diurnal blood pressure pattern, with the highest blood pressure values occurring overnight. The mean nocturnal blood pressure change in the group of women with severe preeclampsia was +9.8mmHg in systolic and +3.1mmHg in diastolic blood pressure.60 Halligan et al. (1996) studied 48 pregnant women (24 normotensive and 24 with preeclampsia), demonstrated that the blood pressure fall at night was greater in the normotensive women and

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smaller in the women with preeclampsia.61 The mean day-night difference for diastolic blood pressure was found to be greater for normotensive women (17.2 mm Hg) than for women with preeclampsia (9.0 mm Hg).61 The mean day-night difference for systolic blood pressure showed a similar pattern, with a greater difference for normotensive women (15.7 mm Hg) than for women with preeclampsia (9.4 mm Hg).61 Seligman’s (1971) study describes similar findings whereby the decrease in blood pressure during sleep is significantly less in women with preeclampsia than that of normotensive patients.62 The group with chronic hypertension showed a markedly different nocturnal blood pressure pattern. In a study by Sawyer et al. (1981) three groups of 15 women in their third trimester were studied: normotensive, chronically hypertensive, and those with mild preeclampsia (blood pressure at or above 160/110 mm Hg with proteinuria and/or oedema). Compared with the overnight systolic blood pressure fall in normotensive women, the fall in the women with chronic hypertension was significantly greater during sleep and significantly less in women with mild preeclampsia. Although the diastolic pressure fell during the night as well, no significant difference was found among the three groups. The circadian rhythm was abolished in the two participants with severe preeclampsia with these women experiencing no decrease or increase in blood pressure during sleep.25 The clinical relevance of establishing the presence of an abnormal blood pressure pattern lies in its proven association in the non-pregnant population with more severe hypertensive target organ damage and increased cardiovascular risk.63-65 Left ventricular hypertrophy, carotid intima-media thickening, microalbuminuria and cerebrovascular disease are more prevalent in non-dippers than in dippers.66,67 Definitions of dippers and non-dippers vary among authors, and a general description of a dipper is someone who shows a reduction in blood pressure of 10% or 10/5 mm Hg during sleep.68 Those who have less than a 10% reduction in blood pressure during sleep are defined as non-dippers.69 The time period measured showing the nocturnal blood pressure decrease shows some variation amongst authors, depending on the definition of night and day. 69 A commonly used definition of daytime is the period from 6 a.m. to 10 p.m., with night time defined as 10 p.m. to 6 a.m. 68 It should be emphasised that for meaningful classification of dippers and non-dippers, it is the blood pressure measurements taken during sleep that are relevant, not merely the blood pressure measurements recorded between strictly defined times. As discussed above, patients with preeclampsia are frequently characterised by altered diurnal blood pressure rhythms. There is also evidence that the nocturnal hypertension often seen in preeclampsia is related to elevated levels of molecules that cause endothelial damage.70 In the

8

general population, the non-dipping blood pressure profile is currently regarded as a risk factor for cardiovascular events and target organ damage. 71 The underlying mechanisms have not been fully clarified, but there is evidence that endothelial activation, dysfunction or damage could play a pivotal role.72 Markers of endothelial dysfunction-activation (molecules such as von Willebrands Factor and soluble Vascular Cell Adhesion Molecule-1) are elevated in women with preeclampsia.70 Impaired endothelial function and assumed accompanying procoagulant changes are long known to be involved in the pathogenesis of atherosclerosis.70 In addition, history of preeclampsia is associated with an increased risk for cardiovascular disease. 70 One study also found that non-dippers and dippers with preeclampsia differ not only in their haemodynamic response during night, but also in their physiological response to darkness, as shown by the blunted nocturnal melatonin secretion in non-dippers.73 Interestingly, animal studies have shown that fetal diurnal rhythms are to a large extent driven by the mother.74 Kennaway et al. (1996) demonstrated that infants born after intrauterine growth restriction and preeclampsia have delayed appearance of melatonin rhythmicity and a drastically reduced day–night difference in melatonin production between 46 and 55 weeks’ post-conception as compared with full-term infants.75 During pregnancy the pineal gland is not the exclusive source of melatonin, which is also secreted from the placenta.4 According to Lanoix et al. (2012), preeclampsia leads to depressed melatonin levels in the placenta.76 Reduced melatonin levels in women with preeclampsia, as showed in this study, might be in part due to reduced placental secretion of melatonin. 4 Studies in animal models of hypertension in pregnancy suggest that shallow placentation and reduction in uteroplacental perfusion during pregnancy triggers the release of biologically active factors which affect the sympathetic tone and lead to generalised vasoconstriction, hypertension and disturbance of the circadian blood pressure rhythm.77 Dysfunction of the autonomic nervous system is suspected to be a major contributor to the increase in peripheral vascular resistance in preeclampsia.4 This overactivity has been suggested as a contributing factor in the loss of nocturnal blood pressure dip.71 Impaired nocturnal melatonin secretion, shown in the study conducted by Bouchlariotou et al. (2014), might be an additional contributor to autonomic nervous system dysfunction and thus indirectly of nocturnal hypertension in preeclampsia. 4 It has been suggested that administration of melatonin may lead to prevention of endothelial structural alterations.4

WHAT IMPLICATIONS DOES BLOOD PRESSURE VARIABILITY HAVE FOR TREATMENT?

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Blood pressure is characterised by marked short-term fluctuations occurring within a 24 hour period (beat-to-beat, minute-to-minute, hour-to-hour, and day-to-night changes) and also by long-term fluctuations occurring over more-prolonged periods of time (days, weeks, months, seasons, and even years).78 Rather than representing 'background noise' or a randomly occurring phenomenon, these variations have consistently been shown to be the result of complex interactions between extrinsic environmental and behavioural factors and intrinsic cardiovascular regulatory mechanisms.78 The adverse cardiovascular impacts of hypertension have been shown to be associated with absolute blood pressure values, however evidence from a number of studies point toward these outcomes also being dependant on the degree of blood pressure variability.78 Increased short-term and long-term blood pressure variability are associated with the development, progression, and severity of cardiac, vascular, and renal damage and with an increased risk of cardiovascular events and mortality. 78 One-off blood pressure measurements are relatively easy to report and quantify however it is unclear which variability index correctly identifies and quantifies true blood pressure variability. 79 Parati et al. (2013) draws attention to the findings from post-hoc analyses of large intervention trials in hypertension that show within-patient visit-to-visit blood pressure variability is a strong prognostic indicator for cardiovascular morbidity and mortality.78 This result has prompted discussion on whether antihypertensive treatment in the non-pregnant population should be targeted not only towards reducing mean blood pressure levels, but also to stabilising blood pressure variability with the aim of achieving consistent blood pressure control over time, which might favour cardiovascular protection78 with some evidence to suggest that amlodipine is effective for minimising blood pressure variability in non-pregnant hypertensive individuals.80 Particularly in the case of preeclampsia, many of the most serious adverse outcomes result from acute episodes of blood pressure variability, such as in the case of cerebral haemorrhage; cerebral haemorrhage being the major cause of maternal mortality in preeclampsia. 81

The Control of Hypertension in Pregnancy Study (CHIPS) based study eligibility on blood pressure measurements falling within the eligible range twice, i.e. based on evidence of sustained hypertension.82 In the event of a patient having labile or episodic hypertension, they may have been excluded from the trial if their second blood pressure reading fell below the required range. The Hypertension and Preeclampsia Intervention Trial At Term (HYPITAT) study also excluded patients that did not have sustained blood pressure within a defined range over the course of two readings taken at least six hours apart.83 There is minimal literature describing this phenomenon in pregnant women, however the body of research around episodic hypertension in the non-pregnant population is growing. The only area where there is substantial literature describing episodic hypertension in women with preeclampsia relates to blunting the hypertensive response associated with intubation, as this

10

hypertensive response has been identified as a direct cause of maternal mortality. There are no published guidelines for the clinical management of this response. 84,85 Chronopharmacology, the study of how biologic rhythms interact with medications, has led to new

understandings

and

concepts

about

the

behavior

of

therapeutic

agents. 86

Chronotherapeutics is a relatively new concept in medicine, and aims to increase the positive effects of medications and manage their adverse effects. 86 Chronotherapy is indicated for medical conditions that show predictable time variation in symptoms and risk for life-threatening events.86 While the guidelines for treating hypertension in pregnancy use absolute measures to start treatment, they do not take into account the important rhythms of hypertension including nighttime and daytime readings. These variations are likely to have strong impacts on pregnancy outcomes, risk and long-term hypertension risk. For detection and of these rhythm variations and subsequent management, 24 h ambulatory blood pressure is essential.

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The Chronobiology of Blood Pressure in Pregnancy: Highlights 

Chronobiology is the study of biological rhythms that examine cyclic phenomena in living organisms. Blood pressure reflects endogenous internal rhythms, which have links to variation between heartbeats, respiratory cycle variation, immediate activity variation, diurnal variation and stages of life variation including pregnancy. Blood pressure has been considered in the past as a definitive, constant, physiological characteristic however it is now well recognised that blood pressure is a continuous variable, impossible to characterise accurately except by multiple or continuous readings under various conditions.

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Hypertensive disorders of pregnancy (HDPs) occur in approximately 10% of first pregnancies and 8% of all pregnancies. Preeclampsia is a leading cause of maternal and neonatal mortality worldwide.

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The 24 hour diurnal circadian rhythm of blood pressure in pregnancy is similar to the non-pregnant state, with a nocturnal decrease, especially during sleep, of 10–20% followed by an increase early in the morning. Preeclampsia appears to interfere with the normal circadian decrease in blood pressure at night, sometimes resulting in no decrease or an increase.

 Approximately 15% of women with preeclampsia have severe, episodic hypertension and At present there is no recommended treatment for women with preeclampsia that have severe, episodic hypertension. can’t be treated. There is minimal literature describing this phenomenon in pregnant women, however the body of research around episodic hypertension in the non-pregnant population is growing. 

The guidelines for treating hypertension in pregnancy use absolute measures to start treatment, they do not take into account the important rhythms of hypertension including nighttime and daytime readings. These variations are likely to have strong impacts on pregnancy outcomes, risk and long-term hypertension risk.

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