Mechanism of development of pre-eclampsia linking breathing disorders to endothelial dysfunction

doi:10.1016/j.mehy.2009.03.007

Medical Hypotheses

Volume 73, Issue 2, August 2009, Pages 163-166

https://doi.org/10.1016/j.mehy.2009.03.007 Get rights and content

Summary

High blood pressure is an important component of pre-eclampsia. The underlying mechanism of development of hypertension in pre-eclampsia is complicated and still remains obscure. Several theories have been advanced including endothelial dysfunction, uteroplacental insufficiency leading to generalized vasoconstriction, increased cardiac output, and sympathetic hyperactivity. Increased blood flow and pressure are thought to lead to capillary dilatation, which damages end-organ sites, leading to hypertension, proteinuria and edema. Additional theories have been put forward based on epidemiological research, implicating immunological and genetic factors. None of these theories have been substantiated. Based on a review of literature this paper postulates that the initiating event for the development of pre-eclampsia is intermittent hypoxia associated with irregular breathing during sleep, hypoapnea, apnea, inadequate respiratory excursions during the waking hours and inadequate cardiopulmonary synchronization (abnormal sympatho-vagal balance).

Section snippets

Background

Despite being one of leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanism responsible for the pathogenesis of pre-eclampsia remains unclear [1], [2]. Evidence shows that inadequate oxygenation from various causes leads to the initiation of an abnormal autonomic response. Several studies show a strong association between obstructive sleep apnea (OSA) and hypertension in the non-pregnant state [3], [4]. Few studies in pregnancy corroborate

Incidence of snoring, hypoapnea and sleep apnea in the non-pregnant state, pregnancy and pre-eclampsia

The incidence of snoring, hypoapnea, and sleep apnea is 9% in non-pregnant females and 14% in pregnant women [9], [10], [11]. By the third trimester, 24% of women were reported to have a snoring problem (symptom of sleep apnea). Habitual snorers had a higher frequency of pregnancy-induced hypertension (14%) compared to 6% of non-habitual snorers. The intrauterine growth retardation incidence was 7% in habitual snorers compared to 2.6% in non-snorers [10]. In this study it was noted that all

Obstructive sleep apnea and abnormal renin–angiotensin system

Pre-eclamptic patients are observed to have an abnormal renin–angiotensin system [20]. There is a significant interaction between angiotensin-converting enzyme gene insertion/deletion polymorphism and OSA, suggesting another mechanism for the development of hypertension [21]. Chronic induced intermittent hypoxia (CIHO) in rats can cause levels of circulating renin activity and angiotensin II to increase, which suggests that an activated renin–angiotensin system may contribute to the

Obstructive sleep apnea associated with endothelial function index and vascular spasms

Pre-eclampsia is known to be associated with vasoconstriction. Mechanical properties of vessels are abnormal in pre-eclamptic patients. Flow-meditated dilation is decreased in pre-eclamptic women [23]. A study conducted in OSA patients revealed that CPAP treatment restored the compromised flow-mediated dilation [24]. In a study comparing normal pregnant with pre-eclamptic patients the latter had higher respiratory disturbance index during sleep and lower endothelial function index [6].

Relationship of autonomic nervous system to normal and abnormal respiration in the non-pregnant, normal pregnant and pre-eclampsia condition

The autonomic (sympatho-vagal) balance is strongly associated with respiration [25]. Increased vagal (parasympathetic) tone is associated with slow breathing and increased tidal volume, while irregular shallow fast breathing is associated with increased sympathetic tone [25], [26], [27]. Studies on both normotensive pregnant and pre-eclamptic women have shown that the vagal response (parasympathetic tone) is decreased in pre-eclampsia [28]. Other studies have concluded that both sympathetic and

Decrease in incidence of pre-eclampsia and improvement of hypertension, with restoration of normal breathing and relaxation exercises

Another line of evidence supporting this theory is the decrease in the incidence of pre-eclampsia following the restoration of normal breathing. In a study by DiPietro et al. induced maternal relaxation during 32nd week of pregnancy resulted in significant changes in maternal heart rate, skin conduction and increased respiratory sinus arrhythmia. Parallel significant alterations of fetal neural behavior were observed including decreased fetal heart rate, and increased fetal heart rate

Summary

There is strong evidence to support the notion that pre-eclampsia is initiated by dysarrhythmic respiration. Either orthostatic stress-induced respiratory changes or sleep apnea or combination of both elicit imbalance of autonomic nervous system towards sympathetic state. The resultant abnormal cardiopulmonary synchronization significantly diminishes vagal balance. The imbalance leads to vascular changes in the mother, fetus and placenta. The cycle of intermittent anoxia from sleep-associated

Conclusion

Based on various epidemiological, experimental animal studies and sleep studies we cited in this article it appears that there is strong evidence that disordered breathing is an important pathogenic mechanism for the development of pre-eclampsia. This is further supported by the evidence cited that the correction of disordered breathing results in the decreased incidence of pre-eclampsia. While these findings are supportive they cannot prove a causal relationship. Further controlled prospective

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Additionally, OSA has been linked to decreased levels of adiponectin and alterations in leptin levels; both of these peptides have been linked to impaired glucose control. All of the above factors have been shown to be related to the development of gestational diabetes and preeclampsia, both of which are well-known to be associated with pregnancy loss [42–44]. Whether it is sleep fragmentation, sleep deprivation, chronic intermittent hypoxemia, or a combination of these factors that predisposes to the above adverse events is unknown.
Sleep-disordered breathing (SDB) is a common disorder that has numerous medical consequences including cardiovascular morbidity. The clinical presentation in women is frequently vague, leading to its under-recognition in this population. Sleep is known to influence several female hormonal cycles including estrogen, progesterone, prolactin, luteinizing hormone (LH), and follicle stimulating hormone (FSH); consequently, sleep disruption may have adverse effects on female health including pregnancy. Miscarriage, defined as the loss of a pregnancy in the first trimester, occurs in one in four pregnancies; in up to half of cases, the cause may be unknown. Risk factors for miscarriage include increased age, increased weight, and a history of polycystic ovarian syndrome, all of which are also risk factors for SDB. Since SDB is frequently accompanied by sleep fragmentation and intermittent hypoxemia, we speculate that these factors may contribute to miscarriage risk. If this is the case, then treatment of SDB may be a possible intervention for subsequent pregnancies.
Pseudo three-dimensional vision-based nail-fold morphological and hemodynamic analysis
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As shown in Tables 5 and 6, the calibers of arteriolar limb, curved segment, and venular limb of capillary for normal subjects are all smaller than the patients with hypertension. It can be explained by that increased blood pressure tends to cause capillary dilation, which damages end-organ sites and leads to hypertension, proteinuria, and edema [12]. Contrast to the capillary, inward eutrophic remodeling of resistance vasculature of small arteries is manifested as reduced lumen, an increase of ratio of media width to lumen diameter, and constant media cross-sectional area for patients with essential hypertension (For review, see [38,20,24]).
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Mechanism of development of pre-eclampsia linking breathing disorders to endothelial dysfunction

Summary

Section snippets

Background

Incidence of snoring, hypoapnea and sleep apnea in the non-pregnant state, pregnancy and pre-eclampsia

Obstructive sleep apnea and abnormal renin–angiotensin system

Obstructive sleep apnea associated with endothelial function index and vascular spasms

Relationship of autonomic nervous system to normal and abnormal respiration in the non-pregnant, normal pregnant and pre-eclampsia condition

Decrease in incidence of pre-eclampsia and improvement of hypertension, with restoration of normal breathing and relaxation exercises

Summary

Conclusion

Chest

Sleep Med Rev

Chest

Sleep Med

Med Hypotheses

Am J Obstet Gynecol

Biol Psychol

Obstet Gynecol

Pregnancy-related hypertension

Hypertensive disorders of pregnancy

Obstructive sleep apnea and hypertension: epidemiology, mechanisms and treatment effects

Minerva Med

Obstructive sleep apnea: implications for cardiac and vascular disease

JAMA

The prevalence and clinical significance of nocturnal hypertension in pregnancy

J Hypertens

Pre-eclampsia is associated with sleep-disordered breathing and endothelial dysfunction

Eur Respir J

Endothelial dysfunction in obstructive sleep apnea

J Clin Sleep Med

Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation

Thorax