Obstructive sleep apnea (OSA) is a well recognized risk factor for cardiovascular disease and, although it is less prevalent in women according to recent studies it is underdiagnosed and independently associated with high blood pressure (BP) and increased arterial stiffness in the female population [1▪].
Preeclampsia occurs in 3–5% of pregnancies in developed countries and in up to 7.5% worldwide  and remains one of the leading causes of maternal death. Furthermore, it increases the overall cardiovascular risk by two to four times and, for this reason, it has been recognized as an independent gender-specific cardiovascular risk factor .
Pregnant women are exposed to several risk factors that are commonly associated with OSA patients, such as an increase in body weight and fluid retention. Therefore, a pathophysiological link between gestational hypertension, preeclampsia and sleep-disordered breathing (SDB) has been postulated.
In this review, we summarize the data on the pathophysiology and the prevalence of this association according to the most recent literature. Furthermore, we review the efficacy of continuous positive airway pressure (CPAP) and the effect on haemodynamics and clinical outcomes of women at risk of preeclampsia.
PREVALENCE OF OBSTRUCTIVE SLEEP APNEA IN PREGNANCY
The precise prevalence of SDB in pregnant women remains unknown, but it is likely to vary during pregnancy, being higher in the third trimester .
Several studies have tried to describe the prevalence by analysing SDB-related symptoms. However, the results were conflicting. Ayrim et al. found the prevalence of snoring during pregnancy in the third trimester to be 20.5%, but Higgins et al. showed that about a third of 4074 pregnant women were classified as being at high risk of OSA, when using the Berlin questionnaire. The Berlin questionnaire  is a simple questionnaire used to screen for sleep apnea and identify the risk (low–high).
Interestingly, Antony et al.[8▪] revealed that the Berlin questionnaire predicts gestational hypertension better than the Epworth Sleepiness Scale , underlining the importance of SDB-related features rather than the isolated symptom of excessive daytime sleepiness.
Other studies have focussed on the actual diagnosis of SDB during pregnancy. Yin et al. studied 69 nonobese women in the third trimester of pregnancy using nocturnal pulse oximetry. They confirmed a low prevalence of SDB, as defined by a 4% oxygen desaturation index greater than 5/h, with only one woman of the studied patients being affected.
However, in contrast to the low prevalence described in this study, it should be mentioned that the prevalence of OSA in the general middle-aged female population in large population-based cohorts was higher, 2% in the 1990s and 3% in 2013 . This difference might be caused by the small sample size and, furthermore, nocturnal pulse oximetry is limited in its accuracy to record different features of sleep disruption caused by SDB.
Recently, Pien et al.[12▪▪] undertook the most comprehensive prospective study in this field so far. The authors enrolled 105 women whose pregnancy was 14 weeks of gestation or less. They followed the women and performed full polysomnography (PSG) during the first and the third trimester of gestation. It was found that during the third trimester of pregnancy, 26.7% of the enrolled women had OSA, with 23 women having mild OSA [apnea-hypopnoea index (AHI) 5–14], four had moderate OSA (AHI 15–29), and in one case the woman had severe OSA (AHI≥ 30). Most importantly, they found an increase of the AHI from the first to the third trimester (2.1 versus 3.7/h, P = 0.009). Of note, the authors deliberately recruited obese women [mean BMI 34.1 (7.9) kg/m2], and their results might not reflect the findings in a more general cohort of pregnant women. However, this study assessed pregnant women using PSGs prospectively for the first time. Although the authors demonstrated that the prevalence and severity of SDB increases during pregnancy, the SDB did not impact the development of gestational hypertension and preeclampsia. On the one hand, from these data it seems likely that there is little impact of OSA on uncomplicated pregnant patients. On the other hand, there is evidence that preeclamptic patients tend to develop upper airway narrowing during sleep and that they complain of snoring which suggests a higher prevalence of SDB . Furthermore, in patients with gestational hypertension, 38% had also developed SDB, and most of those with a respiratory disturbance index (RDI) less than 5/h demonstrated prolonged periods of inspiratory flow limitation during sleep [14▪]. This further supports the concept of SDB in gestational hypertension as being primarily due to partial upper airway obstruction with little or no arterial oxygen desaturation.
PATHOPHYSIOLOGY OF OBSTRUCTIVE SLEEP APNEA DURING PREGNANCY
The female body undergoes significant changes in the physiological and hormonal homeostasis during pregnancy; gestational weight gain, pregnancy-associated naso-pharyngeal oedema, decreased functional residual capacity and an increased frequency of arousals from sleep can contribute to the likelihood of developing SDB .
Some of these changes also occur in OSA, independent of pregnancy status, and potential mechanisms have been hypothesized to explain a link between SDB and the pathogenesis of gestational hypertension and preeclampsia [15–23] (Fig. 1).
Intermittent hypoxia caused by OSA seems to trigger both an elevated sympathetic activation and inflammatory pathways that can lead to endothelial dysfunction (Fig. 2). These responses have largely been studied in animal models  with intermittent hypoxia leading to oxidative stress, inflammation and reductions in antioxidant levels. In humans, the direct association between intermittent hypoxia and preeclampsia has not been clearly demonstrated. Nonetheless, Benyo et al. showed that inducing hypoxia in the human placenta can lead to the production of inflammatory cytokines, which may contribute to the pathophysiology of preeclampsia.
As a result of intermittent hypoxia, an inflammatory response can contribute to endothelial dysfunction in pregnant women. Several studies [26,27] have demonstrated the association of poor sleep quality and short sleep duration, common features of SDB, with an increased inflammatory response, adverse pregnancy outcomes and preeclampsia. However, there is still a lack of evidence that SDB causes an increased inflammatory response through intermittent hypoxia.
Intermittent hypoxia has also been associated with an increased sympathetic activity in early gestation.
Schobel et al. studied a group of patients with preeclampsia using microneurography, a technique that allows visualizing and recording the traffic of nerve impulses that are conducted in peripheral nerves.
They showed that the sympathetic neural activity in a group of patients with preeclampsia was more than twice that of a group of nonpregnant women with hypertension and more than three times as high as that in normotensive pregnant women.
As a direct consequence of an increased sympathetic tone, vasoconstriction occurs which is more pronounced in skeletal muscles of preeclamptic women compared with normotensive pregnant women.
Lastly, intermittent hypoxia might lead to a dysregulation of the hypothalamic-pituitary-adrenal system causing decreased glucocorticoid sensitivity and an increased inflammatory response .
ASSOCIATION OF OBSTRUCTIVE SLEEP APNEA WITH GESTATIONAL HYPERTENSION AND PREECLAMPSIA
The association between SDB, gestational hypertension and preeclampsia has been studied repeatedly. The study by Pien et al.[12▪▪] found that first trimester BMI and maternal age were independent determinants of third trimester OSA, but they found no significant associations between the first or third trimester AHI, OSA or change in AHI with gestational hypertension or preeclampsia. However, Yinon et al. had previously shown in a group of 17 women with preeclamptic toxaemia that pregnant women had a significantly elevated RDI compared with control patients [18.4 (8.4) versus 8.3 (1.3)/h, P < 0.05] and that BP correlated with the RDI and the endothelial function index.
More recently, a systematic review [31▪] underlined the association between maternal SDB and an increased risk of gestational hypertension and gestational diabetes, adjusting for potential confounders.
To demonstrate the haemodynamic effects of OSA in pregnancy, Edwards et al. studied 10 pregnant women with OSA who had no evidence of hypertensive disease and 10 women with OSA and preeclampsia. They found that in the group of patients with OSA and preeclampsia BP rises following upper airway occlusion revealed an increased responsiveness during rapid eye movement (REM) and non-REM sleep.
There is a good association of snoring with preeclampsia, rather than between the AHI and preeclampsia and other clinical outcomes of pregnancy . It has therefore been postulated that it is not the absence of airflow that is the most important feature of SDB in pregnant women at risk of preeclampsia, but potentially the reduction of flow with increased work of breathing [14▪].
Connolly et al. described that patients with preeclampsia had a higher flattening index when compared with nonpreeclamptic female patients from each of the three trimesters of pregnancy and compared with matched nonpregnant female patients. The flattening index gives a measure of inspiratory flow limitation that is derived from the relationship of inspiratory flow to inspiratory duration.
Moreover, Izci et al. could confirm that women with preeclampsia have upper airway narrowing in upright and supine posture contributing to an increased upper airway resistance during sleep. Recently, Bourjeily et al.[35▪▪] confirmed that pregnant women suspected of SDB had greater inspiratory airflow limitation compared with nonpregnant controls.
CONTINUOUS POSITIVE AIRWAY PRESSURE FOR PREGNANT WOMEN AT RISK OF GESTATIONAL HYPERTENSION AND PREECLAMPSIA
Whilst the association of SDB with hypertension and the risk of preeclampsia seem plausible, the impact of CPAP therapy, the standard treatment for OSA, remains to be established. Several studies have investigated the possible role of CPAP as an adjunct treatment for pregnant woman who are at risk of preeclampsia. Some authors could demonstrate an effect of CPAP on BP , but there is still a lack of evidence for CPAP therapy with respect to specific pregnancy-related outcomes.
Blyton et al. and Edwards et al. described in a relatively small sample of women with preeclampsia that CPAP therapy achieved a better control of systolic and diastolic BP. They also determined that CPAP caused a reduction in the cardiac output and the total peripheral vascular resistance.
However, a lack of prospective data makes it difficult to define the effect of CPAP on maternal outcomes. Guilleminault et al. recruited 12 women with risk factors of preeclampsia and studied them using a PSG. The baseline RDI was 8.5 (2.6) events/h and all patients were commenced on CPAP therapy. All women used nasal nocturnal CPAP with a mean usage of 5.4 (0.6) h per night until the end of pregnancy. However, the study showed that the early use of CPAP at appropriate pressures was not sufficient to prevent the occurrence of preeclampsia, early spontaneous abortion or premature births.
A different study tried to establish whether treating SDB using a mandibular advancement device (MAD) would be better tolerated and whether it would achieve better results in terms of BP control. Reid et al.[14▪] randomized 24 patients to a single night of either autoset positive airway pressure or to a night of MAD and nasal strips. They did not find any significant differences in the morning BP measurements, but they described an association between improvement in BP and reduced levels of markers of inflammation, such as the tumour necrosis factor-α (Table 1) [39,40▪▪].
We have highlighted the current aspects of a complex interaction between SDB, hypertension and the risk of preeclampsia. The current level of evidence will be relevant for tailoring future research in this field, as many questions remain unanswered.
Firstly, the exact pathophysiology of preeclampsia remains unknown, but there is mounting evidence that underlines the importance of SDB and intermittent hypoxia. The pathways linking intermittent hypoxia, arousal from sleep, sympathetic activation and hypertension have been demonstrated for OSA, and it is likely that they similarly contribute to the development of gestational hypertension.
Furthermore, the complex interaction between the autonomous nervous system and the hormonal balance in pregnancy has led us to several interesting hypotheses. A study published in Nature by Kanasaki et al. hypothesized a causative role of the catechol-O-methyltransferase (COMT) in preeclampsia. COMT is a bivalent cation-requiring enzyme that contributes to inactivate catecholamines by O-methylation. Kanasaki et al. showed that pregnant mice deficient in COMT show a preeclampsia-like phenotype resulting from an absence of 2-methoxy-oestradiol, a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. These findings suggest that decreased COMT expression may contribute to the development of preeclampsia.
However, further studies revealed different results, and Palmer et al. did not find any significant differences in placental COMT expression in severe preeclampsia compared with either term or preterm normotensive cohorts of pregnant women.
Thus, further studies are required to better understand the relationship between SDB-induced hypoxia, arousal from sleep, sympathetic activation and the development of hypertension and preeclampsia.
In the clinical context, the evidence of an association between SDB and preeclampsia seems to be more obvious. Changes in the ventilation during pregnancy that result in partial airway obstruction and flow limitation combined with symptoms such as snoring are more likely to be associated with preeclampsia and gestational hypertension.
Nevertheless, the best effective way to treat both complete and partial obstruction of the upper airway remains CPAP therapy. Surprisingly, only a few studies have tested the effect of this treatment in patients at risk of preeclampsia. Despite the lack of randomized controlled trials, the existing prospective observational studies have shown a beneficial effect on BP control but not on clinical pregnancy-related outcomes [36–38].
It is difficult to treat hypertension in pregnant women because of the lack of available medication without potential adverse effects on the fetus. CPAP might therefore represent a better treatment with few side-effects in patients at risk of SDB and preeclampsia.
Lastly, the obesity epidemy in the general population has caused a rise in the prevalence of OSA [11,43]. This affects pregnant women and leads to an increased risk of SDB with the associated risk for gestational hypertension and preeclampsia. Further prospective studies are therefore essential to provide data about the effectiveness of CPAP treatment for both gestational hypertension and preeclampsia in women with OSA.
OSA might be associated with the pathophysiology of gestational hypertension and preeclampsia, but the precise pathomechanism remains to be identified. Inspiratory flow limitation is more commonly observed during the third trimester and might reflect the risk of gestational hypertension and preeclampsia better than the clearly defined and symptomatic SDB. Furthermore, the current evidence of the therapeutic benefit of CPAP in pregnant women at risk of preeclampsia is unclear.
Currently, neither the combined guidelines of the European Society of Hypertension and the European Society of Cardiology  nor the collaborative guidance of the National Institute for Health and Care Excellence and the Royal College of Obstetricians and Gynaecologists  recommend any specific treatment for SDB in women with gestational hypertension or preeclampsia.
However, it is likely that an increase in maternal obesity will lead to an increased prevalence of SDB in pregnancy and prospective, and adequately designed studies are therefore required to assess the clinical benefit of CPAP therapy in women at risk of preeclampsia.
Dr M.F. Pengo's research on OSA and hypertension has been partly funded by the Italian Hypertension Society.
Dr M.F. Pengo also wishes to thank Tommaso Fornasiero for his graphic design input. Review criteria References for this review were retrieved from the PUBMED-MEDLINE databases. Search terms included ‘eclampsia and obstructive sleep apnea’, ‘preeclampsia and sleep disordered breathing’, ‘hypertension in pregnancy’, ‘obstructive sleep apnea’ and ‘continuous positive airway pressure’. Most papers considered were full-text papers published in English language between 2001 and 2014.
Conflicts of interest
There are no conflicts of interest.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
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