The dangers of sleep disordered breathing in pregnancy

We spend one third of our life sleeping. As we rest, damaged tissues are repaired and cognitive function and energy levels are restored in preparation for an active day ahead. Sleep deficiency can greatly impact our health, highlighting the importance of good quality sleep. Abnormal breathing patterns during sleep, otherwise known as Sleep Disordered Breathing (SDB), are a common cause of sleep inadequacy. SDB includes a wide spectrum of conditions, from snoring to obstructive sleep apnoea (OSA). OSA occurs when throat muscles relax during sleep, causing the upper airway to collapse. Obstruction reduces airflow for around ten seconds or more, resulting in low levels of blood oxygen saturation (hypoxia). In the long-term, OSA-associated hypoxia can lead to potentially fatal conditions such as hypertension, cardiovascular disease and diabetes mellitus.

Pregnancy-associated SDB
Interestingly, pregnant women are at a higher risk of developing SDB, due to the physiological changes that occur during pregnancy. For example, plasma volume increases and capillary engorgement causes airway mucosa to thicken, resulting in nasal congestion as the lining of the nose, larynx and trachea swells. This can lead to gestational rhinitis development, which usually improves immediately after delivery. Nasal congestion is a major risk factor for SDB, therefore pregnant women are particularly at risk. Furthermore, during the later stages of pregnancy, the gravid uterus causes the diaphragm to elevate, reducing the functional residual capacity of the lungs by 20%. This may impact oxygen reserve and further contribute to upper airway collapsibility. Snoring is also much more frequent in pregnant (14–45%) compared to non-pregnant women of reproductive age (4%).

The strong association between SDB and pregnancy raises a number of questions: i) does SDB cause detrimental effects in the mother and foetus / newborn? ii) what physiological or biological factors predict the development of SDB in this young population? and iii) what are the mechanisms that result in these adverse effects? Professor Bourjeily and her colleagues have dedicated their research efforts to investigating these interesting questions.

Gestational hypertensive disorders
Professor Bourjeily and others have shown that pregnancy-associated SDB (including snoring and OSA) increases the risk of developing gestational hypertensive disorders such as hypertension and pre-eclampsia, even after considering other risk factors such as obesity. Gestational hypertension complicates approximately 6% of all pregnancies and pre-eclampsia is a severe pregnancy disorder, characterised by high blood pressure and either a high level of protein in the urine or other systemic manifestations. The condition may deteriorate further to ‘eclampsia’ and seizures may occur which may threaten the lives of the mother and child. Pre-eclampsia is also associated with pulmonary oedema, liver abnormalities and renal failure. Though pre-eclampsia is a short-lived condition, it has been suggested to be a precursor of future development of cardiovascular disease.

So, how does SDB cause pre-eclampsia? One of the possible mechanisms could be placental hypoxia. In a study, performed by Professor Bourjeily and her team, a quantitative analysis of immunohistochemical markers of hypoxia were compared between the placentas of pregnant women with OSA/snoring and non-snoring controls. Expression of the hypoxia marker carbonic anhydrase was more prevalent in OSA placentas (91.3%) compared to the controls (57.5%). In addition, the team has demonstrated that placenta secreted blood markers are altered in women with OSA compared to controls. Professor Bourjeily hypothesises that placental hypoxia that may occur as a consequence of SDB could trigger a cascade of events that lead to pre-eclampsia. The hypoxic placenta secretes a variety of different soluble molecules into the bloodstream that impacts maternal endothelial function. In fact, endothelial abnormalities have been demonstrated in patients with OSA, regardless of the severity level. Endothelial dysfunction is characterised by an imbalance of hormones that control blood pressure. Consequently, hypertension can develop which, if not monitored, can lead to heart disease.

Furthermore, inflammation could be the missing link between SDB and hypertensive disorders. Sleep disturbance is associated with high levels of interleukin-6 in the later stages of pregnancy. This inflammation marker is strongly associated with pre-eclampsia. Nevertheless, much more research is needed to fully understand this relationship.

Gestational diabetes
In a study conducted on 1,000 patients, Professor Bourjeily also demonstrated that there is a significant association between gestational diabetes and third trimester SDB (which includes snoring, gasping and apnoeas) regardless of other factors such as BMI and smoking. In addition, in a large population-based sample that included over 1.5 million women, a diagnosis of OSA was associated with an increased risk for gestational diabetes, after adjusting for multiple risk factors. Gestational diabetes affects 2–10% of pregnancies and is characterised by glucose intolerance. Serious pregnancy complications can result from gestational diabetes, including pre-eclampsia, increased risk of caesarean delivery and preterm labour. In addition, gestational diabetes is strongly associated with future development of type II diabetes, a highly morbid condition.

Excessively high blood glucose levels, as a result of SDB, may be related to a range of interlinking factors. For example, airflow limitation and hypoxia can result in increased sympathetic activation (part of the nervous system involved in the ‘fight or flight response‘), which can i) inhibit insulin secretion from the pancreas, ii) exacerbate insulin resistance (cells cannot respond to insulin signals which trigger glucose uptake from the blood) or iii) stimulate glucose release from liver cells into the bloodstream. Additionally, oxidative stress can damage pancreatic beta cells, where insulin is produced, resulting in a reduction in insulin secretion. Dr Bourjeily is currently investigating additional pathways that may link SDB and gestational diabetes.

Professor Bourjeily and others have shown that pregnancy-associated SDB (including snoring and OSA) increases the risk of developing gestational hypertensive disorders such as hypertension and pre-eclampsia

Foetal risk and delivery
Results from studies focusing on the consequences of SDB on foetal outcomes are conflicting. SDB (both snoring and OSA) appears to be associated with preterm birth (birth occurring before 37 weeks gestation) in multiple studies, including Dr Bourjeily’s. The risk of growth restriction and small for gestational age remains controversial. Dr Bourjeily is currently investigating the risk of growth restriction and other neonatal outcomes in a large population-based dataset that linked maternal and neonatal records. Other potential adverse foetal impacts include reduced heart and growth rate. Despite these inconsistent findings, the majority of studies provide supportive evidence that suggests that women who snore, have short sleep duration and OSA are at a higher risk of caesarean delivery, compared to controls.

Future studies
The work of Professor Bourjeily and her colleagues has greatly advanced our knowledge regarding the effects of pregnancy-induced SDB. However, more research is needed to fully understand mechanisms behind the association. The team are now focussing their research efforts on exploring why SDB prevalence more than doubles in later stages of pregnancy compared to earlier stages. By determining the physiological factors that predict the onset of SDB in late pregnancy, the team are aiming to create a model, alongside simple testing, that can be used as a preventative tool, to identify SDB development. The patient can then be treated before the SDB becomes more severe. As SDB is a relatively easy condition to treat with ways that are not thought to negatively impact the foetus, investigating this condition that may impact up to a third of all pregnant women should be a priority.

The majority of studies provide supportive evidence that suggests that women who snore, have short sleep duration and OSA are at a higher risk of caesarean delivery