Abstract
The proportion of the world’s population that is obese has tripled over the last 40 years, according to data from the World Health Organization. Women are more likely to be obese than their age- and country-matched male counterparts; women of reproductive age are no exception. Sleep-disordered breathing (SDB), a spectrum of conditions that range in increasing severity from loud snoring to obstructive sleep apnoea (OSA), is often co-morbid with obesity; in studies, 15–20% of obese pregnant women have OSA and the prevalence of OSA increases with age, BMI and in the presence of other co-morbidities.
Introduction
The proportion of the world’s population that is obese has tripled over the last 40 years, according to data from the World Health Organization. Women are more likely to be obese than their age- and country-matched male counterparts; women of reproductive age are no exception.1 Sleep-disordered breathing (SDB), a spectrum of conditions that range in increasing severity from loud snoring to obstructive sleep apnoea (OSA), is often co-morbid with obesity; in studies, 15–20% of obese pregnant women have OSA and the prevalence of OSA increases with age, BMI and in the presence of other co-morbidities.2–5 In low-risk populations of pregnant women, SDB impacts close to a third of pregnant women by the third trimester,6 but OSA impacts 9–27% of pregnancies by term.2–5 OSA results from repeated partial to complete upper airway obstruction during sleep that resolves with arousal; this phenomenon results in poor sleep, episodic hypoxaemia and hypercarbia. Pregnancy-related physical and hormonal changes can produce or worsen SDB; snoring is common in the third trimester.4,6,7 In the general pregnant population, OSA is likely underappreciated due to a number of factors, including no validated screening tools and a lack of provider awareness.8 This has been compounded by the perception that OSA is a disease of older people, especially older men, and differences in the signs and symptoms of OSA seen in women compared to men.9,10
Untreated OSA in post-menopausal women is well-established as a co-morbidity with cardiovascular, pulmonary and metabolic diseases; similarly, several recent studies have shown that OSA may also be associated with serious adverse maternal and fetal outcomes.2,3,5,11–14 In this chapter, we will discuss the following: pregnancy as a vulnerable period for the development or worsening of SDB, the associations between OSA and adverse maternal and fetal outcomes described in recent studies, the current peri-partum OSA screening approaches and recommendations regarding peri-partum management of OSA.
Pregnancy as a Vulnerable Period for Sleep-disordered Breathing
A number of pregnancy-related physiologic changes predispose women to sleep disruptions, including gastro-oesophageal reflux, nocturia, fetal movements, musculoskeletal changes producing discomfort, nasal hyperemia and SDB.15 Pre-pregnancy obesity and pregnancy-related weight gain are known risk factors for SDB in pregnancy, but other physiologic changes of pregnancy can also produce symptoms of SDB or worsen pre-existing SDB. For example, the upper airway of pregnant women undergoes mucosal hyperemia, narrowing of the oropharyngeal diameter and an increased Mallampati score (a measure of pharyngeal dimension that predicts difficult intubation). Decreased functional residual capacity and increased oxygen consumption can also exacerbate SDB.16 These changes are dynamic as pregnancy progresses, and can be exacerbated by hypertensive disorders of pregnancy (HDP), which are often associated with marked fluid retention.9,17 HDP are a spectrum of diseases that includes chronic hypertension (CHTN), gestational hypertension, pre-eclampsia and eclampsia.18 Some pregnancy-related factors may actually be protective, for example the increased respiratory drive or the recommendation for the lateral sleep position.
SDB in pregnancy likely exists as two entities, although studies to date have failed to differentiate between them. Some women likely enter pregnancy with diagnosed or undiagnosed SDB and may experience worsening of their pre-existing airway obstruction (chronic OSA complicated by pregnancy). Other pregnant women may develop SDB in pregnancy related to various factors: weight-gain, respiratory changes of pregnancy or HDP (gestational OSA). Small studies have suggested that gestational OSA may improve or resolve entirely after pregnancy.19 The impact and natural history of chronic OSA complicated by pregnancy vs gestational OSA during and after pregnancy have not been well-described in the literature to date. However, some literature has suggested that outcomes of SDB may vary based on whether the condition has preceded pregnancy or developed during pregnancy.20
Two recent studies have provided preliminary evidence for the existence of these two phenotypes. Although neither tested women for OSA prior to pregnancy (as that would be a difficult task given rates of unplanned pregnancies) they do demonstrate the de novo development of OSA as pregnancy progresses.4,5 Pien et al. conducted overnight, in-lab polysomnography (PSG) studies on a cohort of pregnant women during early and late pregnancy. More women ruled in for OSA in the third trimester compared to the first (26.7% vs 10.5%).4 The strongest predictors of developing OSA in the third trimester in this cohort were age and BMI. Using the same apnoea-hypopnoea index (AHI) threshold, but a less inclusive definition of hypopnoea, another recent prospective study of a large cohort of nulliparous pregnant women found that more women had an AHI >5/h in mid-pregnancy compared to early pregnancy (8.3% vs 3.6%) using home sleep testing.5 The differences in the prevalence of SDB in these two cohorts may be due to differences in body habitus and co-morbidities, as well as differences in method used to define the condition (in-laboratory vs in-home). A small study of recently post-partum women demonstrated a 20% prevalence of moderate to severe OSA (AHI > 15/h) in women with a mean BMI = 30 kg m–2.21
The Associations of OSA in Pregnancy with Adverse Maternal Outcomes
Several retrospective and prospective recent studies, as well as national registries or population-based samples have provided evidence that women with OSA have a significantly increased risk of adverse maternal complications during pregnancy (Table 13.1).2–5,12–14,22–28 These studies have consistently shown an increased risk of HDP, including CHTN, as well as gestational diabetes (GDM) for women with OSA in pregnancy. However, two large population-based studies also demonstrated increased risks of severe pregnancy complications such as cardiomyopathy, congestive heart failure, hysterectomy, intensive care unit admission14 and maternal mortality after controlling for obesity.3
Table 13.1 Selected studies of hypertensive disorders of pregnancy and gestational diabetes risk in women with obstructive sleep apnoea that included objective sleep testing
| Authors, reference number | Study type | Number of mothers studied | Inclusion criteria | OSA status of mother | Gestational age at time of sleep testing | Adjusted odds ratio (95% confidence interval) | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Gestational hypertension | Pre-eclampsia | Hypertensive disorders of pregnancya | Eclampsia | Gestational diabetes | ||||||
| Bisson et al.47 | Case-control | 52 | Gestational diabetes; non-diabetic controls | Level 2 home sleep test | 24–33 weeks | – | – | – | – | No association |
| Bourjeily et al.14 | Retrospective, cross-sectional | 1 577 632 | OSA in pregnancy | ICD-9-CM codes | Varied | 1.7 (1.4, 2.0) | 2.22 (1.9, 2.5) | – | 2.95 (1.1, 8.0) | 1.5 (1.3, 1.7) |
| Champagne et al.22 | Case-control | 50 | Gestational HTN; normotensive controls | PSG ; AHI > 15 | Varied | 7.5 (3.5, 16.2) | – | – | – | – |
| Chen et al.12 | Retrospective, cross-sectional | 791 | – | ICD code assigned after PSG | Varied | 3.2 (2.1, 4.7) | 1.6 (2.2, 11.3)b | – | – | 1.6 (1.1, 2.5) |
| Facco et al.23 | Retrospective cohort | 143 | PSG in hospital records | AHI > 5 on PSG | Varied | 2.9 (1.1, 7.9)c | – | – | – | – |
| Facco et al.24 | Prospective cohort | 188 | High of risk pre-eclampsiad | AHI > 5 on level 3 home sleep test | 6–20 | – | No association | – | – |
|
| 28–37 | – | No association | – | – | – | |||||
| Facco et al.5 | Prospective cohort | 3705 | Nulliparity, singleton | AHI > 5 on level 3 home sleep test | 6–15 | – | 1.94 (1.07, 3.5) | 1.5 (0.9, 2.3)a | – | 3.5 (2.0, 6.2) |
| 22–31 | – | 2.0 (1.2, 3.2) | 1.7 (1.2, 2.5) | – | 2.8 (1.6, 4.8) | |||||
| Louis et al.25 | Retrospective cohort | 171 | OSA in pregnancy ; BMI-matched controls | PSG ; No PSG testing of controls | Varied | – | 2.0 (0.8, 5.0) | – | – | – |
| Louis et al. 2 | Prospective cohort | 182 | BMI > 30 kg/m2 | AHI > 5 on level 3 home sleep test | All gestational ages | – | 3.5 (1.3, 9.9) | – | – | No association |
| Louis et al.3 | Retrospective, cross-sectional | 55,781,965 inpatient discharges | – | ICD-9-CM codes | – | 1.3 (1.1, 1.5) | 2.5 (2.2, 2.9) | – | 5.4 (3.3, 8.9) | 1.9 (1.7, 2.1) |
| O’Brien et al.26 | Cross-sectional | 67 | Hypertensive disorderse; normotensive controls | Portable PSG; AHI > 5 | Varied | – | – | 2.0 (1.4, 2.8)e | – | – |
| Pamidi et al.13 | Meta-analysis | 16 studies included | – | PSG | varied | – | – | 2.3 (1.1, 4.5) | – | Not pooled |
| – | symptoms | varied | – | – | 3.1 (2.3, 4.3)f | – | 2.8 (2.0, 4.0) | |||
| Pien et al.4 | Prospective cohort | 105 | Stratified by BMI | In-lab PSG | 8–14 | – | 0.4 (0.1, 3.7) f | – | 2.4 (0.2, 23.7) | |
| repeated, 33–34 | – | 0.5 (0.1, 1.9) f | – | 2.1 (0.3, 13.3) | ||||||
| Reid et al.27 | Cross-sectional | 60 | Gestational HTN; normotensive controls | PSG | > 32 weeks | 8.31 (2.07, 33.43) | – | – | – | – |
| Xu et al.28 | Meta-analysis | 5 studies included | – | In-lab PSG or home sleep test or symptom-based | Varied | – | 2.0 (1.3, 2.9) | – | – | 1.4 (0.6, 3.2) |
| 3 studies included | Excluded symptom-based | Varied | – | 2.3 (1.8, 3.2) | – | – | ||||
a Hypertensive-disorders of pregnancy composite outcome included: mild, severe and superimposed pre-eclampsia and eclampsia, plus antepartum gestational hypertension.
b Composite outcome of pre-eclampsia and eclampsia.
c Composite outcome for moderate to severe OSA included gestational hypertension, pre-eclampsia, severe pre-eclampsia, eclampsia and gestational diabetes.
d High risk for pre-eclampsia defined as having either BMI > 30 kg/m2, chronic hypertension, pregestational diabetes mellitus (type 1 or 2), prior history of pre-eclampsia, and/or twin gestation.
e Hypertensive disorders composite inclusion criteria: chronic hypertension, gestational hypertension or pre-eclampsia.
f Composite outcome included gestational hypertension or pre-eclampsia.
AHI, apnoea-hypopnoea index; BMI, body mass index; HTN, hypertension; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; OSA, obstructive sleep apnoea; PSG, polysomnography
Chronic Hypertension in Pregnancy
CHTN is part of the spectrum of HDP. It is defined by the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy as blood pressure >140 mmHg systolic and/or 90 mmHg diastolic or use of antihypertensive medications prior to pregnancy or before 20 weeks’ gestation.18 CHTN seems to be an important co-morbidity for OSA, regardless of pregnancy status.29 The recent large Nulliparous Pregnancy Outcomes Sleep Disordered Breathing (nuMom2b-SDB) substudy supported the findings of smaller, earlier studies that CHTN is significantly more common among pregnant women with OSA, and that this prevalence increases with OSA severity (2% vs 8%, OSA negative vs OSA positive; p <0.001).5 However, the number of women in this large trial with OSA was small (n = 114). A recent large database study by Bourjeily et al. showed a high prevalence of CHTN among gravidas with OSA compared to gravidas without OSA (29% vs 3%, p < 0.001).14 These findings are confirmed by four smaller prospective studies where OSA was measured by objective sleep testing and defined as AHI >5/h.2,26,30,31 CHTN in pregnancy is a known risk factor for pre-eclampsia; 17–29% of women with CHTN will go on to develop superimposed pre-eclampsia.32 Though this association is not entirely surprising, the co-existence of these two conditions at an early age is worthy of attention, as it indicates that the risk of cardiovascular risk in women starts at a young age and further draws attention to pregnancy being a potential window for early intervention to reduce the risk of cardiovascular disease.
Hypertensive Disorders of Pregnancy
Gestational hypertension is characterized by a new onset of elevated blood pressure after 20 weeks’ gestation in the absence of proteinuria. Pre-eclampsia, in contrast, is diagnosed after 20 weeks’ gestation with blood pressure elevation in addition to proteinuria or other systemic dysfunction.18 Early-onset pre-eclampsia (before 34 weeks) is associated with more severe morbidity for both mother and fetus; the two phenotypes may differ in their underlying pathophysiology.33 In high-resource countries, HDP affect approximately 4–10% of pregnant women, but these disorders are more common in low-resource countries.34 HDP are a significant contributor to maternal morbidity and mortality worldwide from secondary causes, including haemorrhagic stroke, acute cardiovascular disease and acute renal insufficiency.35 The impact of these disorders can have far-reaching ramifications for a woman’s long-term health; several studies have shown that women with pre-eclampsia have an increased risk for developing subsequent cardiovascular disease.18,36 OSA shares multiple co-morbidities with HDP such as CHTN, diabetes mellitus, obesity and advanced maternal age. However, only recently has OSA been linked with HDP.
Several recent studies and two 2014 meta-analyses have confirmed that OSA during pregnancy is associated with an increased risk of developing pre-eclampsia, while others have shown that women with HDP are at increased risk of having SDB (Table 13.1).2–5,12–14,22–28 In 2017 the nuMom2b-SDB substudy reported an increased risk of pre-eclampsia for mild and severe OSA in a large cohort of pregnant women that underwent unattended, level 3 home sleep testing at two time points in pregnancy, after adjusting for age, body mass index, weight gain and CHTN.5 This risk increased for women with severe OSA (AHI >15/h).5 The number of women who developed pre-eclampsia in this cohort was within the range reported by population studies of the incidence of pre-eclampsia (approximately 3–6%). While this represents the largest prospective cohort studied to date, only 16 women developed pre-eclampsia of the 114 women that had AHI >5 on home sleep testing early in pregnancy. 2,4,30 Three of the studies included in Table 13.1 that showed an association between HDP and OSA enrolled women with HDP and compared them to controls and found that the incidence of OSA was higher in the HDP groups.22,26,27
Three large, retrospective, population-based dataset studies have been conducted to date in Taiwan and in the United States; all three of these studies have shown an association between pre-eclampsia and OSA after controlling for obesity.3,12,14 Two meta-analyses confirmed the association.13,28
The underlying pathophysiological mechanisms for HDP are not well elucidated, and treatments are limited. The mechanisms that link OSA to HDP and other adverse maternal outcomes have not been defined. However, several pathways have been proposed by integrating data from non-pregnant populations and animal studies, as well as preliminary studies in pregnant women with OSA.37–40 Studies have not yet elucidated the effect of OSA treatment on the risk of HDP; additional studies are needed to determine if treatment of OSA with continuous positive airway pressure (CPAP) may play a role in the prevention of HDP.41,42
Cardiovascular Diseases
Several studies suggest that HDP can have long-term health consequences, particularly from cardiovascular disease.36 It is unknown, however, whether HDP cause cardiovascular disease, or whether HDP are an early manifestation of cardiovascular disease in women who will later develop more clinically apparent disease. Some have hypothesized that the double insult of OSA in pregnancy and HDP may confer additional long-term cardiovascular risk.19,43 The association of OSA with long-term cardiovascular disease in non-pregnant adults is well-established.29,44 Evidence from the large, national inpatient database study by Louis et al. showed that pregnant women with OSA were at significantly increased risk of having co-morbid cardiomyopathy (aOR 9.0, 95% CI 7.47–10.87), congestive heart failure (aOR 8.94, 95% CI 7.45–10.73) and pulmonary oedema (aOR 7.5, 95% CI 4.63–12.15) during their pregnancy or delivery admission. This study also showed that pregnant women with OSA were five times more likely to die in the hospital during a pregnancy or delivery admission than women without OSA.3 These effects were unchanged after controlling for obesity, but there was no distinction made for OSA that pre-existed pregnancy. Recently, data from the National Perinatal Information Center demonstrated a similarly increased risk of adverse maternal cardiovascular outcomes in women with OSA. After adjusting for obesity and co-morbidities, women with OSA (by ICD-9 code) were at greater risk of developing pulmonary oedema (aOR 5.1, 95% CI 2.3–11.1), congestive heart failure (aOR 3.6, 95% CI 2.3–5.7) and cardiomyopathy (aOR 3.6, 95% CI 2.3–5.6). Though the latter study did not demonstrate an increased risk of mortality, it showed a significantly increased risk of admission to the intensive care unit. Data from the large, prospective nuMom2b Heart Health study may clarify the impact of OSA in pregnancy on a woman’s future cardiovascular health.45 Cardiovascular disease is one of the leading causes of maternal death in high-resource nations.46
Gestational Diabetes Mellitus
Several studies have investigated the association between OSA in pregnancy and GDM (Table 13.1).3–5,12–14,30,47 This was demonstrated in a 2014 meta-analysis (pooled aOR 1.86, 95% CI 1.30–2.42) 13 and two large population-based studies.3,14 The nuMom2b substudy also showed an increased risk of GDM for mothers with OSA after adjusting for age, BMI, CHTN and pregnancy-related weight gain.48 The risk of GDM was increased for women with severe OSA (AHI >15/h) (aOR 8.44, 95% CI 1.90–37.60) and for women with OSA in mid-pregnancy.48 More so, the prevalence of SDB defined as an AHI >5 events per hour of sleep using in-laboratory PSG in women with GDM is elevated and has been proposed to be as high as 70% in a sample consisting mainly of African American women.49 However, other studies with more racial diversity did not show similarly elevated prevalence.50 Mechanisms examining the link of SDB to GDM have been hypothesized, but mechanistic data are sorely lacking.50, 51 To date, no studies in pregnant women have examined the effect of OSA treatment with CPAP therapy on glucose tolerance, although there is some modest data to suggest that it may improve glycemic control in non-pregnant adults.52 Studies are needed to elucidate if nocturnal CPAP therapy may impact the risk of GDM in pregnant women.
The Associations of OSA in Pregnancy with Adverse Fetal Outcomes
Questions about the potential impact of chronic sleep disruption, nocturnal hypoxaemia and the neuroendocrine alterations associated with OSA on the placenta, and fetal wellbeing and growth have been the focus of several preliminary studies. However, the results and outcomes reported have been inconsistent. The studies that used objective measures to define OSA and study its impact on fetal outcomes are summarized in Table 13.2.
Fetal Growth Restriction
OSA in pregnancy and fetal growth restriction (FGR) share several risk factors: obesity, advanced maternal age and HDP. Some have suggested that common underlying pathways may connect these co-morbidities.4,5,23 Observational studies of pregnant women that live at high altitude with chronically low arterial oxygen partial pressures demonstrate an increased risk of both HDP and FGR.53,54 This association has been investigated through in vitro and animal studies that suggest that the partial pressure of oxygen plays a crucial role in placental development, and that disruptions of oxygen partial pressure may give rise to the abnormal placental development that is characteristic of both HDP and FGR.55,56 In a 2014 meta-analysis, Pamidi et al. reviewed seven studies that investigated the association between SDB and low neonatal birth weight, but reported no significant association between the two (Table 13.2).13 In another 2014 meta-analysis, Ding et al. analyzed 11 studies that reported FGR (as opposed to neonatal birth weight) and calculated an increased risk of FGR for women with SDB (Table 13.2).57 Both of these meta-analyses included studies with heterogeneous methods of determining SDB status, including symptom-based assessments, which have not been shown to be reliable in pregnancy.
Table 13.2 Fetal and neonatal complications in studies of parturients with obstructive sleep apnoea
| Author | Study type | No. of mothers studied | OSA status of mother | Pre-term birth(<32 wks) | Pre-term birth(< 37 wks) | 5-min Apgar <7 | NICU/ SCN | Hyper-bilirubinemia | Peri-natal death | LGA | SGA | LBW |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bin et al.11a | R |
| ICD code | – |
|
|
| – |
|
| 0.8 (0.6–1.1) | – |
| Chen et al.12 | R |
| ICD code | – |
|
| – | – | – | – | 1.3 (1.1–1.7) | 1.8 (1.3–2.4) |
| Ding et al.57 | SR | 24 studies analyzed | Heterogeneous | – |
|
|
| – | – | – | 1.4 (1.2,1.7) | 1.9 (1.4,2.5) |
| Felder et al.58 | R | 2 707 207 overall | ICD code | – | 1.5 (1.2, 1.8) | – | – | – | – | – | – | – |
| Louis et al.3 | R | 55 781 965 overall | ICD code | – |
| – | – |
| – | 1.2 (1.0–1.5)d | – | |
| Louis et al.2 | P |
| AHI > 5 HST |
|
| – |
|
| – | – | – | – |
| Pamidi et al.13 | SR | 7 studies analyzed | Heterogeneous | – | – | – | – | – | – | – | – | 1.4 (1.1,1.7) |
| Pien et al.4 | P | 105 | In-lab PSG | – |
| – | – | – | – | – | – | 1.7 (0.4–7.3) |
All studies include objective methods to define obstructive sleep apnoea; meta-analyses include both symptom-based and objective assessments.
aAdjusted relative risk (95% CI) reported by Bin YS et al.
bReported as ‘Early Onset Delivery (ICD-9 CM 644.2x)’ by Louis JM et al.3
cReported as ‘Stillbirth (ICD-9 CM 656.4x, V27.x)’ by Louis JM et al.3
dReported as ‘Poor fetal growth (ICD-9 CM 656.5x)’ by Louis JM et al.3
R, retrospective, population-based, cross-sectional analysis; C, controls; OSA, obstructive sleep apnoea; SR, systematic review; P, prospective, observational; OSA, obstructive sleep apnoea; HST, home sleep test; PSG, polysomnography; NICU, neonatal intensive care unit; SCN, special care nursery; LGA, large for gestational age); SGA, small for gestational age; LBW, low birth weight <2500 g
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