Sleep disordered breathing in women of childbearing age & during pregnancy

Transcription

1 Review Article Indian J Med Res 131, February 2010, pp Sleep disordered breathing in women of childbearing age & during pregnancy Katéri Agnès Champagne, R. John Kimoff, Peter Charles Barriga * & Kevin Schwartzman Department of Medicine, Respiratory Epidemiology & Clinical Research Unit, McGill University Health Centre & * Department of Microbiology, Santa Cabrini Hospital, Montreal, Quebec, Canada Received November 12, 2008 Obstructive sleep apnoea (OSA) affects 11 per cent of pre-menopausal women though it often remains undetected. Women may present differently than men, and the classic findings of snoring, witnessed apnoeas and sleepiness may not be observed. Factors which predispose to OSA include polycystic ovarian syndrome, obesity, retromicrognathia, and hypothyroidism. OSA may contribute to neurocognitive dysfunction, depression, hypertension and metabolic syndrome. Emerging evidence indicates that snoring and OSA increase during pregnancy. For normal women with normotensive, low-risk pregnancies the prevalence of OSA is very low. Among normotensive pregnant women with high risk pregnancies, the prevalence of OSA is high and is even higher among those with gestational hypertension/preeclampsia during pregnancy. Incident snoring, which is a marker for OSA, is associated with an increased risk of developing gestational hypertension. Recent studies indicate that OSA per se is an independent risk factor for gestational hypertension/pre-eclampsia and may contribute to other poor obstetrical outcomes. The diagnostic test of choice for OSA is a polysomnography with electroencephalogram. Milder degree of disease than what is usually considered clinically significant among men or non-pregnant women appears to be relevant for foetomaternal outcomes. There seems to be benefit for blood pressure control to treating even milder degrees of OSA with CPAP, both acutely and over the 9 months of pregnancy. Chronic hypertensive women should be strongly considered for diagnosis and treatment of OSA prior to or beginning as early as possible in pregnancy to help maintain blood pressure control. Increasing awareness of OSA among maternal health care providers is important given the potential benefits for pregnancy and other health-related outcomes associated with identification and treatment of OSA. Key words Gender - gestational hypertension - obesity - preeclampsia - pregnancy - sleep apnoea Sleep apnoea is a prevalent, yet often unrecognized condition that may have major adverse consequences for women in their childbearing years. By far the most common form of sleep apnoea is obstructive sleep apnoea (OSA), where repeated dynamic collapse of the upper airway during sleep leads to frequent, intermittent cessation of airflow despite ongoing respiratory efforts. Upper airway resistance syndrome, a milder form of obstructive sleep apnoea syndrome (OSAS) is characterized by increasing respiratory efforts to maintain breathing and is terminated by an arousal. It is part of the continuum of OSA 1 though it may require special diagnostic technology to demonstrate its presence 2. Rarely disorders of ventilatory drive can 285

2 286 INDIAN J MED RES, FEBRUARY 2010 lead to central sleep apnoea, characterized by repeated pauses in respiratory efforts. Oxygen desaturation may occur with both types of sleep apnoea. These respiratory disturbances are often terminated by transient arousals from sleep, which are associated with re-opening of the airways or resumption of respiratory efforts. OSAS was first recognized among older obese men who presented with excessive daytime sleepiness, loud habitual snoring and witnessed apnoeas. Though this classic presentation holds true, it does not represent the only presentation of OSAS in the general population. Overemphasis on this presentation may hinder the recognition of different presentations including among the younger, non obese individuals and women. Since the first retrieved case report of OSA in pregnancy in , there are several studies supporting an association between OSA and hypertensive disorders of pregnancy, suggesting that OSA does not spare younger women. The first section reviews sleep disordered breathing in non pregnant women of child-bearing age including the epidemiologic data, the clinical presentations among women, risk factors, tools for screening, casefinding, and cardiovascular, metabolic and psychiatric consequences of untreated obstructive sleep apnoea and the second section, reviews snoring and sleepdisordered breathing (SDB) during pregnancy. SLEEP DISORDERED BREATHING IN NON- PREGNANT WOMEN OF CHILD-BEARING AGE Epidemiology The OSA is a frequent but often unrecognized condition, especially in younger women. In the Wisconsin Sleep Cohort Study, a population-based study of American workers, the prevalence of moderate to severe OSA [defined as an apnoea-hypopnoea index (AHI) > 15 events/h of sleep] among women, yr old was 4.4 per cent (95% CI %) while presence of at least mild degree (AHI 5) of OSA was present among 6.5 per cent (95% CI %) of the women 4. In the same cohort, among pre-menopausal women, the prevalence of mild sleep apnoea was 10.8 per cent whereas 3.6 per cent had at least moderate obstructive sleep apnoea 5. Recent Indian data demonstrated similar prevalence of OSA in an urban sample. Of middle class women, yr old, 7.4 per cent had at least mild sleep apnoea (AHI >5); 2.1 per cent had mild sleep apnoea on polysomnography associated with excessive daytime sleepiness 6. OSA is often unrecognized and therefore untreated. Ninety three per cent of women with moderate to severe OSA were not clinically diagnosed in the Wisconsin Sleep Cohort Study despite access to health care 7. Underdiagnosis was most frequently encountered among women, younger, poorer, non Caucasian, less educated individuals who had not yet developed hypertension or atherosclerotic disorder 7. Burden of disease The burden of disease associated with untreated OSA is important for society because it is a prevalent condition, affecting all age groups, and associated with significant social, work, and health impact. In comparison to persons without obstructive sleep apnoea, the presence of moderate or severe obstructive sleep apnoea was associated with an odds ratio of 2.9 (95% CI 1.5 to 5.6) of incident hypertension over a 4 yr follow-up period. Furthermore, even minimal degree of obstructive sleep apnoea (an AHI of ) was associated with greater odds of developing hypertension at 4 yr compared with those with no sleep apnoea 8. This association between obstructive sleep apnoea and hypertension is present in younger (40-59 yr old) but not older populations (>60 yr old) 9. In a case-control study of 103 women selected in a cardiology clinic and matched to 50 age-matched women from the population registry, the presence of obstructive sleep apnoea (AHI >5) was an independent risk factor for prevalent coronary disease with an odds ratio of 4.1 (95% CI ) adjusted for age, diabetes, hypertension, smoking, body mass index 10. OSA is an independent risk factor for prevalent and incident strokes OSA is an independent risk factor for incident atrial fibrillation 14. OSA is associated with prevalent congestive heart failure 15,16, prevalent glucose intolerance and insulin resistance even after adjustment for confounders 17,18. Moreover, the oxygen desaturation index (number of episodes of reduction in oxygen saturation by >4%, per hour of sleep) is a better predictor of insulin resistance than body mass index 19. However, the association between OSA and metabolic abnormalities has not yet been demonstrated in the Indian population. In a case-control study from India, among patients with OSA obesity, not obstructive sleep apnoea was associated with insulin resistance, lipid abnormalities, leptin and adiponectin levels 20. However, because of the sample size, a clinically significant association could not be excluded 20.

3 Champagne et al: OSA & pregnancy 287 Clinical presentation of obstructive sleep apnoea in women The classic OSAS presentation that is, older obese man with loud and habitual snoring, witnessed apnoeas and excessive daytime sleepiness only represents a fraction of all cases with OSA in a population-based sample 21. In a sleep laboratory sample where women with obstructive sleep apnoea were matched to men for age, AHI, BMI and Epworth Sleepiness score, women complained more frequently of insomnia and nocturnal palpitations, were less likely to report witnessed apnoeas, were more often known for depression, hypothyroidism, asthma and allergies than men 22. Compared to men with OSA, women referred for evaluation at a sleep lab more frequently, had a previous diagnosis of migraine, fibromyalgia, depression or irritable bowel syndrome and more commonly reported night sweats and lack of energy 23. Taken together, these studies suggest that the reasons for consultation, the symptoms and comorbidities differ in women compared to men, possibly contributing to an under-recognition of the syndrome by physicians but also by the general population as both may have focused on the classic obstructive sleep apnoea syndrome presentation for years. Risk factors While women are generally less likely than men to develop obstructive sleep apnoea, other risk factors include age, obesity, craniofacial features associated with a narrowed upper airway (long, narrow face 24, large tonsils, retro-micrognathia), smoking, chronic rhinitis 25, asthma 26, polycystic ovary syndrome 27, and menopause. Obesity is a well-demonstrated risk factor for obstructive sleep apnoea whether measured by BMI, neck circumference, waist/hip ratio, waist circumference, skin-fold thickness, weight 4. Though a body mass index above 30 kg/m 2 is used in western populations, World Health Organization defines obesity among Indian women as a body mass index > 25 kg/ m 2 or a waist-hip ratio >0.8 or waist circumference > 88 cm 6. These obesity measures were demonstrated to be significant risk factors for obstructive sleep apnoea among Indian women 6. Among adults with mild obstructive sleep apnoea (AHI >5), obesity accounts for 41 per cent of the attributable risk and 58 per cent among those with moderate to severe (AHI >15) sleep apnoea 28. Because of the worldwide obesity epidemic, taking into account that 25 per cent of Indian urban men and 36 per cent of women are obese 20, the strong link between obesity and OSA, its prevalence will be a growing problem including among women of childbearing age. Craniofacial anatomy could be especially important in Asian populations 25. In a case-control study, craniofacial features including typical increased maxillomandibular protusion were more important risk factors for obstructive sleep apnoea than obesity among FarEast Asians (Japanese, Chinese, Korean) than among Caucasians 29. In a case-control study of 105 Asian living in United States (including a small number of Americans of Indian origin) matched for BMI, age and sex to 99 Caucasians, Asians tended to have significantly more severe OSA on the polysomnography though of similar severity on questionnaire-based assessment of symptoms 30. The odds ratio for Asians to have severe OSA (AHI >50 or minimum oxygen saturation <69%) was 2.51 (95% CI ) compared to Caucasians 30. Chronic rhinitis including allergic rhinitis is a risk factor for incident snoring, a marker of OSA 31,32 and is a risk factor for OSA in children. Polycystic ovarian syndrome is an important risk factor relevant to women of reproductive age. In presence of polycystic ovarian syndrome, the odds of having OSA is 30.2 (95% CI ) compared to normal women 27. The prevalence of obstructive sleep apnoea among young women with polycystic ovarian syndrome could be as high as 70 per cent 33. Routine risk assessment for OSA is now recommended for all women with polycystic ovarian syndrome 34. Menopause is associated with a 2.6 odds ratio of having obstructive sleep apnoea (AHI >5), adjusted for age, body habitus, smoking, exercise, alcohol, education, cardiovascular disease, self-rated evaluation of health 5. Pregnancy is a risk factor for snoring and OSA in obese women 38. In an Indian sub-urban community-based study 6, risk factors for obstructive sleep apnoea were shown to overlap risk factors identified in western society, namely, obesity (body mass index >25 or waist hip ratio >0.8 in women), male gender, and age. Upper socio-economic class was a risk factor in India and could be due to residual confounding. Craniofacial features were not evaluated in this study 6. Screening and case-finding of obstructive sleep apnoea among women of childbearing age No screening tool has been specifically developed and validated to help identify women of childbearing

4 288 INDIAN J MED RES, FEBRUARY 2010 age or more specifically during pregnancy who may have obstructive sleep apnoea. The most commonly used screening questionnaire, the Berlin Questionnaire with validated versions in India 39 focuses on the classic presentation of obstructive sleep apnoea with questions related to snoring, respiratory pauses, obesity and hypertension. It has been validated initially in an Internist and Family Physician practice 40 then used in different countries and settings including cardiology clinics 14,41, stroke clinics 42 and preop setting 43, where populations were older (average yr old), often with a predominance of men and a higher prevalence of the classic presentation of obstructive sleep apnoea. We could not retrieve a study validating the Berlin questionnaire against the reference method in a community-based sample of women of childbearing age or in an obstetrical population. The Epworth Sleepiness Scale is a discriminative tool of sleepiness measuring on a graded scale the propensity to falling asleep in 8 situations where different levels of attention are required 44. It is not a discriminative or evaluative tool for obstructive sleep apnoea. Though OSA is often recognized in sleep clinics to cause excessive daytime sleepiness, sleepiness was absent among half of those diagnosed with moderate sleep apnoea on polysomnography in a population-based study 45. In the same study, excessive daytime sleepiness was frequently encountered among those without evidence of obstructive sleep apnoea. Interestingly, the most common causes of excessive daytime sleepiness were not related to obstructive sleep apnoea syndrome itself 45,46. There is evidence that the Epworth Sleepiness Scale is less likely to capture adequately the construct of sleepiness in non pregnant women compared to men in population-based studies 47. In a population-based study of pregnant women, snoring accounted for less than 2 per cent of the variance in sleepiness 48. Measuring subjective sleepiness is useful clinically and recommended once obstructive sleep apnoea is suspected to guide on the urgency of the management and the management itself but this scale should not be used to screen for obstructive sleep apnoea per se. There is a need to develop a screening tool that will recognize the peculiar characteristics of obstructive sleep apnoea among young women prior to and during pregnancy to facilitate research in this population and to guide clinicians in practice. Case-finding Identification of young women at higher risk for obstructive sleep apnoea is complicated as they are unlikely to have yet developed medical complications such as hypertension or depression due to unrecognized OSA. Nonetheless, once hypothyroidism, obesity, depression, hypertension, metabolic syndrome or cardiovascular disease are present, health care provider should consider the possibility of underlying obstructive sleep apnoea. This is especially relevant in the presence of smaller upper airways. Women who have allergic rhinitis, asthma, nasal congestion of any cause, mouth breathing, are at higher risk as well for obstructive sleep apnoea. Women with hirsutism, irregular menstruations, glucose intolerance/insulin resistance should be considered for both polycystic ovarian syndrome and obstructive sleep apnoea. SLEEP DISORDERED BREATHING DURING PREGNANCY Pregnancy is often the only time that women of childbearing age might encounter a health care provider. This is a unique opportunity for the screening and case-finding of women at risk or with unrecognized obstructive sleep apnoea, hopefully years prior to the development of the full blown complications of untreated obstructive sleep apnoea and may be even to prevent its development. This section reviews the published literature which addresses the association between pregnancy and sleepdisordered breathing (SDB), the association between SDB and gestational hypertension/pre-eclampsia, the association between SDB and other adverse maternofoetal outcomes, and the impact of treating sleepdisordered breathing on obstetrical outcomes. Finally two special considerations: fertility and anaesthesia in the context of SDB will be discussed. A search of the English and French literature on pregnancy and SDB yielded several case-series and larger observational studies as well as a few interventional trials. Several papers were excluded due to unclear or missing information. These include a casecontrol study comparing pregnant women with OSA but with and without hypertension as participants were selected specifically based on blood pressure values, no information was provided as to how many, among those approached, had gestational hypertension or preeclampsia and foetal weight data were not provided 49, one article in Japanese 50, one in German 51, four without information on obstetrical outcomes 52-55, one providing information on severity of obstructive sleep apnoea in pregnancy and post-partum but no information on the outcome of those pregnancies 56.

5 Champagne et al: OSA & pregnancy 289 Case report data summary This summary includes data from 22 papers containing information on 47 pregnancies among 43 women 3, Baseline characteristics: Mean age was 29.1 yr (range yr). Most were primigravid and all pregnancies were singleton. Based on BMI, 57 per cent were obese or morbidly obese, 14 per cent were overweight, 24 per cent had a normal weight, 5 per cent were underweight. Sleep characteristics: Sleep apnoea diagnosis was made on clinical grounds alone in 13, on polysomnography and clinical features prior to pregnancy in 13; in the first trimester in 5, in the last trimester in 5, post partum in 6. All but three had obstructive sleep apnoea. Two had exclusively central apnoeas 62,71. One had central and obstructive sleep apnoea presenting in the context of hypothyroidism combined with a lingual thyroid 66. Based on the polysomnography results 1, OSA was severe in 16, moderate in 9, mild in 4, unspecified in three. The nadir of saturation was below 90 per cent in 27 of 28 parturients, below 80 per cent in 14, and below 50 per cent in 6. The baby whose mother had the lowest saturation (20%) died in utero at 26 wk. Twenty women received no treatment for sleep apnoea during pregnancy, one was intubated for apnoea and delivered immediately at 29 wk 71, one had a tracheostomy at 22 wk 59, and the remaining women used positive airway pressure (continuous or bi-level). Positive airway pressure was initiated prior to pregnancy in 14 women, during the first trimester in 6, and in the third trimester in 6. Reported risk factors for OSA include elevated BMI, asthma or respiratory allergies, and narrow upper airway (micrognathia, retrognathia, crowded oropharynx, ogival hard palate, narrow nasal passage). In 15 women, sleep apnoea was documented prior to pregnancy. Eleven had documented persistance of sleep apnoea post-partum. In 13 women, obstructive sleep apnoea worsened in pregnancy based on an increase in snoring, sleepiness, AHI, or CPAP requirements. Post-partum, severity of sleep apnoea was decreased clinically or on repeat polysomnography when performed but did not disappear. In addition, in one case-series, ten women were diagnosed in pregnancy with OSA and had a repeat polysomnography three months post-partum. Based on data provided in the graphs, the median AHI was 54 in pregnancy and 18 post-partum, suggesting marked improvement post partum 56. Maternal outcomes: Sixteen of the 47 pregnancies were preceded or complicated by increased blood pressure. Eleven developed a hypertensive disorder during pregnancy. Seven were labelled as pre-eclampsia, although not all met unequivocal criteria for this diagnosis. Two additional women had borderline blood pressure : one at term (140/88 mm of Hg) 61 and one from the onset of pregnancy ( /90-91) 75. Two had chronic hypertension 65,72. There were no reported cases of haemolysis elevated liver enzymes low platelet (HELLP) syndrome or eclampsia. One woman had severe pulmonary hypertension with right heart failure during pregnancy 67. Treatment was initiated at 29 wk of gestation. She lost 47 kg with CPAP at night and oxygen in the daytime, and corrected her right heart failure and improved her pulmonary hypertension prior to delivery. One completely reversed her severe pulmonary hypertension (100 mmhg systolic by right heart catheterization) and polycythemia with BiPAP prior to pregnancy 62. Three developed gestational diabetes 59,61,65. One woman had insulin treated diabetes mellitus since age One woman had a 4 yr history of treated diabetes type II which resolved with CPAP and weight loss prior to pregnancy though she developed gestational diabetes 65. Three of the four with impaired glucose metabolism also had a hypertensive disorder. Foetal outcomes: Several reports documented acute foetal distress in response to maternal apnoeas. Five foetuses had either low scalp ph, decelerations or decreased foetal heart rate variability associated with maternal desaturating apnoeas. Four of the five foetuses with documented acute distress had an adjusted birth weight below the 10 th percentile. For 7 other pregnancies where acute foetal distress was evaluated but found to be absent, 3 infants had birth weights below the 10 th percentile, two at the 25 th, and two were above the 75 th percentile for birth weight. Birth weights in grams or percentiles were available for 25 infants. We adjusted birth weights for gestational age, sex and parity and expressed them in percentiles according to American population charts 78. Of these 25 infants, the mean birth weight percentile was 19 per cent; 16 had birth weights below the 10 th percentile, four were between the 10 th and 25 th percentiles, one was at the 50 th percentile, two were between the 75 th and 90 th percentiles, and another two were above the

6 290 INDIAN J MED RES, FEBRUARY th percentile. This distribution is dramatically different from normal expected weights adjusted for race, parity, sex, and gestational age, and is even more striking when one considers that these mostly obese women would be expected to have larger, not smaller babies 79. These observations suggest that sleep apnoea is associated with chronic compromise of maternalplacental-foetal circulation even in the absence of documented acute abnormalities with maternal apnoeas on the foetal heart monitoring. Overall, pregnancy with clinically significant maternal sleep apnoea was complicated for the mother (hypertensive disorder of pregnancy or right heart failure/pulmonary hypertension) in 30 per cent and for the child (birth weight below 10 th percentile) in 64 per cent where reported. Complications for either the mother or the child as defined above occurred at most, in 86 per cent of pregnancies where clear data were available. Most pregnancies with maternal or foetal complications were not treated at all or treatment was initiated late, often after complications had occurred. Among the pregnancies not complicated by gestational hypertension, pulmonary hypertension or small for gestational age babies, most were treated prior to or during the first trimester. Treatment of sleep apnoea was associated with fewer foetomaternal complications. Taken together the initial reported cases suggest that clinically significant maternal sleep apnoea is a risk factor for complications for the mother (hypertensive disorders, pulmonary hypertension, and right heart failure) and the baby (small birth weight). Reports of pregnant women whose sleep apnoea was treated, suggest better outcomes for both mother and baby, however, these data reflect case reports and not results heralding from randomized controlled trials. DATA FROM LARGER OBSERVATIONAL AND INTERVENTIONAL STUDIES (i) Association between pregnancy and sleepdisordered breathing There are several studies on snoring and other symptoms suggestive of OSA during pregnancy, conducted in different countries, all confirming the increase in snoring and symptoms suggestive of obstructive sleep apnoea from pre-pregnancy status to the end of pregnancy or among pregnant women compared to non pregnant women 35-37,48, In addition, there are a few studies performing sleep tests using different technologies on pregnant women. In a study involving 267 young, healthy pregnant women yr old with health care coverage and antenatal care early in pregnancy, a cardiorespiratory monitoring without electroencephalogram was performed at 6 months of gestation. All had AHI below 5. Thirty five had at least one 5 per cent-oxygen saturation drop including 8 without snoring. Thirty had loud snoring. Of the 267 women enrolled, none developed an hypertensive disorder of pregnancy. The group of loud snorers as well as those with documented oxygen drops had a larger increase in 24 h blood pressure from the first to the third trimester compared to the women with no snoring and without oxyhaemoglobin saturation drops 85. Eleven pregnant women with a BMI >30 were compared to 11 pregnant women with a normal BMI for OSA as determined by a polysomnography with EEG performed at 15 and 34 wk of gestation. The mean AHI were higher for the obese group though every women had an index below 10 on the first polysomnography. On the second polysomnography, the mean AHI was higher for obese and one reached an index above 10, the threshold for OSA in the study 86. One abstract reports the preliminary results of a longitudinal study on incident OSA during pregnancy. Seventy one pregnant women with a mean body mass index of 28 had a polysomnography in the first and again in the third trimester. Six had OSA on the first polysomnography compared to 18 by the third trimester. Incident obstructive sleep apnoea in pregnancy was associated with higher age, body mass index and neck circumference. In this preliminary data report, there was no association between hypertensive disorders of pregnancy and obstructive sleep apnoea 38. Together, this suggests that obstructive sleep apnoea is rare in healthy, normal women with low-risk pregnancy and that pregnancy is a risk factor for incident OSA, especially among obese women. (ii) Association of OSA with gestational hypertension/ pre-eclampsia Gestational hypertension complicates 6-8 per cent of pregnancies 87. The National Heart, Lung, Blood Institute working group on Research in Pregnancy defines gestational hypertension as a new onset of systolic blood pressure 140 mmhg or a diastolic blood pressure 90 mmhg after mid-pregnancy. When associated with proteinuria, it is termed preeclampsia or alternatively gestational hypertension with proteinuria 88. It is associated with intrauterine growth restriction, neonatal intensive care admission,

7 Champagne et al: OSA & pregnancy 291 and poorer neonatal outcomes 89 ; HELLP syndrome, and rarely eclampsia in the mother. Risk factors for pre-eclampsia 90 include nulliparity, diabetes, pre-existing hypertension, obesity especially if central 91, dyslipidaemia 92, depression 93, renal disease, asthma 94, personal and familial history of gestational hypertension, multifetal gestation, black race, insulin resistance, thrombophilia, living in high altitude zones 95,96, collagen vascular disease/autoimmune diseases 97, and hydatiform mole. Based on a large population study, per cent of the attributable risk for severe or early pre-eclampsia can be predicted by 3 or 4 pre-existing conditions: obesity, diabetes, hypertension, in addition to prior pre-eclampsia in multiparous women 98. Long term cohort studies have demonstrated that the morbidity and mortality for mothers whose pregnancy was complicated by hypertension extends long after delivery. Gestational hypertension or preeclampsia is an independent risk factor for chronic hypertension 99, fatal stroke 100, cardiovascular death 99, and metabolic syndrome As already described, the early reports of clinically significant maternal sleep apnoea suggested an association with hypertensive disorders of pregnancy. In addition, because of shared risk factors and similar long term cardiovascular and metabolic complications with obstructive sleep apnoea and with hypertensive disorders of pregnancy, interest has focused on the potential associations between maternal OSA and gestational hypertension or pre-eclampsia. Snoring is a risk factor for gestational hypertension with an adjusted odds ratio of 2.03 (95% CI ) 36. In another study conducted in a different country, the results were confirmed. Snoring is a risk factor for pregnancy-induced hypertension with an adjusted odds ratio of 1.82 (95% CI ) after adjustments for pre-pregnancy body mass index, weight gain during pregnancy, neck circumference, smoking, alcohol and age in a second study 37. The combination of snoring and exacerbation of sleepiness in pregnancy were associated with a crude odds ratio of 2.6 (95% CI ) for hypertensive disorders of pregnancy 80. In a casecontrol study, snoring was a risk factor for gestational hypertension but not pre-eclampsia 104. In conclusion, snoring is a marker of gestational hypertension. Subsequently, case-control studies using overnight recordings were used. Three case-control studies compared normotensive women with pregnancyinduced hypertension or pre-eclamptic women for the presence of obstructive sleep apnoea The studies had different populations, technologies, respiratory event definitions, and adjustments if any, for confounders. Nonetheless, all these showed an association between respiratory obstruction and hypertensive pregnancies. In the first case-control study, 15 women with preeclampsia were compared with an equal number of women with normotensive uncomplicated pregnancies for the presence of OSA. Compared to women in their third trimester of a normal pregnancy, pre-eclamptic women had a similar apnoea-hypopnoea index but were spending twice as much time with inspiratory flow limitation 106. In the second case-control study, 17 pre-eclamptic women were compared with 25 normotensive pregnant women with uncomplicated pregnancies for the presence of OSA. Age, pre-pregnancy body mass index and gestational age at the time of the sleep test were similar in both groups. Pre-eclamptic women had significantly more respiratory events per hour than controls; and more oxygen desaturation per hour of sleep 105. In the third case-control study conducted in our own institution, 17 pregnant women with new onset of hypertension in pregnancy were compared with 33 normotensive pregnant women, recruited in a high risk tertiary care centre stratified for gestational age. Recruitment took place in a high risk obstetrics tertiary care facility. Complete overnight unattended polysomnography including nasal pressure was performed with manual scoring of sleep-wake state and respiratory events 1. Obstructive sleep apnoea was present in 82 per cent of the subjects with gestational hypertension vs 45 per cent of the normotensive controls. The crude odds ratio of having OSA given gestational hypertension was 5.6 (95% CI ) and was 7.5 (95% CI ), when adjusted for gestational age, maternal age, pre-gravid body mass index, prior pregnancy, and prior live births 107. Together, these studies suggest that among healthy women with normotensive, low-risk pregnancies, the prevalence of OSA is likely low. In contrast, among women with hypertensive disorders of pregnancy, the prevalence of OSA will vary with measurement as is described in the non pregnant populations 108. Desaturating obstructive sleep apnoea is uncommon in low risk pregnancies but was present among preeclamptic

8 292 INDIAN J MED RES, FEBRUARY 2010 women 105. Obstructive sleep apnoea was most prevalent among high risk hypertensive pregnancies but also prevalent among high risk normotensive pregnant women. The presence of OSA among high-risk normotensive pregnancies is not surprising knowing that at least some of the co-morbidities defining the highrisk pregnancies (obesity, insulin resistance, glucose intolerance) are also associated with OSA 103 and that poor obstetrical outcomes are clustered among some women and are not independent events 109,110. Therefore, recruiting women with complications or risk factors for poor obstetrical outcome was likely to recruit also women at risk for obstructive sleep apnoea whereas recruitment of normotensive controls with normal pregnancy in the community is likely to select those with the lowest prevalence of OSA. In conclusion, OSA is an independent risk factor for hypertensive disorders of pregnancy. (iii) Association of OSA with other adverse maternofoetal outcomes As discussed above, the initial case reports suggested that OSA could impair foetal growth and lower Apgar scores. Subsequently, questionnaire-based studies were performed to address the association between snoring and fetal growth. In one study, snoring was a risk factor for intrauterine growth restriction with an odds ratio of 3.45 adjusted for weight, age, and smoking and a risk factor for a low APGAR score 36. The combination of snoring and exacerbation of sleepiness in pregnancy was not associated with intrauterine growth restriction 80. Finally, in a study specifically on snoring and foetal outcome, no association between snoring and low birth weight was found though intrauterine growth restriction was a very rare event (2/350 births) 35. Following some of the initial case-reports detailing foetal decelerations on non stress test with maternal apnoeas, a case-control study was conducted, involving 35 pregnant women with chronic snoring or witnessed apnoeas who had a polysomnography with simultaneous non stress test. OSA was confirmed in four, of which three with adequate non stress tests had foetal heart decelerations associated with maternal desaturations compared to only one foetus among the 31 controls. APGAR score and birth weight were lower for the 4 women with confirmed OSA though no adjustment for confounders could be done 111. In another case-control study which was underpowered to detect an effect of 2 per cent desaturation, the crude odds ratio of having intrauterine growth restriction in presence of >5 2 per cent desaturation per hour of recording was 1.67 (95% CI ) 112. Considering the limitations of the technology used, the impact of not correcting for time asleep in a population known for its poor sleep quality, this study does not exclude a significant impact of obstructive sleep apnoea on the mother or the foetus. In conclusion, maternal snoring may contribute to lower the APGAR score but is not associated with lower birth weight. Preliminary reports suggest that obstructive sleep apnoea may cause foetal decelerations, lower birth weight and APGAR scores. (iv) Treatment of sleep apnoea and improvement of obstetrical outcome In the non pregnant population, CPAP is the treatment of choice for moderate and severe obstructive sleep apnoea. CPAP is considered a safe intervention with demonstrated benefits on quality of life, mood, 24 h blood pressure control 113,114. From the summary of case reports previously presented, earlier treatment (mostly CPAP) seemed associated with the best outcomes though most of those treated women also had a milder degree of disease. In a case-series of 12 pregnant women with OSA in whom CPAP was initiated prior to or early in pregnancy, there was an improvement in sleepiness, fatigue over time with a good tolerance of therapy 75. In another caseseries with early CPAP intervention among 12 pregnant women at risk for pre-eclampsia and documented OSA 115, among the 7 with chronic hypertension, blood pressure was well-maintained with CPAP and there was no need for additional blood pressure medication in the third trimester. However, among the 5 with either obesity or past pre-eclampsia, despite CPAP use, 4 complicated with either pre-eclampsia (in one), spontaneous abortion (in two) or preterm delivery (in one) 115. Two non-randomized interventional studies with CPAP intervention among women with preeclampsia and mild obstructive sleep apnoea reported on one hand a mean nocturnal decrease of 20 mmhg on beatto-beat blood pressure monitoring with a single night of CPAP 116 and a normalization of cardiac output and 3 mmhg decrease among those with CPAP treatment whereas those without intervention increased by 3 mmhg on finger arterial photoplethysmography 117. There are no randomized controlled trials addressing whether OSA among normotensive pre-

9 Champagne et al: OSA & pregnancy 293 pregnancy women should be treated and it is unlikely that a trial discontinuing a proven beneficial treatment, even in the context of pregnancy will take place. Only one randomized controlled trial of CPAP among pregnant women was retrieved. In this trial 118, women presenting in the first 8 wk of a pregnancy with a past history of hypertension or documented hypertension at the first antenatal visit and presenting chronic snoring were randomly allocated to polysomnography and CPAP treatment in addition to standard antihypertensive therapy or to antihypertensive therapy alone (no polysomnography, no CPAP). Seven pregnant women with chronic hypertension and snoring were allocated to CPAP treatment. None of them had a AHI > 5, a usual threshold to define OSA in the non pregnant population 1. Nine pregnant women with chronic hypertension served as controls. Systolic and diastolic blood pressure levels decreased starting at the 30 th wk of gestation in the treated group whereas blood pressure levels increased at the point in the usual care arm. At 35 wk, CPAP-treated women required less blood pressure medication and had a significantly lower mean daytime blood pressure, 87 mmhg compared to controls whose mean blood pressure was 108 mmhg 118. Pregnancy outcomes (APGAR, birth weight, healthcare utilization, pre-eclampsia) favoured the treatment group in this small trial. Those results are especially important in the context of pregnancy when physicians and women alike want to avoid medication and when antihypertensive drugs are known to impede foetal growth 119. This preliminary study suggests that even minimal degree of OSA (AHI <5 in chronic snorer) is harmful in the context of a hypertensive pregnancy in a similar fashion to what is observed in the non pregnant population where apnoeahypopnoea indices as low as increase by 42 per cent the chance of incident hypertension at 4 yr 8 and by 60 per cent the incidence of depression at 4 yr 120. It suggests that current scoring criteria have very little discriminative power if only one hypopnoea per 10 h of sleep (an AHI of 0.1) is already increasing risk of complications compared to zero. Nonetheless, this is in agreement with a population-based study where arousal index was a stronger predictor of hypertension than the AHI (where hypopnoeas required a 3%-desaturation) or any oxygen-saturation variable 121. It suggests that current standard threshold to initiate CPAP therapy (apnoea-hypopnoea index >5 with symptoms) might be too high in the context of pregnancy. It supports that standard OSA treatment with CPAP initiated early in pregnancy is beneficial for blood pressure control among pregnant women with pre-pregnancy or early pregnancy diagnosis of chronic hypertension in the context of chronic snoring even in the absence of OSA reaching standard non pregnancy status criteria. In conclusion, preliminary results on the impact of CPAP among chronically snoring pregnant women with chronic hypertension are encouraging as well as preliminary results on the acute impact of CPAP among new onset of hypertension with proteinuria in pregnancy. Those studies need to be repeated with proper randomization and concealed treatment allocation over a longer observation period to ascertain benefits and absence of harm. Unresolved issues At the moment, there are still many unresolved issues around treatment of obstructive sleep apnoea in pregnancy: which population should be treated and which should not, if any, when should treatment be initiated; whether initiation once complications are noticed is still worth it; which technologies to use; how to score the events and which threshold to use in different settings. We have to keep in mind that gestational hypertension/pre-eclampsia is probably the end-product of several pathways 122, only one of which could be related to unrecognized OSA. Trials of CPAP among pregnant women are unlikely to find a complete disappearance of this maternal complication or its related placento-foetal manifestation, intrauterine growth restriction. Despite the foregoing uncertainty, on the basis of the available data, taken together with current standards of practice in the non pregnant population, we propose a practical approach to snoring and obstructive sleep apnoea management during pregnancy (Table). In women who are already treated with positive airway pressure (CPAP or BiPAP) pre-pregnancy, treatment should be continued, with consideration for re-adjustment towards wk of gestation or sooner as clinically indicated. Women with known but not yet treated obstructive sleep apnoea, rapid initiation of treatment with CPAP is recommended with readjustment. Women with a new suspicion raised during pregnancy that a woman may have had unrecognized OSA pre-pregnancy especially in presence of a past medical history of chronic hypertension, depression, metabolic syndrome, obesity, chronic rhinitis,

10 294 INDIAN J MED RES, FEBRUARY 2010 polycystic ovarian syndrome, or cardiovascular disease, or craniofacial features associated with narrow upper airway or pre-pregnancy symptoms suggestive of OSA should be strongly considered for investigation and rapid treatment for OSA. Though it is usually considered that asymptomatic individuals with documented OSA do not need treatment in the non pregnant population, one has to keep in mind that cardiovascular complications are independent of symptoms in the non pregnant population as well as in the few studies performed during pregnancy. Among women with snoring and either chronic hypertension or newly documented hypertension early in pregnancy, a polysomnography with EEG should be performed and early initiation of therapy is advocated even in presence of only minimal disease (AHI 0.1-5), regardless of symptoms suggestive of OSA. For women with new onset of symptoms suggestive of incident sleep apnoea in pregnancy, documentation of the condition with polysomnography with EEG is recommended if treatment is contemplated. Because occasional snoring occurs in up to half of the pregnant women near term and a quarter of all pregnant women snore regularly at term and because most symptoms of obstructive sleep apnoea are non specific and may overlap with normal symptoms of pregnancy (fatigue, sleepiness), the decision to investigate and to treat needs to be individualized based on intensity and spectrum of symptoms, their impact on quality of life and sleep; risk of accident at work or at the wheel in presence of sleepiness, concomittent risk factors Table. Recommended clinical management for obstructive sleep apnoea during pregnancy A. Treated OSA prior to pregnancy 1. Continue current treatment, 2. Assess the need for immediate reassessment of adequacy of treatment, 3. Plan for readjustment towards wk or changing to CPAP if treatment insufficient 4. Plan for a post-partum readjustment of CPAP once weight has stabilized or as clinically indicated B. Documented but untreated OSA prior 1. Initiate CPAP and assess adequacy of control, to pregnancy 2. Plan for readjustment after wk of gestation and if clinically indicated 3. Plan for a post-partum readjustment of CPAP once weight has stabilized or as clinically indicated C. New suspicion raised during pregnancy that a woman may have had unrecognized OSA pre-pregnancy 1. Investigate, 2. Initiate CPAP and assess adequacy of control, 3. Plan for readjustment after wk of gestation and if clinically indicated 4. Plan for a post-partum readjustment of CPAP once weight has stabilized or as clinically indicated Chronic hypertension 1. With snoring: manage as in C. 2. Without snoring: in presence of obstructive sleep apnoea symptoms, complications other than hypertension that could be related to OSA or who is at risk based on physical examination, manage as above (new suspicion of OSA prepregnancy) New symptoms suggestive of new-onset of OSA during pregnancy New onset of gestational hypertension, pre-eclampsia, intrauterine growth restriction 1. Manage as C (like a woman with unrecognized prepregnancy OSA) a) If pre-pregnancy, the woman was at risk, symptomatic or with complications that could be related to OSA, or b) If symptoms are interfering significantly with quality of life or may represent a risk (including excessive sleepiness at the wheel or at work), 2. Insist on conservative measures (see text) alone for the other women 1. Alone, not an indication for investigation for OSA 2. In a woman who, pre-pregnancy was at risk based on physical examination, symptomatic or with complications that could be related to OSA a. Weight the benefits vs feasibility of investigating and treating OSA immediately; b. Plan for an investigation and treatment plan post-partum OSA, obstructive sleep apnoea The current recommendations are overall based on weak evidence: one randomized controlled trial of CPAP among 12 women who snored and presented chronic hypertension; several randomized controlled trials of CPAP among non pregnant population; a few observational studies or non randomized intervention studies during pregnancy and the large experience in the world of CPAP in non pregnant population where it has been shown to be a safe and beneficial intervention. One should understand that poor foetomaternal outcomes will still occur despite obstructive sleep apnoea treatment as OSA is one of many risk factors for poor foetomaternal outcomes

11 Champagne et al: OSA & pregnancy 295 for gestational hypertension and foetal compromise, co-morbidities, gestational age, accessibility and acceptability of diagnostic facility and of therapy; severity of abnormalities in terms of sleep architecture, arousal index, apnoea-hypopnea index, oxygen indices; gestational age. If therapy is used, CPAP device is the treatment of choice. Tolerance to CPAP has been shown to be very good (>80%) in the highly selected and motivated population participating in the reported research studies, better than what is usually observed in the non pregnant population. Conservative treatment of nasal obstruction with external nasal dilator, inhaled corticosteroids 123,124, avoiding allergens in the context of allergies, avoiding excessive weight gain, alcohol and smoking in addition to proper position (elevated head and avoiding supine sleep) should be encouraged in all and may have a positive clinical benefit as an only therapy among the mildest cases of obstructive sleep apnoea. Mandibular advancement device is usually not initiated during pregnancy because of the delay required for proper adjustment. If already adjusted prior to pregnancy, it should be continued. One may need closer surveillance of side effects because of increased laxicity and pregnancy-related gingivitis and needs for readjustments through pregnancy. Because we do not have evidence supporting treatment of obstructive sleep apnoea once gestational hypertension/ pre-eclampsia has developed, we do not recommend immediate polysomnography with EEG in women without risk factors for or a history suggestive of OSA pre-pregnancy and discourage empirical CPAP therapy. It is unlikely to reverse the process at that point in most though it may slow it down and contribute to prolong gestation in the most severe sleep apnoea cases until the foetus is mature. Clinicians may clearly face logistic and time-constraints in attempting to perform diagnostic tests in an unstable mother with threatened urgent delivery. We recommend performing a post-partum polysomnography with EEG once weight has stabilized (or earlier if there is suspicion that the condition is more severe) in women whose pregnancy complicated with gestational hypertension or pre-eclampsia if considered at risk for OSA based on physical habitus or past medical history. There are insufficient data to support an association between OSA and intrauterine growth restriction to recommend an investigation for obstructive sleep apnoea in the sole presence of intrauterine growth restriction. Because delivery is associated with a decrease in severity of OSA 56,107, we recommend repeating the diagnostic polysomnography after delivery once weight has stabilized to distinguish between gestational and standard obstructive sleep apnoea in the less severe and to readjust therapy in the more severe. A comprehensive weight programme with exercise should be offered in those with excess weight prior to a future pregnancy with consideration for bariatric surgery among morbidly obese women. Closer surveillance of OSA during subsequent pregnancies is indicated. (v) Special considerations 1. Obstructive sleep apnoea and fertility Relevant to women of childbearing age, OSA may affect hormonal profile among pre-menopausal women 125, regularity of menstruation cycles 126 and hence, it could impair female fecundity. Obesity is already an established risk factor for subfecundity 127. However, it is not known how much of the association between obesity and fertility is confounded by obstructive sleep apnoea. Polycystic ovarian syndrome is a common condition affecting 5-10 per cent of women. It is associated with oligomenorrhoea due to chronic anovulation, signs of excessive androgen levels and subfecundity. Obesity, dyslipidaemia, hypertension, insulin resistance and glucose intolerance are often associated. Polycystic ovarian syndrome leads to premature asymptomatic atherosclerotic disease 128. Several studies have demonstrated a strong association between polycystic ovarian syndrome and OSA, independent of obesity. The prevalence of OSA among young women with polycystic ovarian syndrome is 70 per cent 33. Despite recent recommendations to assess risk for OSA in all women with polycystic ovarian syndrome 34. In an observational study 126, among premenopausal women with oligo- or amenorrhoea, the odds of having upper airway resistance syndrome, a milder form of OSA, was 5 (95% CI ). Further, the dysmenorrhoea corrected in 60 per cent of the women after 3 months of obstructive sleep apnoea specific therapy with CPAP 126. Preliminary data suggest that untreated OSA among women may lead to endocrinologic abnormalities that could interfere with the probability of successful pregnancy though this topic clearly needs further investigation.