Sleep-Disordered Breathing in Pregnancy

Transcription

1 Sleep-Disordered Breathing in Pregnancy Louise M. O Brien, Ph.D., M.S. Associate Professor Sleep Disorders Center & Department of Obstetrics & Gynecology Michigan Medicine

2 Conflict of Interest Disclosures for Speakers 1. I do not have any relationships with any entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients, OR X 2. I have the following relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients: Type of Potential Conflict Details of Potential Conflict Grant/Research Support Phillips Respironics Inc., ResMed Consultant Speakers Bureaus Financial support Other X 3. The material presented in this lecture has no relationship with any of these potential conflicts, OR 4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture: 1. Poyares et al. Pre-eclampsia and nasal CPAP: part 2. Hypertension during pregnancy, chronic snoring, and early nasal CPAP intervention. Sleep Med Dec;9(1): Epub 2007 Jul Blyton DM, Sullivan CE, Edwards N. Reduced nocturnal cardiac output associated with preeclampsia is minimized with the use of nocturnal nasal CPAP.Sleep Feb 1;27(1): Blyton DM, Skilton MR, Edwards N, Hennessy A, Celermajer DS, Sullivan CE. Treatment of sleep disordered breathing reverses low fetal activity levels in preeclampsia. Sleep 2013 Jan 1;36(1):15-2

3 Sleep-Disordered Breathing What do we know about SDB in pregnancy? Habitual snoring affects 5-10% of non-pregnant women but up to 35% of pregnant women (Redline et al 1994, Bixler et al 2001, Bourjeily 2010, O Brien 2012) In women with pre-eclampsia, up to 85% have habitual snoring (Izci 2005, Izci2006,Reid 2011, O Brien 2014) OSA affects 3% of nullips in early pregnancy and 8% by mid-pregnancy (Facco et al 2017) OSA present in about 15% of obese women in early pregnancy OSA present in about 50% of women with pre-eclampsia (Louis et al 2013) (Reid 2011, O Brien 2014)

4 Evidence suggests strong link between SDB and hypertension in pregnancy 1 st case description of SDB and pre-eclampsia in 1996 (Lefcourt & Rodis 1996) 1 st study suggesting link between SDB and hypertension during pregnancy in 2000 (Franklin et al 2000) Pamidi 2014

5 Recent multicenter trial of approx n=3000 nulliparous women found aor of 1.94 (95% CI ) for pre-eclampsia in women with OSA (Facco et al 2017)

6 Timing of Snoring and Maternal Hypertension Compared to non snoring controls, chronic habitual snoring was not independently associated with gestational hypertension or pre-eclampsia BUT New pregnancy-onset snoring was independently associated with gestational hypertension AND pre-eclampsia: OR 2.4[ ] GHTN OR 1.6 [ ] pree ** **p<0.001 vs. controls O Brien 2012

7 OSA in Hypertensive Pregnancies N=51 pregnant women with hypertension unselected for sleep problems Mean gestation 27±7 weeks 41% African American 78% obese 61% reported habitual snoring (snoring 3 nights/wk) Baseline PSG results: - Mean AHI=13.5 (range ) - 80% of women had AHI 1-41% had AHI 5-16% had AHI 15 OSA - 12% had AHI 30 Pooled relative risk for OSA in hypertensive women who snored, vs. non-snoring hypertensives, was 2.0 ( ) O Brien 2014

8 Is snoring a good marker for OSA? O Brien et al unpublished

9 Is snoring a good marker for OSA? Pamidi 2016

10 Can we use a screening tool to identify OSA risk? Berlin Questionnaire STOP-BANG There are no validated screening tools for OSA in pregnant women: however we currently have an ongoing study that will develop one..watch this space O Brien et al unpublished

11 What about obesity? 15%-25% of pregnant women with a BMI 30 have OSA (Louis 2013, Facco 2017) Data from n=21 women with BMI 40: - BMI 40, 67% have OSA. Odds ratio for OSA is 5.3 ( ) - BMI 40 AND habitual snoring, 81% have OSA. Odds ratio for OSA is 8.7 ( ) - BMI 40 AND hypertension, 81% have OSA. Odds ratio for OSA is 3.1 ( ) regardless of whether snoring present or not O Brien unpublished

12 Obesity is complicated: E.g. when looking at SDB and hypertension, maybe we should not just adjust for BMI in a regression model Take a step back and review the bigger picture because SDB may be only part of pathway to HTN and obesity is playing a big role. We hypothesized that frequent snoring mediates the association of pre-pregnancy BMI and GHTN New methods in mediation analysis allow us to look at the total effect of obesity on HTN which has two components; 1) direct effect 2) indirect effect via SDB Important to only include incident SDB and incident HTN as this analysis is causal mediation

13 Potential pathway: Causal diagram representing direct and indirect (mediated) pathways of associations between maternal BMI, snoring frequency and hypertensive disorders of pregnancy Covariates 1: education, maternal age, smoking Covariates 2: education, parity, history of HTN Dunietz (submitted)

14 Dunietz (submitted)

15 Message: Frequent pregnancy-onset snoring plays an indirect role in the association of pre-pregnancy BMI and hypertensive disorders of pregnancy It explains about; one third of the total association between maternal BMI and hypertensive disorders of pregnancy in women who were overweight at the start of their pregnancy, and almost half of the total association between maternal BMI and hypertensive disorders of pregnancy in women who were obese. This approach accounts for the temporal aspect of these associations Dunietz (submitted)

16 What about Gestational Diabetes? SDB is associated with metabolic dysregulation Shaw et al 2008

17 Meta-analysis of 9,795 participants enrolled in epidemiological observational studies for SDB and GDM Luque-Fernandez, 2013 Recent multicenter trial of approx n=3000 nulliparous women found aor of 3.5 (95% CI ) for gestational diabetes in women with OSA (Facco et al 2017)

18 Does Maternal SDB Impact the Fetus?

19 Maternal SDB and IUGR..logical? SDB Vasoconstriction O 2 desats Hypertension Reduced placental delivery Maternal hypoxia assoc. to fetus with fetal movements and bradycardia Fetal growth restriction

20 Maternal SDB and IUGR..logical? In animal models exposure to hypoxia during gestation associated with stunted fetal growth (Gozal et al 2003) Brief exposures to hypoxia in late pregnancy associated with reduced birth weight in rats (Schwartz et al 1998)

21 SDB and Fetal Growth Joel-Cohen & Schoenfeld 1978 (Franklin et al 2000)

22 Reported Symptoms Witnessed apnea: bigger babies Chronic habitual snoring: smaller babies O Brien 2013

23 Polysomnography Pamidi 2016

24 Epidemiological studies of OSA Dx Bin 2016

25

26 Uterine environment: Metabolic dysregulation High blood pressure: Vasoconstriction

27 Fig2 Subjective Measures of SDB Study Predictor Design OR (95%CI) Objective Measures of SDB OR (95%CI) Study Odds Ratio Warland (under review)

28 SDB and Fetal Growth OSA (n=14) Control (n=27) (Fung et al 2013) Serial measures of fetal growth in n=54 controls, n=34 untreated OSA, n=14 treated OSA: - Fetal growth problems defined as birth weight <10th centile, or a slowing of fetal growth by >30% during the last trimester. - In a logistic regression model, after accounting for co-morbid hypertension, diabetes, anti-hypertensive and anti-diabetic medications, maternal age, and smoking, untreated OSA was associated with a 3-fold increased odds of fetal growth problems (OR 3.0, 95%CI , p=0.03). - There were no differences in fetal growth trajectories between non-osa and treated OSA (Kneitel, Treadwell & O Brien under review)

29 What about preterm birth?

30 Fig1 Subjective Measures of SDB Study Predictor Design OR (95%CI) Objective Measures of SDB OR (95%CI) Odds Ratio Warland (under review)

31 SDB and Time to Delivery Some studies suggest a relationship between sleep disturbance and preterm birth although many studies do not. Delivery is typically measured as either preterm vs. full term OR mean gestational age. No study has yet used survival analysis to investigate this despite delivery being a time to event. Now also consider intensity: - Non snoring controls - Infrequent-quiet snorers - Frequent-quiet snorers - Frequent-loud snorers Recall: timing of snoring: chronic vs. pregnancy-onset Included non-hypertensive, non-diabetic women in order to estimate the impact of habitual snoring without these key confounders

32 SDB and Time to Delivery In n=954 non-hypertensive, non-diabetic women, there was an increased hazard ratio for earlier delivery in chronic loud frequent snorers vs. controls: HR 1.60, (95% CI 1.04, 2.45) These women delivered approximately 6 days earlier; 25% were considered early term ( weeks) Dunietz (under review)

33 % chorangiosis OSA and the Placenta The feto-placental weight ratio, a common metric of the balance between fetal and placental growth, is reduced as the severity of OSA increases: Chorangiosis, an increase in the number of vessels in the chorionic villi, likely a result of a hypoxic stimulus as nrbc s were also elevated 0 OSA Control PAP O Brien (unpublished)

34 Treatment of SDB in Pregnancy Population Attributable Risk: If there is a causal relationship between SDB and hypertensive disorders of pregnancy, treating SDB could reduce hypertension in pregnancy by up to 20% O Brien 2012

35 Treatment of SDB Positional Therapy If AHI lower when non-supine: avoid supine position - Up to 1/3 mild (even moderate) cases can be position-dependent 80% of pregnant women spend some time sleeping supine (O Brien & Warland 2014) 45-degree elevation: Typical Positional therapy Sleep position to promote side sleep Zaremba 2015

36 Why is sleep position important in pregnancy? Posture in late pregnancy can have a profound effect on maternal cardiovascular control

37 Gravid uterus compresses the inferior vena cava resulting in: venous return ejection fraction impaired uterine perfusion cardiac output Maternal supine hypotensive syndrome Supine Lateral

38

39 Supine sleep independently associated with stillbirth (OR, 8.0; 95% CI, ). Supine sleep independently associated with low birth weight (OR, 5.0; 95% CI, ). When low birth weight was added to the stillbirth model, the OR for the relationship between Risk is higher for term (aor 10.26, ) vs. preterm babies (aor 3.12, ) supine sleep and stillbirth was almost eliminated (OR, 4.9; 95% CI, ) ( McCowan 2017) Thus low birth weight appears to mediate the effects of supine sleep on stillbirth. If supine sleep has a causative role in low birth weight and subsequently stillbirth, up to 17% of low birth weight, and consequently 26% of stillbirths, might be prevented by changing maternal sleep position.

40 Supine sleep position is not good for fetal wellbeing: Warland (under review) Supine non-supine In the supine position: - fetal heart rate variability reduced - Fetal behavior change from active to quiescence (low oxygen consuming state). In the presence of a stressor (uteroplacental perfusion or hypoxia), shift to a low oxygen consuming state would be a protective reaction. Maternal supine position may be disadvantageous for fetal wellbeing and in compromised pregnancies may be a sufficient stressor to contribute to fetal demise. Stone 2016

41 Positional therapy isn t always sufficient..

42 Treatment of SDB with PAP First line treatment is PAP Meta-analyses of randomized studies representing over 1400 subjects show that PAP improves daytime and nocturnal BP. (Bazzano et al 2007, Haentjens et al 2007) Small studies suggest that BP may be reduced when PAP is used in pregnant women: Sydney, Australia: Saskatoon, Canada - Edwards et al 2000 n=11 - Reid et al 2013 n=13 - Blyton et al 2004 n=12 Stanford, USA: - Guilleminault et al 2004 n=12 - Poyares et al 2007 n=7 - Guilleminault et al 2007 n=12

43 Edwards et al 2000

44 HTN, SDB and Fetal Movements? Due to impaired cardiac output and increased peripheral vascular resistance Uteroplacental hypoperfusion and fetal hypoxemia Edwards & Sullivan 2008

45 Alpha-methyl dopa dose increased in controls; constant or decreased in CPAP Poyares et al 2008

46 Auto-PAP in Pregnant Women with Hypertension N=48 APAP and n=77 standard of care

47 Positive Airway Pressure (PAP) Therapy Mean gestation at enrollment: 28.1±7.2 weeks Mean PAP use 54 days: (range days) Mean PAP pressure: 10cmH 2 0 (range 5-18cmH 2 O) Remote monitoring of compliance data using web-based technology 70% of pregnant women were compliant users O Brien unpublished

48 Compliant Subject

49 Non-Compliant Subject

50 Auto-PAP and Blood Pressure O Brien unpublished

51 Auto-PAP, Blood Pressure, and Medication Standard of Care comparison group (hypertensive women, no APAP): - About 55% of women developed worsening BP and ended up with a diagnosis of pre-eclampsia after enrollment despite antihypertensives - Other 45% remained CHTN/GHTN although 80% had increased meds APAP group - Non-compliant users: - About 65% of women developed worsening BP and ended up with a diagnosis of pre-eclampsia after enrollment despite antihypertensives - Other 35% remained CHTN/GHTN although 90% had increased meds APAP group Compliant users ( 4 hours/night and 4 nights/week): - About 27% of women developed worsening BP and ended up with a diagnosis of pre-eclampsia after enrollment despite antihypertensives - Other 73% remained CHTN/GHTN and only 10% had increased meds (90% had stable or even decreased meds)

52 Infant Outcomes APAP in pregnancy is associated with improved infant birth weight: Infants born to women who used APAP during pregnancy, compared to infants born to women who did not use APAP, have larger birth weight (3036±833g vs. 2485±1050g, p=0.08) even after accounting for duration of APAP use APAP is associated with longer gestation. Women who used APAP continued their pregnancies for a mean of 2.5 weeks longer than non-users (37.7±2.8 weeks vs. 35.1±4.1 weeks, p=0.03). This is a clinically significant duration that may have long-term impact on infant health. O Brien unpublished

53 Case Report: Treatment of Early Onset Pre-eclampsia by CPAP: Pregnancy progressed an additional 30 days after CPAP allowing the infant to gain about 2lbs Biochemical/angiogenic markers of preeclampsia improved after CPAP then worsened around 35/40 Whitehead 2015

54 PE024: Case 1 32yo Caucasian, BMI 24 G4 P1 Fetal demise #1 at 20/40 Fetal demise #2 at 19/40 Premature delivery at 27/40 - NICU All due to pre-eclampsia Enrolled on trial at 21/40 AHI=1 Did not develop pre-eclampsia Delivered healthy male infant at 36+2/40 weighing 6lb 1oz Interestingly, the placenta was normal except for one small infarct, unlike her previous placenta which showed typical histological changes. Was this due to APAP?

55 Case 2 PE047: 34yo African American, GHTN, BMI 42 G1 P0 BPs at enrollment >150/80mmHg - Morning after baseline PSG, subject in triage with non-reactive FHR, reduced FM, and severe maternal desats - OBGYN plan to deliver that day (37/40) - Study team paged by OBGYN; decision made to start PAP immediately Subsequently found to have severe OSA on study PSG (AHI=117) On PAP: - FHR became reactive - Maternal SpO2 normal - Discharged and continued pregnancy for another week - Delivered healthy 6lb 3oz female infant

56 Thank you! Research Coordinators: Mallory Newsted Lori Kempf, CCRP Mary Groll-Brown, PSGT Jocelynn Owusu, MPH Collaborators: Alexandra S. Bullough, MBChB, FRCA (Anaesthesiology) Mark C. Chames, MD (Obstetrics) Marcie C. Treadwell, MD (Obstetrics) Timothy R. B. Johnson, MD (Obstetrics) Galit Dunietz, PhD (Epidemiology/Sleep Medicine) Ronald D. Chervin, MD, MS (Sleep Medicine) Anita V. Shelgikar, MD (Sleep Medicine) Roseanne Armitage, PhD (Psychiatry) Rob Brook, MD (Cardiovascular Medicine) Colin Sullivan, MBBS, PhD, FRACP, University of Sydney Christian Guilleminault, MD, Stanford University Support: Gilmore Fund, IRWG, MICHR, NIH NHLBI, Respironics

57