Sleep Disordered Breathing in Pregnancy and Post-Delivery: Associations with Cardiometabolic Health - American Thoracic Society
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Sleep Disordered Breathing in Pregnancy and Post-Delivery:
Associations with Cardiometabolic Health
Journal: American Journal of Respiratory and Critical Care Medicine
Manuscript ID Blue-202104-0971OC.R3
Manuscript Type: OC - Original Contribution
Fo
Date Submitted by the
06-Jan-2022
Author:
Complete List of Authors: Facco, Francesca; University of Pittsburgh,
rR
Redline, Susan; Brigham and Women’s Hospital, Division of Sleep and
Circadian Disorders; Harvard Medical School, Division of Sleep Medicine
Hunter, Shannon; Research Triangle Institute
Zee, Phyllis; Northwestern University Feinberg School of Medicine
ev
Grobman , William ; Northwestern University Feinberg School of
Medicine
Silver, Robert; University of Utah Health
iew
Louis, Judette; Morsani College of Medicine, University of South Florida,
Division of Maternal Fetal Medicine, Department of Obstetrics &
Gynecology
Pien, Grace; Johns Hopkins University School of Medicine, Division of
Pulmonary and Critical Care Medicine
Mercer, Brian; MetroHealth Medical Center
On
Chung, Judith ; University of California Irvine College of Medicine
Bairey Merz, Noel; Cedars-Sinai Medical Center
Haas, David; Indiana University, Obstetrics and Gynecology
Nhan-Chang, Chia-Ling; Columbia University Medical Center
Simhan , Hyagriv; University of Pittsburgh
ly
Schubert, Frank; Indiana University School of Medicine
Parry, Samuel; University of Pennsylvania Perelman School of Medicine
Reddy, Uma; Yale School of Medicine
Saade, George; The University of Texas Medical Branch at Galveston
Hoffman , Matthew; Christiana Care Health System
Levine, Lisa; University of Pennsylvania Perelman School of Medicine
Wapner, Ronald; Columbia University Medical Center
Parker, Corette; Research Triangle Institute
15.05 Sleep Disordered Breathing: Cardiovascular Interactions < SLEEP,
Subject Category:
15.09 Sleep Disordered Breathing: Outcomes < SLEEP
sleep disordered breathing, pregnancy, postpartum, cardiometabolic
Keywords:
health, hypertensionly
On
iew
ev
rR
Fo
Page 1 of 64Page 2 of 64
1
2 TITLE: Sleep Disordered Breathing in Pregnancy and Post-Delivery: Associations with
3 Cardiometabolic Health
4
5 Francesca L. Facco, MD1, Susan Redline, MD2, Shannon M. Hunter , MS3, Phyllis P. Zee, MD4,
6 William A. Grobman, MD5 , Robert M. Silver, MD6, Judette M. Louis, MD7 , Grace W. Pien, MD8,
7 Brian Mercer, MD9, Judith H. Chung, MD, PhD10, C. Noel Bairey Merz, MD11, David M. Haas,
8 MD 12, Chia-Ling Nhan-Chang, MD 13, Hyagriv N. Simhan, MD1, Frank P. Schubert, MD12,
9 Samuel Parry, MD 14, Uma Reddy, MD15, George R. Saade, MD16, Matthew K. Hoffman, MD17,
10 Lisa D. Levine, MD12 Ronald J. Wapner, MD13, Corette B. Parker, PhD3 for the NICHD
11 NuMoM2b and NHLBI NuMoM2b Heart Health Study Networks
12
13
14
15
16
17 1. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh
Fo
18 School of Medicine, Pittsburgh, PA
19 2.Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts
20 3. RTI International, Research Triangle Park, North Carolina
rR
21 4. Department of Neurology, Northwestern University, Chicago, IL
22 5. Department of Obstetrics, Gynecology-Maternal Fetal Medicine & Preventive Medicine,
23 Northwestern University, Chicago, IL
ev
24 6. Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah
25 7. University of South Florida Morsani College of Medicine, Tampa, FL.
26 8. Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD
iew
27 9. Department of Obstetrics and Gynecology, Case Western Reserve, MetroHealth, Cleveland,
28 OH
29 10. Department of Obstetrics and Gynecology, University of California, Irvine, Irvine, California
30 11. Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles,
31 California
On
32 12. Department of Obstetrics and Gynecology, School of Medicine, Indiana University,
33 Indianapolis, IN11
34 13. Department of Obstetrics and Gynecology, Columbia University, New York, New York
35
ly
14. Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA
36 15. Department of Obstetrics, Gynecology & Reproductive Services, Yale University, New
37 Haven, CT
38 16. Department of Obstetrics and Gynecology, University of Texas Medical Branch, University
39 of Texas, Galveston, TX.
40 17. Department of Obstetrics and Gynecology, Christiana Care Health System, Wilmington, DE,
41 USA
42
43 Corresponding Author:
44 Francesca Facco, MD
45 Associate Professor, Department of Obstetrics and Gynecology
46 Magee-Womens Hospital
47 300 Halket Street
48 Room 2233
49 Pittsburgh, PA 15213
50 Work phone: 412-641-5406
51 Cell: 312-933-1881
52 Fax: 412-641-1133
1Page 3 of 64
53 Email: faccof@upmc.edu
54
55 All authors meet the following criteria:
56 Substantial contributions to the conception or design of the work; or the acquisition, analysis, or
57 interpretation of data for the work; AND
58 Drafting the work or revising it critically for important intellectual content; AND
59 Final approval of the version to be published; AND
60 Agreement to be accountable for all aspects of the work in ensuring that questions related to the
61 accuracy or integrity of any part of the work are appropriately investigated and resolved.
62
63
64 This study is supported by cooperative agreement funding from the National Heart, Lung, and
Fo
65 Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human
66 Development: U10-HL119991; U10-HL119989; U10-HL120034; U10-HL119990; U10-
67 HL120006; U10-HL119992; U10-HL120019; U10-HL119993; and U10-HL120018. Support was
rR
68 also provided by the National Institutes of Health: Office of Research on Women’s Health
69 through U10-HL-119991; Office of Behavioral and Social Sciences Research through U10-
70 HL119991 and U10-HL119992; and the National Center for Advancing Translational Sciences –
71 UL-1-TR000124, UL-1-TR000153, UL-1-TR000439, and UL-1-TR001108; and the Barbra
ev
72 Streisand Women’s Cardiovascular Research and Education Program, and the Erika J. Glazer
73 Women’s Heart Research Initiative, Cedars-Sinai Medical Center, Los Angeles. The content of
74
iew
this article is solely the responsibility of the authors and does not necessarily represent the
75 official views of the National Institutes of Health.
76 Short Running: Sleep Disordered Breathing in Pregnancy and Post-Delivery
77 ClinicalTrials.gov Registration number NCT02231398.
On
78 Subject Category: 15.9 Sleep Disordered Breathing: Outcomes
79 Total word count max =3635
ly
80 Abstract = 250 words
81 This article has an online data supplement, which is accessible from this issue's table of content
82 online at www.atsjournals.org
83
2Page 4 of 64
84 ABSTRACT
85 Rationale: Knowledge gaps exist regarding health implications of sleep disordered breathing
86 (SDB) identified in pregnancy and/or post-delivery.
87 Objective: To determine whether SDB in pregnancy and/or post-delivery is associated with
88 hypertension (HTN) and metabolic syndrome (MS).
89 Methods: The nuMoM2b Heart Health Study (n=4,508) followed participants initially recruited
90 during their first pregnancy. Participants returned for a visit 2-7 years after pregnancy. This
91 study examined a subgroup who underwent SDB assessments during their first pregnancy
92 (n=1,964) and a repeat SDB assessment post-delivery (n=1,222). Two SDB definitions were
Fo
93 considered: apnea-hypopnea index (AHI) ≥5; oxygen desaturation index (ODI) ≥5. Associations
rR
94 between SDB and incident HTN and MS were evaluated with adjusted risk ratios (aRR).
ev
95 Results: The aRR for MS given an AHI ≥5 during pregnancy was 1.44 (95% CI 1.08, 1.93), but
96 no association with HTN was found. ODI ≥5 in pregnancy was associated with both an
iew
97 increased risk for HTN (aRR 2.02, 95% CI 1.30, 3.14) and MS (aRR 1.53, 95% CI 1.19, 1.97).
98 Participants with an AHI ≥5 in pregnancy that persisted post-delivery were at higher risk for both
On
99 HTN (aRR 3.77, 95% CI 1.84, 7.73) and MS (aRR 2.46, 95% 1.59, 3.76). Similar associations
100 were observed for persistent post-delivery ODI ≥5.
ly
101 Conclusions: An AHI ≥5 in pregnancy was associated with an increased risk of MS. An ODI ≥5
102 in pregnancy was significantly associated with both HTN and MS. Participants with persistent
103 elevations in AHI and ODI both during pregnancy and at 2-7 post-delivery were at the highest
104 risk for HTN and MS.
105
106
3Page 5 of 64
107
108 Introduction
109 Sleep disordered breathing (SDB) characterized by recurrent apneas and hypopneas,
110 intermittent hypoxemia, and sleep disruption, is increasingly recognized in pregnancy. Pregnant
111 individuals are at increased risk for SDB, predominantly obstructive sleep apnea (OSA),
112 compared to their non-pregnant counter-parts, due to physical and hormonal changes that occur
113 during pregnancy.(1, 2) A meta-analysis of 33 studies found that the pooled overall prevalence
114 of SDB during pregnancy was 15% (95% CI 12–18%).(3)
115 While epidemiologic data from cohorts of middle-aged and older adults indicate that SDB
Fo
116 is associated with adverse cardiometabolic outcomes,(4-6) less is known about how SDB in
rR
117 pregnancy and in the post-delivery period impacts maternal health. In pregnancy, increases in
118 inflammation, oxidative stress, and sympathetic nervous system activity, all of which can be
ev
119 exacerbated by SDB, can lead to adverse maternal health events.(2, 7) Indeed, SDB in
120 pregnancy has been associated with a 2-3-fold increased risk for preeclampsia and gestational
iew
121 diabetes mellitus (GDM).(3, 8) These and other adverse pregnancy outcomes (APOs) are risk
122 factors for later development of hypertension (HTN) and metabolic disease.(9-12) The post-
On
123 partum period is also of unique relevance regarding SDB epidemiology given the likely impact of
124 post-partum weight retention on SDB risk.(13-15) Thus, there is a critical need to elucidate
ly
125 whether SDB identified in pregnancy and/or in the post-delivery period is associated with
126 cardiovascular and metabolic health in young adults.
127 The Nulliparous Pregnancy Outcomes Study: Monitoring Mothers‐to‐be Heart Health Study
128 (nuMoM2b-HHS) was a post-delivery follow-up study of participants initially recruited during
129 their first pregnancy to the parent nuMoM2b study. A subset of women in the parent study
130 underwent evaluation for SDB during their first pregnancy (“nuMoM2b SDB Substudy”), and
131 were offered a repeat assessment post-delivery.(16-18) We utilized the nuMoM2b data to
132 address the knowledge gap that exists regarding health implications of SDB identified in
4Page 6 of 64
133 pregnancy and/or post-delivery. Specifically, our objective was to determine whether SDB in
134 pregnancy and/or post-delivery is associated with hypertension (HTN) and metabolic syndrome.
135
136
137 Methods
138 Details of the nuMoM2b study, and the nuMoM2b-SDB Substudy have been previously
139 published.(18) (16) Inclusion criteria for the nuMoM2b study were nulliparity (no prior delivery
140 ≥20 weeks’ gestation) and a viable singleton pregnancy at screening (60–136 weeks’ gestation).
Fo
141 Participants were excluded from the nuMoM2b-SDB Substudy if they were currently using
142 continuous positive airway pressure (CPAP) treatment for SDB, had severe asthma, or required
rR
143 oxygen supplementation.
ev
144 nuMoM2b-HHS Methods
iew
145 The complete methods of the follow-up nuMoM2b‐HHS are described elsewhere.(17)
146 Briefly, contacts/interviews began at least 6 months after delivery. An in‐person nuMoM2b‐HHS
On
147 visit was conducted 2 to 7 years after the index pregnancy ended. Participants were asked to
148 fast for 8 hours before the visit. Blood pressure (BP), anthropometric measurements, and
ly
149 biological specimens were collected using standardized protocols. Participants in the nuMoM2b-
150 HHS were eligible to participate in a follow-up assessment of SDB if they had participated in the
151 nuMoM2b-SDB Substudy while pregnant.
152 nuMoM2b-HHS Outcomes (see online supplement for additional details)
153 Incident HTN was defined as HTN that developed after the index pregnancy, as
154 determined by BP measurement (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) or use of
155 an antihypertensive medication for BP control at the 2‐ to 7‐year post-delivery visit.
5Page 7 of 64
156 Metabolic syndrome (MS) was defined as the presence of 3 of the following 5 criteria:
157 elevated waist circumference (≥88 cm (non-Asian) or ≥80 cm (Asian)); elevated triglycerides
158 (≥150 mg/dL) or use of a triglyceride-lowering medication; elevated fasting glucose (≥100
159 md/dL) or use of a glucose‐lowering medication; elevated BP (systolic BP ≥130 mm Hg or a
160 diastolic BP ≥85 mm Hg) or use of an antihypertensive medication; and reduced high‐density
161 lipoprotein levels (Page 8 of 64
182 ≥15 events per hour.(20) Post hoc tests using orthogonal contrasts were used to assess the
183 exposure-response relationships for linear and quadratic trends in risk on the log scale across
184 the SDB categories.
185 In a similar fashion, a secondary analysis was performed using the AHI and ODI data
186 obtained at the 2-7 year follow-up visit. We also examined the trajectory of SDB (by both
187 definitions) in pregnancy and at the follow-up visit by defining 4 groups: those with no SDB at
188 either time point, those with SDB in pregnancy that persisted at the 2-7 year follow-up, those
189 with SDB in pregnancy that resolved at follow-up, and those with new onset SDB at the 2-7 year
190 follow-up visit.
Fo
191 Baseline characteristics of the index pregnancy and cardiovascular characteristics at the
rR
192 2-7 year follow-up visit were summarized according to SDB status during pregnancy. Similarly,
193 cardiovascular characteristics at the 2-7-year follow-up visit were also summarized by SDB
ev
194 status at follow-up.
iew
195 Analyses during pregnancy were restricted to participants who had an early or mid-
196 pregnancy sleep study with adequate data and attended the in-person nuMoM2b-HHS
197 cardiovascular assessment. Participants with baseline chronic HTN in pregnancy were excluded
On
198 from the HTN analyses; likewise, those with preexisting diabetes were excluded from the MS
ly
199 analyses.
200 Crude and adjusted risk ratios (RR) and 95% confidence intervals (CI) were estimated
201 using Poisson regression with robust standard errors to relate SDB to incident HTN and MS.(21)
202 P-values from likelihood ratio tests were reported. Adjustment covariates chosen a priori
203 included: age and body mass index (BMI) in early pregnancy, self-identified race, and years
204 from delivery of the index pregnancy to the HHS follow-up visit. Similar methods were used for
205 the cross-sectional analyses of SDB in the post-delivery period, with age and BMI at the time of
206 the HHS follow up visit and race used as adjustment covariates. In all our adjusted analyses
207 BMI was included as a linear and a quadratic term.
7Page 9 of 64
208 We also considered having a hypertensive disorder of pregnancy (HDP, i.e., gestational
209 hypertension and preeclampsia) during the index pregnancy as a mediator in the associations of
210 SDB during pregnancy with HTN post-delivery and HDP or GDM during pregnancy as a
211 mediator in the associations of SDB during pregnancy with MS post-delivery.
212 All tests were performed at a nominal significance level of α=05. All single degree-of-
213 freedom tests were two-sided. No correction was made for multiple comparisons. Analyses
214 were performed using SAS 9.4 (Cary, NC). Some of the results of these studies have been
215 previously reported in the form of an abstract.(22)
216
Fo
217 Results
218 A total of 4,508 participants attended a nuMoM2b-HHS in-person visit between February
rR
219 4, 2014 and October 9, 2017. Among these 1,964 had a HSAT from the index pregnancy with
ev
220 1,863 having adequate sleep study data available (406 with early pregnancy data only; 92 with
221 mid-pregnancy data only; 1,365 with both early and mid-pregnancy data, Figure 1). Median
iew
222 (interquartile range) time between delivery of the index pregnancy and the HHS in-person visit
223 was 36 (28-42) months.
On
224 Among nuMoM2b-HHS participants who had both early and mid-pregnancy sleep study
225 data, 127 (9.3%) had an AHI≥5 at either the early or mid-pregnancy SDB assessment. Baseline
ly
226 characteristics according to AHI category during pregnancy for the nuMoM2b-HHS participants
227 are presented in Table 1. Participants with an AHI≥5 in pregnancy were older, had higher BMIs
228 in early pregnancy, and had a lower rate of weight gain in pregnancy.
229 A repeat sleep study at the 2-7 year follow-up visit was conducted on 1,222 of the 1,964
230 participants who completed a sleep study during pregnancy. The participants who did not
231 complete the follow-up sleep assessment were less likely to be non-Hispanic White and had a
232 longer latency from delivery to the HHS follow-up (see supplement Table S1). Adequate follow-
233 up sleep study data were available on 1,069 participants (Figure 2). SDB defined as an AHI≥5
234 was found in 133 of the 1069 (12.4%) participants with follow-up sleep data when studied at a
8Page 10 of 64
235 median (interquartile range) of 32 (13) months post-delivery. Of the 844 participants with SDB
236 data from all timepoints (i.e., at both the early and mid-pregnancy visits, and at the follow-up
237 visit), 710 (84.1%) did not have SDB-AHI during pregnancy or at follow-up, 49 (5.8%) had SDB-
238 AHI in pregnancy that persisted at follow-up, 22 (2.6%) had SDB-AHI in pregnancy that resolved
239 at follow-up, and 63 (7.5%) had new-onset SDB-AHI detected at the 2-7 year follow-up visit.
240 Cardiovascular and metabolic characteristics and outcome rates at the 2-7 year follow-
241 up visit based on AHI status in pregnancy are presented in Table 2. Participants with SDB-AHI
242 in pregnancy had higher BMIs; larger waist circumference; higher systolic and diastolic BP,
243 triglyceride levels and fasting blood glucose; and lower HDL-C levels at 2-7 years post-delivery.
244 At follow-up, incident HTN was more common in participants with an SDB-AHI during
Fo
245 pregnancy (15.7% vs. 6.2 %, pPage 11 of 64
262 similar statistically significant risk was observed separately for ODI≥5 at mid-pregnancy but not
263 early pregnancy.
264 In adjusted analyses, SDB-ODI in pregnancy was associated with an increased risk of
265 MS (aRR 1.53, 95% CI 1.19, 1.97). This risk was also separately observed for both early and
266 mid-pregnancy and the risk increased with increasing categories of ODI severity. Notably,
267 participants with an ODI≥15 in mid-pregnancy had an aRR of 2.57(95% CI 0.82, 8.01) for MS
268 (p=0.02 for linear trend).
269 To better understand the relationships between SDB in pregnancy and MS, we
270 examined the individual components of MS in relation to the presence of SDB-AHI or SDB-ODI
271 in pregnancy. In adjusted analyses, an SDB-AHI in pregnancy was associated with elevated
Fo
272 triglycerides and reduced HDL. SDB-ODI in pregnancy was associated with elevated
rR
273 triglycerides and elevated BP (data shown in Tables S2 and S3 in the supplement).
274 Given the associations between AHI and ODI in pregnancy and hypertensive disorders
ev
275 of pregnancy and GDM, and the relationship between these pregnancy complications and later
iew
276 life cardiometabolic disease, we performed a mediation analysis aimed at assessing the
277 controlled direct effect of SDB in pregnancy on HTN and MS at the 2-7 year follow-up. In these
278 analyses we did not observe a statistically significant controlled direct effect (AHI only, without
On
279 mediation or interaction) between SDB-AHI and the outcomes. Similarly, no direct effect was
280 observed for SDB-ODI on HTN risk at 2-7 year follow-up. However, the controlled direct effect
ly
281 of SDB-ODI in pregnancy on MS was statistically significant. A total excess aRR of 0.60 (95%
282 CI: 0.10, 1.09) was observed with SDB-ODI in pregnancy and the proportion explained by
283 mediation and/or interaction was estimated at ≤11% with 95% confidence (data in Supplement
284 Tables S4 and S5).
285 Cardiovascular and metabolic characteristics and outcome rates at 2-7 year follow-up by
286 current SDB status by AHI are detailed in the supplement (Table S6). In summary, participants
287 with an SDB-AHI at the 2-7 year follow-up had higher BMIs; larger waist circumferences; higher
288 systolic and diastolic BP, triglyceride levels, and fasting blood glucose levels; and lower HDL-C
10Page 12 of 64 289 levels. Incident HTN was more common in participants with a post-delivery SDB-AHI (19.5% 290 vs. 5.3 %, p
Page 13 of 64
316 were generally stronger when SDB was defined using the ODI, which quantified the frequency
317 of drops in oxygen saturation of at least 3%, than the AHI, which was defined by a combination
318 of changes in airflow and oxygen saturation. Participants with persistent elevations in AHI or
319 ODI during pregnancy and 2-7 year follow-up visits were at more than 3-fold increased risk for
320 incident HTN and more than a 2-fold increased risk for MS. Our data suggest that the simpler
321 measure of ODI can identify those at increased risk just as well, if not better, than AHI.
322 In non-pregnant populations that have been followed after a SDB diagnosis, such as the
323 Wisconsin Sleep Cohort, increasing AHI has been linked to higher rates of incident HTN.(23)
324 In our prospective analysis of SDB in pregnancy, we did not find an association between AHI in
Fo
325 pregnancy and incident HTN. However, there was an association between the ODI in pregnancy
326 and incident HTN. AHI and ODI are very tightly correlated, but we found that the ODI tended to
rR
327 be slightly higher than AHI, meaning that there were oxygen desaturation events that were not
ev
328 associated with clearly evident respiratory events (apneas and hypopneas). In our analysis, the
329 difference between ODI and AHI during pregnancy could not be explained by an asthma
iew
330 diagnosis or restless legs syndrome symptoms (see supplement). However, it was correlated
331 with BMI, as was AHI. It may be that there were subtle respiratory flow events that did not
On
332 reach the amplitude criteria for hypopnea but impaired ventilation, leading to oxygen
333 desaturations. Other researchers found that the difference between AHI and ODI increases
ly
334 progressively with obesity level and similarly postulated that higher BMI may result in
335 desaturation events even in the absence of notable changes in breathing amplitude as
336 measured during routine sleep studies.(24)
337 Our data demonstrated a relationship between pregnancy ODI and MS, and a weaker
338 association (demonstrated only in analysis of AHI in early or mid-pregnancy) between
339 pregnancy AHI and MS. This association has been reported in prior cohorts, but this is the first
340 large prospective study in young women to confirm this association.(25) It is important to note
341 that unlike the HTN analyses, we cannot assert that the MS was incident in the follow-up period
342 as we do not have assessments of fasting blood glucose and lipids pre-pregnancy for
12Page 14 of 64
343 comparison. Furthermore, how best to interpret this relationship between SDB and MS is
344 complicated by the very tight relationship of both SDB and MS with BMI. Yet, even after
345 adjustment for BMI (linear and quadratic), the associations between SDB measures and MS
346 remained statistically significant. Also, notably, in our mediation analysis we considered
347 pregnancy complications and found that ODI ≥5 in pregnancy had a significant controlled direct
348 effect on MS risk unrelated to the impact of HDP and GDM.
349 In our cross-sectional analyses of AHI and ODI at the 2-7 year follow-up period, we
350 demonstrated strong associations between AHI and ODI with both HTN and MS. We found
351 significant exposure-response relationships between increasing AHI values and higher rates of
Fo
352 both outcomes, and a significant exposure-response relationship between increasing ODI and
353 incident HTN. When we examined these associations in relation to prior sleep data from
rR
354 pregnancy, we found that participants who had persistent SDB (defined either by AHI or ODI)
ev
355 were at the highest risk.
356 A major strength of this study is the combined prospective and cross-sectional design
iew
357 from pregnancy through 2-7 years of follow-up in which the pregnancy AHI and ODI results
358 were blinded to the care providers, investigators, and participants (unless an urgent alert was
On
359 identified-see online supplement for details). This limited the possibility of ascertainment bias.
360 Our SDB ascertainment was optimized using an independent and blinded central reading
ly
361 center. We were able to control for important confounding factors including BMI (BMI in early
362 pregnancy for prospective analysis, BMI at HHS visit for cross sectional analysis) and we had
363 objective assessments of cardiovascular and metabolic outcomes at the 2-7 year follow-up visit.
364 However, given the observational and voluntary nature of the study and moderate adjusted risk
365 ratios, the possibility of residual confounding due to selection bias and unmeasured
366 confounders cannot be definitively excluded. Additionally, given sample size limitations, we
367 were unable to perform a meaningful analysis considering the impact of intercurrent
368 pregnancies on the HTN and MS risk. Also, we do not have objective SDB data from all of our
369 participants at the 2-7 year follow-up. While it was offered to most nuMoM2b-SDB Substudy
13Page 15 of 64
370 participants, only 62.2% repeated sleep testing at the 2-7 year follow-up assessment. We also
371 recognize the limitations of utilizing a Level 3 HSAT for measuring AHI. Unattended home sleep
372 apnea testing may modestly under-estimate the AHI/ODI values due to over-estimation of sleep
373 time, leading to some degree of misclassification bias.(26) Unlike full PSG, our home sleep
374 testing procedures did not employ electroencephalogram (EEG) so that events associated with
375 arousals (without desaturations) were not ascertained. Finally, because many analyses were
376 done and adjustment for multiple statistical testing was not performed, chance alone might be
377 responsible for some statistically significant results.
378 Although we found associations with AHI, ODI and incident HTN and MS, we cannot
Fo
379 conclude that universal screening for and treatment of SDB in pregnancy and/or in the post-
380 delivery period would reduce the risks of these adverse outcomes. The most widely prescribed
rR
381 treatment for SDB is continuous positive air pressure (CPAP). The benefit of treatment with
ev
382 CPAP has been reliably demonstrated when excessive daytime sleepiness and sleep quality
383 are used as endpoints.(27, 28) CPAP has also been demonstrated in randomized, controlled
iew
384 trials to reduce blood pressure.(29, 30) However, data conflict regarding whether treatment of
385 SDB can reduce the risk of developing HTN, other cardiovascular disease, or diabetes.(31-34)
On
386 This is especially true for milder forms of SDB (AHIPage 16 of 64
396 can reliably be used to identify individuals at risk, and to study if treatment with CPAP during or
397 after pregnancy can modify these risks.
Fo
rR
ev
iew
On
ly
15Page 17 of 64
1. Ayyar L, Shaib F, Guntupalli K. Sleep-Disordered Breathing in Pregnancy. Sleep Med Clin 2018; 13: 349-
357.
2. Izci-Balserak B, Pien GW. Sleep-disordered breathing and pregnancy: potential mechanisms and
evidence for maternal and fetal morbidity. Curr Opin Pulm Med 2010; 16: 574-582.
3. Liu L, Su G, Wang S, Zhu B. The prevalence of obstructive sleep apnea and its association with
pregnancy-related health outcomes: a systematic review and meta-analysis. Sleep Breath 2018.
4. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;
373: 82-93.
5. Reichmuth KJ, Austin D, Skatrud JB, Young T. Association of sleep apnea and type II diabetes: a
population-based study. Am J Respir Crit Care Med 2005; 172: 1590-1595.
6. Marshall NS, Wong KK, Phillips CL, Liu PY, Knuiman MW, Grunstein RR. Is sleep apnea an independent
risk factor for prevalent and incident diabetes in the Busselton Health Study? J Clin Sleep Med
2009; 5: 15-20.
7. Izci Balserak B. Sleep disordered breathing in pregnancy. Breathe (Sheff) 2015; 11: 268-277.
8. Facco FL, Parker CB, Reddy UM, Silver RM, Koch MA, Louis JM, Basner RC, Chung JH, Nhan-Chang CL,
Fo
Pien GW, Redline S, Grobman WA, Wing DA, Simhan HN, Haas DM, Mercer BM, Parry S, Mobley
D, Hunter S, Saade GR, Schubert FP, Zee PC. Association Between Sleep-Disordered Breathing
and Hypertensive Disorders of Pregnancy and Gestational Diabetes Mellitus. Obstet Gynecol
rR
2017; 129: 31-41.
9. Rich-Edwards JW, McElrath TF, Karumanchi SA, Seely EW. Breathing life into the lifecourse approach:
pregnancy history and cardiovascular disease in women. Hypertension 2010; 56: 331-334.
ev
10. Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk: opportunities for
intervention and screening? BMJ 2002; 325: 157-160.
11. Smith GN, Walker MC, Liu A, Wen SW, Swansburg M, Ramshaw H, White RR, Roddy M, Hladunewich
iew
M, Pre-Eclampsia New Emerging T. A history of preeclampsia identifies women who have
underlying cardiovascular risk factors. Am J Obstet Gynecol 2009; 200: 58 e51-58.
12. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and
cancer in later life: systematic review and meta-analysis. BMJ 2007; 335: 974.
13. Street LM, Aschenbrenner CA, Houle TT, Pinyan CW, Eisenach JC. Gestational Obstructive Sleep
On
Apnea: Biomarker Screening Models and Lack of Postpartum Resolution. J Clin Sleep Med 2018;
14: 549-555.
14. Sharkey KM, Boni GM, Quattrucci JA, Blatch S, Carr SN. Women with Postpartum Weight Retention
ly
Have Delayed Wake Times and Decreased Sleep Efficiency During the Perinatal Period: A Brief
Report. Sleep Health 2016; 2: 225-228.
15. Kapsimalis F, Kryger M. Sleep breathing disorders in the U.S. female population. J Womens Health
(Larchmt) 2009; 18: 1211-1219.
16. Haas DM, Parker CB, Wing DA, Parry S, Grobman WA, Mercer BM, Simhan HN, Hoffman MK, Silver
RM, Wadhwa P, Iams JD, Koch MA, Caritis SN, Wapner RJ, Esplin MS, Elovitz MA, Foroud T,
Peaceman AM, Saade GR, Willinger M, Reddy UM, NuMo Mbs. A description of the methods of
the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be (nuMoM2b). Am J Obstet
Gynecol 2015; 212: 539 e531-539 e524.
17. Haas DM, Ehrenthal DB, Koch MA, Catov JM, Barnes SE, Facco F, Parker CB, Mercer BM, Bairey-Merz
CN, Silver RM, Wapner RJ, Simhan HN, Hoffman MK, Grobman WA, Greenland P, Wing DA,
Saade GR, Parry S, Zee PC, Reddy UM, Pemberton VL, Burwen DR, National Heart L, Blood
Institute nuMo MbHHSN. Pregnancy as a Window to Future Cardiovascular Health: Design and
Implementation of the nuMoM2b Heart Health Study. Am J Epidemiol 2016; 183: 519-530.
18. Facco FL, Parker CB, Reddy UM, Silver RM, Louis JM, Basner RC, Chung JH, Schubert FP, Pien GW,
Redline S, Mobley DR, Koch MA, Simhan HN, Nhan-Chang CL, Parry S, Grobman WA, Haas DM,
16Page 18 of 64
Wing DA, Mercer BM, Saade GR, Zee PC. NuMoM2b Sleep-Disordered Breathing study:
objectives and methods. Am J Obstet Gynecol 2015; 212: 542 e541-127.
19. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage
PJ, Smith SC, Jr., Spertus JA, Costa F, American Heart A, National Heart L, Blood I. Diagnosis and
management of the metabolic syndrome: an American Heart Association/National Heart, Lung,
and Blood Institute Scientific Statement. Circulation 2005; 112: 2735-2752.
20. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, Marcus CL, Mehra R, Parthasarathy S,
Quan SF, Redline S, Strohl KP, Davidson Ward SL, Tangredi MM, American Academy of Sleep M.
Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of
Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the
American Academy of Sleep Medicine. J Clin Sleep Med 2012; 8: 597-619.
21. Zou G. A modified poisson regression approach to prospective studies with binary data. Am J
Epidemiol 2004; 159: 702-706.
22. Facco F. Sleep Disordered Breathing in Pregnancy and 2-7 Years Post-Delivery: Associations with
Hypertension and Metabolic Syndrome. Society for Maternal Fetal Medicine; 2021.
23. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-
disordered breathing and hypertension. N Engl J Med 2000; 342: 1378-1384.
24. Ernst G, Bosio M, Salvado A, Dibur E, Nigro C, Borsini E. Difference between apnea-hypopnea index
(AHI) and oxygen desaturation index (ODI): proportional increase associated with degree of
Fo
obesity. Sleep Breath 2016; 20: 1175-1183.
25. Xu S, Wan Y, Xu M, Ming J, Xing Y, An F, Ji Q. The association between obstructive sleep apnea and
metabolic syndrome: a systematic review and meta-analysis. BMC Pulm Med 2015; 15: 105.
rR
26. Chai-Coetzer CL, Antic NA, Rowland LS, Catcheside PG, Esterman A, Reed RL, Williams H, Dunn S,
McEvoy RD. A simplified model of screening questionnaire and home monitoring for obstructive
sleep apnoea in primary care. Thorax 2011; 66: 213-219.
ev
27. Weaver TE, Mancini C, Maislin G, Cater J, Staley B, Landis JR, Ferguson KA, George CF, Schulman DA,
Greenberg H. Continuous positive airway pressure treatment of sleepy patients with milder
obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP)
iew
randomized clinical trial. American Journal of Respiratory and Critical Care Medicine 2012; 186:
677-683.
28. Jenkinson C, Davies RJ, Mullins R, Stradling JR. Comparison of therapeutic and subtherapeutic nasal
continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective
On
parallel trial. Lancet 1999; 353: 2100-2105.
29. Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebo-controlled trial of continuous
positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir
Crit Care Med 2001; 163: 344-348.
ly
30. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson C, Stradling JR, Davies RJ.
Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive
airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002; 359: 204-
210.
31. Haentjens P, Van Meerhaeghe A, Moscariello A, De Weerdt S, Poppe K, Dupont A, Velkeniers B. The
impact of continuous positive airway pressure on blood pressure in patients with obstructive
sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials.
Archives of internal medicine 2007; 167: 757-764.
32. Bratton DJ, Stradling JR, Barbe F, Kohler M. Effect of CPAP on blood pressure in patients with
minimally symptomatic obstructive sleep apnoea: a meta-analysis using individual patient data
from four randomised controlled trials. Thorax 2014; 69: 1128-1135.
33. Barbe F, Duran-Cantolla J, Sanchez-de-la-Torre M, Martinez-Alonso M, Carmona C, Barcelo A, Chiner
E, Masa JF, Gonzalez M, Marin JM, Garcia-Rio F, Diaz de Atauri J, Teran J, Mayos M, de la Pena
M, Monasterio C, del Campo F, Montserrat JM, Spanish S, Breathing N. Effect of continuous
positive airway pressure on the incidence of hypertension and cardiovascular events in
nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. JAMA 2012;
307: 2161-2168.
17Page 19 of 64
34. McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano O, Chen R, Drager LF, Liu Z, Chen G,
Du B, McArdle N, Mukherjee S, Tripathi M, Billot L, Li Q, Lorenzi-Filho G, Barbe F, Redline S,
Wang J, Arima H, Neal B, White DP, Grunstein RR, Zhong N, Anderson CS, Investigators S,
Coordinators. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J
Med 2016; 375: 919-931.
Fo
rR
ev
iew
On
ly
18Page 20 of 64
1
2 TITLE: Sleep Disordered Breathing in Pregnancy and Post-Delivery: Associations with
3 Cardiometabolic Health
4
5 Francesca L. Facco, MD1, Susan Redline, MD2, Shannon M. Hunter , MS3, Phyllis P. Zee, MD4,
6 William A. Grobman, MD5 , Robert M. Silver, MD6, Judette M. Louis, MD7 , Grace W. Pien, MD8,
7 Brian Mercer, MD9, Judith H. Chung, MD, PhD10, C. Noel Bairey Merz, MD11, David M. Haas,
8 MD 12, Chia-Ling Nhan-Chang, MD 13, Hyagriv N. Simhan, MD1, Frank P. Schubert, MD12,
9 Samuel Parry, MD 14, Uma Reddy, MD15, George R. Saade, MD16, Matthew K. Hoffman, MD17,
10 Lisa D. Levine, MD12 Ronald J. Wapner, MD13, Corette B. Parker, PhD3 for the NICHD
11 NuMoM2b and NHLBI NuMoM2b Heart Health Study Networks
12
13
14
15
16
17 1. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh
Fo
18 School of Medicine, Pittsburgh, PA
19 2.Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts
20 3. RTI International, Research Triangle Park, North Carolina
rR
21 4. Department of Neurology, Northwestern University, Chicago, IL
22 5. Department of Obstetrics, Gynecology-Maternal Fetal Medicine & Preventive Medicine,
23 Northwestern University, Chicago, IL
ev
24 6. Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah
25 7. University of South Florida Morsani College of Medicine, Tampa, FL.
26 8. Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD
iew
27 9. Department of Obstetrics and Gynecology, Case Western Reserve, MetroHealth, Cleveland,
28 OH
29 10. Department of Obstetrics and Gynecology, University of California, Irvine, Irvine, California
30 11. Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles,
31 California
On
32 12. Department of Obstetrics and Gynecology, School of Medicine, Indiana University,
33 Indianapolis, IN11
34 13. Department of Obstetrics and Gynecology, Columbia University, New York, New York
35
ly
14. Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA
36 15. Department of Obstetrics, Gynecology & Reproductive Services, Yale University, New
37 Haven, CT
38 16. Department of Obstetrics and Gynecology, University of Texas Medical Branch, University
39 of Texas, Galveston, TX.
40 17. Department of Obstetrics and Gynecology, Christiana Care Health System, Wilmington, DE,
41 USA
42
43 Corresponding Author:
44 Francesca Facco, MD
45 Associate Professor, Department of Obstetrics and Gynecology
46 Magee-Womens Hospital
47 300 Halket Street
48 Room 2233
49 Pittsburgh, PA 15213
50 Work phone: 412-641-5406
51 Cell: 312-933-1881
52 Fax: 412-641-1133
1Page 21 of 64
53 Email: faccof@upmc.edu
54
55 All authors meet the following criteria:
56 Substantial contributions to the conception or design of the work; or the acquisition, analysis, or
57 interpretation of data for the work; AND
58 Drafting the work or revising it critically for important intellectual content; AND
59 Final approval of the version to be published; AND
60 Agreement to be accountable for all aspects of the work in ensuring that questions related to the
61 accuracy or integrity of any part of the work are appropriately investigated and resolved.
62
63
64 This study is supported by cooperative agreement funding from the National Heart, Lung, and
Fo
65 Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human
66 Development: U10-HL119991; U10-HL119989; U10-HL120034; U10-HL119990; U10-
67 HL120006; U10-HL119992; U10-HL120019; U10-HL119993; and U10-HL120018. Support was
rR
68 also provided by the National Institutes of Health: Office of Research on Women’s Health
69 through U10-HL-119991; Office of Behavioral and Social Sciences Research through U10-
70 HL119991 and U10-HL119992; and the National Center for Advancing Translational Sciences –
71 UL-1-TR000124, UL-1-TR000153, UL-1-TR000439, and UL-1-TR001108; and the Barbra
ev
72 Streisand Women’s Cardiovascular Research and Education Program, and the Erika J. Glazer
73 Women’s Heart Research Initiative, Cedars-Sinai Medical Center, Los Angeles. The content of
74
iew
this article is solely the responsibility of the authors and does not necessarily represent the
75 official views of the National Institutes of Health.
76 Short Running: Sleep Disordered Breathing in Pregnancy and Post-Delivery
77 ClinicalTrials.gov Registration number NCT02231398.
On
78 Subject Category: 15.9 Sleep Disordered Breathing: Outcomes
79 Total word count max =3635
ly
80 Abstract = 250 words
81 This article has an online data supplement, which is accessible from this issue's table of content
82 online at www.atsjournals.org
83
2Page 22 of 64
84 ABSTRACT
85 Rationale: Knowledge gaps exist regarding health implications of sleep disordered breathing
86 (SDB) identified in pregnancy and/or post-delivery.
87 Objective: To determine whether SDB in pregnancy and/or post-delivery is associated with
88 hypertension (HTN) and metabolic syndrome (MS).
89 Methods: The nuMoM2b Heart Health Study (n=4,508) followed participants initially recruited
90 during their first pregnancy. Participants returned for a visit 2-7 years after pregnancy. This
91 study examined a subgroup who underwent SDB assessments during their first pregnancy
92 (n=1,964) and a repeat SDB assessment post-delivery (n=1,222). Two SDB definitions were
Fo
93 considered: apnea-hypopnea index (AHI) ≥5; oxygen desaturation index (ODI) ≥5. Associations
rR
94 between SDB and incident HTN and MS were evaluated with adjusted risk ratios (aRR).
ev
95 Results: The aRR for MS given an AHI ≥5 during pregnancy was 1.44 (95% CI 1.08, 1.93), but
96 no association with HTN was found. ODI ≥5 in pregnancy was associated with both an
iew
97 increased risk for HTN (aRR 2.02, 95% CI 1.30, 3.14) and MS (aRR 1.53, 95% CI 1.19, 1.97).
98 Participants with an AHI ≥5 in pregnancy that persisted post-delivery were at higher risk for both
On
99 HTN (aRR 3.77, 95% CI 1.84, 7.73) and MS (aRR 2.46, 95% 1.59, 3.76). Similar associations
100 were observed for persistent post-delivery ODI ≥5.
ly
101 Conclusions: An AHI ≥5 in pregnancy was associated with an increased risk of MS. An ODI ≥5
102 in pregnancy was significantly associated with both HTN and MS. Participants with persistent
103 elevations in AHI and ODI both during pregnancy and at 2-7 post-delivery were at the highest
104 risk for HTN and MS.
105
106
3Page 23 of 64
107
108 Introduction
109 Sleep disordered breathing (SDB) characterized by recurrent apneas and hypopneas,
110 intermittent hypoxemia, and sleep disruption, is increasingly recognized in pregnancy. Pregnant
111 individuals are at increased risk for SDB, predominantly obstructive sleep apnea (OSA),
112 compared to their non-pregnant counter-parts, due to physical and hormonal changes that occur
113 during pregnancy.(1, 2) A meta-analysis of 33 studies found that the pooled overall prevalence
114 of SDB during pregnancy was 15% (95% CI 12–18%).(3)
115 While epidemiologic data from cohorts of middle-aged and older adults indicate that SDB
Fo
116 is associated with adverse cardiometabolic outcomes,(4-6) less is known about how SDB in
rR
117 pregnancy and in the post-delivery period impacts maternal health. In pregnancy, increases in
118 inflammation, oxidative stress, and sympathetic nervous system activity, all of which can be
ev
119 exacerbated by SDB, can lead to adverse maternal health events.(2, 7) Indeed, SDB in
120 pregnancy has been associated with a 2-3-fold increased risk for preeclampsia and gestational
iew
121 diabetes mellitus (GDM).(3, 8) These and other adverse pregnancy outcomes (APOs) are risk
122 factors for later development of hypertension (HTN) and metabolic disease.(9-12) The post-
On
123 partum period is also of unique relevance regarding SDB epidemiology given the likely impact of
124 post-partum weight retention on SDB risk.(13-15) Thus, there is a critical need to elucidate
ly
125 whether SDB identified in pregnancy and/or in the post-delivery period is associated with
126 cardiovascular and metabolic health in young adults.
127 The Nulliparous Pregnancy Outcomes Study: Monitoring Mothers‐to‐be Heart Health Study
128 (nuMoM2b-HHS) was a post-delivery follow-up study of participants initially recruited during
129 their first pregnancy to the parent nuMoM2b study. A subset of women in the parent study
130 underwent evaluation for SDB during their first pregnancy (“nuMoM2b SDB Substudy”), and
131 were offered a repeat assessment post-delivery.(16-18) We utilized the nuMoM2b data to
132 address the knowledge gap that exists regarding health implications of SDB identified in
4Page 24 of 64
133 pregnancy and/or post-delivery. Specifically, our objective was to determine whether SDB in
134 pregnancy and/or post-delivery is associated with hypertension (HTN) and metabolic syndrome.
135
136
137 Methods
138 Details of the nuMoM2b study, and the nuMoM2b-SDB Substudy have been previously
139 published.(18) (16) Inclusion criteria for the nuMoM2b study were nulliparity (no prior delivery
140 ≥20 weeks’ gestation) and a viable singleton pregnancy at screening (60–136 weeks’ gestation).
Fo
141 Participants were excluded from the nuMoM2b-SDB Substudy if they were currently using
142 continuous positive airway pressure (CPAP) treatment for SDB, had severe asthma, or required
rR
143 oxygen supplementation.
ev
144 nuMoM2b-HHS Methods
iew
145 The complete methods of the follow-up nuMoM2b‐HHS are described elsewhere.(17)
146 Briefly, contacts/interviews began at least 6 months after delivery. An in‐person nuMoM2b‐HHS
On
147 visit was conducted 2 to 7 years after the index pregnancy ended. Participants were asked to
148 fast for 8 hours before the visit. Blood pressure (BP), anthropometric measurements, and
ly
149 biological specimens were collected using standardized protocols. Participants in the nuMoM2b-
150 HHS were eligible to participate in a follow-up assessment of SDB if they had participated in the
151 nuMoM2b-SDB Substudy while pregnant.
152 nuMoM2b-HHS Outcomes (see online supplement for additional details)
153 Incident HTN was defined as HTN that developed after the index pregnancy, as
154 determined by BP measurement (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) or use of
155 an antihypertensive medication for BP control at the 2‐ to 7‐year post-delivery visit.
5Page 25 of 64
156 Metabolic syndrome (MS) was defined as the presence of 3 of the following 5 criteria:
157 elevated waist circumference (≥88 cm (non-Asian) or ≥80 cm (Asian)); elevated triglycerides
158 (≥150 mg/dL) or use of a triglyceride-lowering medication; elevated fasting glucose (≥100
159 md/dL) or use of a glucose‐lowering medication; elevated BP (systolic BP ≥130 mm Hg or a
160 diastolic BP ≥85 mm Hg) or use of an antihypertensive medication; and reduced high‐density
161 lipoprotein levels (Page 26 of 64
182 ≥15 events per hour.(20) Post hoc tests using orthogonal contrasts were used to assess the
183 exposure-response relationships for linear and quadratic trends in risk on the log scale across
184 the SDB categories.
185 In a similar fashion, a secondary analysis was performed using the AHI and ODI data
186 obtained at the 2-7 year follow-up visit. We also examined the trajectory of SDB (by both
187 definitions) in pregnancy and at the follow-up visit by defining 4 groups: those with no SDB at
188 either time point, those with SDB in pregnancy that persisted at the 2-7 year follow-up, those
189 with SDB in pregnancy that resolved at follow-up, and those with new onset SDB at the 2-7 year
190 follow-up visit.
Fo
191 Baseline characteristics of the index pregnancy and cardiovascular characteristics at the
rR
192 2-7 year follow-up visit were summarized according to SDB status during pregnancy. Similarly,
193 cardiovascular characteristics at the 2-7-year follow-up visit were also summarized by SDB
ev
194 status at follow-up.
iew
195 Analyses during pregnancy were restricted to participants who had an early or mid-
196 pregnancy sleep study with adequate data and attended the in-person nuMoM2b-HHS
197 cardiovascular assessment. Participants with baseline chronic HTN in pregnancy were excluded
On
198 from the HTN analyses; likewise, those with preexisting diabetes were excluded from the MS
ly
199 analyses.
200 Crude and adjusted risk ratios (RR) and 95% confidence intervals (CI) were estimated
201 using Poisson regression with robust standard errors to relate SDB to incident HTN and MS.(21)
202 P-values from likelihood ratio tests were reported. Adjustment covariates chosen a priori
203 included: age and body mass index (BMI) in early pregnancy, self-identified race, and years
204 from delivery of the index pregnancy to the HHS follow-up visit. Similar methods were used for
205 the cross-sectional analyses of SDB in the post-delivery period, with age and BMI at the time of
206 the HHS follow up visit and race used as adjustment covariates. In all our adjusted analyses
207 BMI was included as a linear and a quadratic term.
7Page 27 of 64
208 We also considered having a hypertensive disorder of pregnancy (HDP, i.e., gestational
209 hypertension and preeclampsia) during the index pregnancy as a mediator in the associations of
210 SDB during pregnancy with HTN post-delivery and HDP or GDM during pregnancy as a
211 mediator in the associations of SDB during pregnancy with MS post-delivery.
212 All tests were performed at a nominal significance level of α=05. All single degree-of-
213 freedom tests were two-sided. No correction was made for multiple comparisons. Analyses
214 were performed using SAS 9.4 (Cary, NC). Some of the results of these studies have been
215 previously reported in the form of an abstract.(22)
216
Fo
217 Results
218 A total of 4,508 participants attended a nuMoM2b-HHS in-person visit between February
rR
219 4, 2014 and October 9, 2017. Among these 1,964 had a HSAT from the index pregnancy with
ev
220 1,863 having adequate sleep study data available (406 with early pregnancy data only; 92 with
221 mid-pregnancy data only; 1,365 with both early and mid-pregnancy data, Figure 1). Median
iew
222 (interquartile range) time between delivery of the index pregnancy and the HHS in-person visit
223 was 36 (28-42) months.
On
224 Among nuMoM2b-HHS participants who had both early and mid-pregnancy sleep study
225 data, 127 (9.3%) had an AHI≥5 at either the early or mid-pregnancy SDB assessment. Baseline
ly
226 characteristics according to AHI category during pregnancy for the nuMoM2b-HHS participants
227 are presented in Table 1. Participants with an AHI≥5 in pregnancy were older, had higher BMIs
228 in early pregnancy, and had a lower rate of weight gain in pregnancy.
229 A repeat sleep study at the 2-7 year follow-up visit was conducted on 1,222 of the 1,964
230 participants who completed a sleep study during pregnancy. The participants who did not
231 complete the follow-up sleep assessment were less likely to be non-Hispanic White and had a
232 longer latency from delivery to the HHS follow-up (see supplement Table S1). Adequate follow-
233 up sleep study data were available on 1,069 participants (Figure 2). SDB defined as an AHI≥5
234 was found in 133 of the 1069 (12.4%) participants with follow-up sleep data when studied at a
8Page 28 of 64
235 median (interquartile range) of 32 (13) months post-delivery. Of the 844 participants with SDB
236 data from all timepoints (i.e., at both the early and mid-pregnancy visits, and at the follow-up
237 visit), 710 (84.1%) did not have SDB-AHI during pregnancy or at follow-up, 49 (5.8%) had SDB-
238 AHI in pregnancy that persisted at follow-up, 22 (2.6%) had SDB-AHI in pregnancy that resolved
239 at follow-up, and 63 (7.5%) had new-onset SDB-AHI detected at the 2-7 year follow-up visit.
240 Cardiovascular and metabolic characteristics and outcome rates at the 2-7 year follow-
241 up visit based on AHI status in pregnancy are presented in Table 2. Participants with SDB-AHI
242 in pregnancy had higher BMIs; larger waist circumference; higher systolic and diastolic BP,
243 triglyceride levels and fasting blood glucose; and lower HDL-C levels at 2-7 years post-delivery.
244 At follow-up, incident HTN was more common in participants with an SDB-AHI during
Fo
245 pregnancy (15.7% vs. 6.2 %, pPage 29 of 64
262 similar statistically significant risk was observed separately for ODI≥5 at mid-pregnancy but not
263 early pregnancy.
264 In adjusted analyses, SDB-ODI in pregnancy was associated with an increased risk of
265 MS (aRR 1.53, 95% CI 1.19, 1.97). This risk was also separately observed for both early and
266 mid-pregnancy and the risk increased with increasing categories of ODI severity. Notably,
267 participants with an ODI≥15 in mid-pregnancy had an aRR of 2.57(95% CI 0.82, 8.01) for MS
268 (p=0.02 for linear trend).
269 To better understand the relationships between SDB in pregnancy and MS, we
270 examined the individual components of MS in relation to the presence of SDB-AHI or SDB-ODI
271 in pregnancy. In adjusted analyses, an SDB-AHI in pregnancy was associated with elevated
Fo
272 triglycerides and reduced HDL. SDB-ODI in pregnancy was associated with elevated
rR
273 triglycerides and elevated BP (data shown in Tables S2 and S3 in the supplement).
274 Given the associations between AHI and ODI in pregnancy and hypertensive disorders
ev
275 of pregnancy and GDM, and the relationship between these pregnancy complications and later
iew
276 life cardiometabolic disease, we performed a mediation analysis aimed at assessing the
277 controlled direct effect of SDB in pregnancy on HTN and MS at the 2-7 year follow-up. In these
278 analyses we did not observe a statistically significant controlled direct effect (AHI only, without
On
279 mediation or interaction) between SDB-AHI and the outcomes. Similarly, no direct effect was
280 observed for SDB-ODI on HTN risk at 2-7 year follow-up. However, the controlled direct effect
ly
281 of SDB-ODI in pregnancy on MS was statistically significant. A total excess aRR of 0.60 (95%
282 CI: 0.10, 1.09) was observed with SDB-ODI in pregnancy and the proportion explained by
283 mediation and/or interaction was estimated at ≤11% with 95% confidence (data in Supplement
284 Tables S4 and S5).
285 Cardiovascular and metabolic characteristics and outcome rates at 2-7 year follow-up by
286 current SDB status by AHI are detailed in the supplement (Table S6). In summary, participants
287 with an SDB-AHI at the 2-7 year follow-up had higher BMIs; larger waist circumferences; higher
288 systolic and diastolic BP, triglyceride levels, and fasting blood glucose levels; and lower HDL-C
10Page 30 of 64 289 levels. Incident HTN was more common in participants with a post-delivery SDB-AHI (19.5% 290 vs. 5.3 %, p
Page 31 of 64
316 were generally stronger when SDB was defined using the ODI, which quantified the frequency
317 of drops in oxygen saturation of at least 3%, than the AHI, which was defined by a combination
318 of changes in airflow and oxygen saturation. Participants with persistent elevations in AHI or
319 ODI during pregnancy and 2-7 year follow-up visits were at more than 3-fold increased risk for
320 incident HTN and more than a 2-fold increased risk for MS. Our data suggest that the simpler
321 measure of ODI can identify those at increased risk just as well, if not better, than AHI.
322 In non-pregnant populations that have been followed after a SDB diagnosis, such as the
323 Wisconsin Sleep Cohort, increasing AHI has been linked to higher rates of incident HTN.(23)
324 In our prospective analysis of SDB in pregnancy, we did not find an association between AHI in
Fo
325 pregnancy and incident HTN. However, there was an association between the ODI in pregnancy
326 and incident HTN. AHI and ODI are very tightly correlated, but we found that the ODI tended to
rR
327 be slightly higher than AHI, meaning that there were oxygen desaturation events that were not
ev
328 associated with clearly evident respiratory events (apneas and hypopneas). In our analysis, the
329 difference between ODI and AHI during pregnancy could not be explained by an asthma
iew
330 diagnosis or restless legs syndrome symptoms (see supplement). However, it was correlated
331 with BMI, as was AHI. It may be that there were subtle respiratory flow events that did not
On
332 reach the amplitude criteria for hypopnea but impaired ventilation, leading to oxygen
333 desaturations. Other researchers found that the difference between AHI and ODI increases
ly
334 progressively with obesity level and similarly postulated that higher BMI may result in
335 desaturation events even in the absence of notable changes in breathing amplitude as
336 measured during routine sleep studies.(24)
337 Our data demonstrated a relationship between pregnancy ODI and MS, and a weaker
338 association (demonstrated only in analysis of AHI in early or mid-pregnancy) between
339 pregnancy AHI and MS. This association has been reported in prior cohorts, but this is the first
340 large prospective study in young women to confirm this association.(25) It is important to note
341 that unlike the HTN analyses, we cannot assert that the MS was incident in the follow-up period
342 as we do not have assessments of fasting blood glucose and lipids pre-pregnancy for
12You can also read
