Abstract
Rationale
Maternal obstructive sleep apnea–hypopnea (OSAH) is associated with hypertensive disorders of pregnancy (HDP). OSAH treatment with positive airway pressure (PAP) in the general population lowers blood pressure (BP). However, there are limited data on the effects of PAP therapy in maternal OSAH.
Objectives
Our primary objective was to assess the feasibility of recruitment to a pilot randomized trial and adherence to PAP therapy for OSAH in women with HDP. Secondary objectives included assessment of PAP effects on 24-h BP, arterial stiffness, and maternal and fetal outcomes.
Methods
Women with singleton pregnancies at ⩾12 weeks’ gestation and hypertension underwent home level 2 polysomnography; those with mild to moderate OSAH (apnea–hypopnea index ⩾ 5 events/h; women with severe OSAH with apnea–hypopnea index > 30 events/h and oxygen desaturation index > 30 were excluded) were randomized to either PAP or nasal dilator strip (NDS; control) therapy. After PAP education, adherence was monitored online with episodic phone or in-person support by research personnel. Twenty-four-hour BP and arterial stiffness were assessed at baseline and before delivery. Maternal and fetal outcomes were also recorded.
Results
Of 105 potentially eligible participants, 67 agreed to undergo screening for OSAH over 38 months; 48 women meeting OSAH inclusion criteria were randomized to PAP (n = 27) or NDS (n = 21) therapy. Of these, 14 PAP (52%) and 13 NDS (62%) participants completed all predelivery measurements, with lack of completion due to urgent delivery (19% in the PAP group, 14% in the NDS group), PAP intolerance at initiation (19%), or other factors. Mean PAP use was 3.1 ± 2.5 h/night, with use ⩾4 h/night on 38.4 ± 33.7% of nights during 9.6 ± 4.0 weeks of treatment. BP was controlled within the target range in most participants. There were no differences in mean change in 24-hour BP or arterial stiffness measurements or in adverse maternal and fetal outcomes between the PAP and NDS groups in either intention-to-treat or per-protocol analyses.
Conclusions
PAP adherence was suboptimal in this HDP cohort despite education and troubleshooting. Further work is required to identify optimal OSAH treatment strategies during pregnancy.
Clinical trial registered with www.clinicaltrials.gov (NCT 03309826).
Keywords: OSAH, HDP, PAP treatment
Hypertensive disorders of pregnancy (HDP), which include preeclampsia, complicate up to 10% of pregnancies (1). Despite recent advances in prevention and management, HDP and their complications remain leading causes of maternal and infant morbidity and mortality (1). Obstructive sleep apnea–hypopnea (OSAH) may develop or worsen during pregnancy and is estimated to affect up to 25% of women by the third trimester (2). There is growing evidence that maternal OSAH is linked to HDP and may worsen pregnancy outcomes in affected women and their infants (3), with studies reporting a significantly higher risk (from 1.7-fold to more than 3-fold) of HDP including preeclampsia in the presence of maternal OSAH (4, 5). Loss of nocturnal blood pressure (BP) dipping, which in the general population predicts cardiovascular morbidity, is prevalent in HDP. We recently reported that the severity of maternal OSAH was inversely correlated with nocturnal BP dipping (6). Our group also recently showed that over the course of pregnancy, the trajectory of arterial stiffness, a marker of cardiovascular morbidity and mortality, predicts the development of preeclampsia (7). In a secondary analysis of that study, we found that in women with OSAH, excessive daytime sleepiness was associated with increased arterial stiffness. Furthermore, midgestation OSAH was associated with an odds ratio of 3.4 (95% confidence interval [CI], 0.9–12.9) for preeclampsia, which increased to 5.7 (95% CI, 1.1–26.0) in women with OSAH and hypersomnolence (8).
In the general population, treatment of OSAH with positive airway pressure (PAP) lowers BP, can restore nocturnal BP dipping, and improves arterial stiffness (9). Although treatment of maternal OSAH could therefore provide a novel strategy for improving outcomes in patients with HDP, there are to date only limited data on the feasibility and effects of PAP treatment in women with OSAH and HDP (10–21). Early studies showed improved BP with PAP (17) but no effect on pregnancy outcomes (18). One nonrandomized study demonstrated a reduction in severe hypertensive syndrome in women with OSAH and daytime sleepiness treated with PAP (11). Another recent randomized controlled trial (RCT) demonstrated improvements in office BP in mostly nonhypertensive pregnant women who were adherent to PAP treatment (21). In contrast, one nonrandomized study revealed a minimal reduction in a composite hypertension outcome between untreated (64% of 77 women) and treated OSAH (57% of 23 women) (12). An RCT of obstructive sleep apnea (OSA) screening and autotitrating PAP (APAP) treatment showed no difference in pregnancy outcomes between groups, though only six participants received APAP, and adherence was poor (13). In a recent RCT, APAP therapy (n = 42) versus control (n = 43) did not diminish composite cardiometabolic risk, although APAP compliance was very poor (20).
To adequately address the impact of PAP treatment for maternal OSAH on pregnancy outcomes, large-scale RCTs are required. The aim of the present study was to a conduct a pilot RCT to obtain data to optimally design and power future large-scale trials. The primary objective of the study was to evaluate feasibility, measured as the rates of recruitment and completion; adequate (>4 h/night) PAP adherence (the primary outcome measure); and protocol completion. The secondary objectives were to obtain preliminary data on the effect of PAP treatment on 24-hour BP, arterial stiffness, and maternal and fetal outcomes.
Preliminary findings from this study were presented at the American Thoracic Society International Conference in San Francisco in May 2022.
Methods
We conducted a pilot RCT evaluating therapeutic PAP versus a control intervention of nasal dilator strip (NDS) therapy, with recruitment from November 2017 to January 2021. The trial was registered at ClinicalTrials.gov (NCT 03309826) and was approved by the McGill University Health Centre Research Ethics Board, and all participants provided written informed consent.
Study Population and Randomization
We recruited women from our obstetrical clinics who were ⩾18 years of age with singleton pregnancies at ⩾12 weeks’ gestation with hypertension, defined by daytime systolic BP ⩾ 140 mm Hg and/or diastolic BP ⩾ 90 mm Hg or current antihypertensive treatment, either before (chronic hypertension) or after (pregnancy-induced hypertension) 20 weeks’ gestation. Exclusion criteria were current severe preeclamsia-eclampsia requiring immediate delivery, chronic kidney disease (serum creatinine > 100 mmol/L), other known secondary causes of hypertension, active cardiac disease or stroke within 3 months, malignancy, other psychiatric or chronic medical condition, active smoking, use of alcohol or illicit drugs, and current/recent treatment for OSAH or another medical sleep disorder.
Participants underwent in-home level 2 polysomnography (PSG) to ascertain OSAH, defined by an apnea–hypopnea index (AHI) ⩾5 events/h. Participants with severe OSAH (AHI ⩾ 30 events/h) with either severe daytime sleepiness (Epworth sleepiness scale [ESS] score ⩾ 15) or nocturnal hypoxemia (4% oxygen desaturation index [ODI] ⩾ 30 events/h or arterial oxygen saturation < 80% for >10% of total sleep time) were excluded because of safety concerns. Eligible participants were randomized 1:1 with block sizes of four to PAP or NDS therapy from November 2017 to December 2019 (using Research Electronic Data Capture; https://www.project-redcap.org/). Given challenges with recruitment, we amended the protocol to 3:1 randomization for PAP versus NDS with approval from our study statistician (A.B.) from December 2019 to January 2021. Randomization was stratified according to chronic versus pregnancy-induced hypertension. All outcome data were analyzed blinded to treatment status.
Study Interventions
PAP was delivered using an APAP device (Airsense 10 [A10]; ResMed) equipped with telemetry capability. Participants received PAP education and underwent mask fitting and treatment initiation with trained, experienced study personnel. Therapy was initiated in APAP mode at 5–15 cm H2O, with the goal of switching remotely to fixed mode after >7 nights of treatment using the 95th percentile APAP level. For patients with difficulty tolerating therapy, the option of continued treatment with APAP was offered. Objective adherence, leaks, and PAP efficacy were monitored online. PAP requirements may change during pregnancy (weight gain, rhinitis); for patients in fixed mode, if AHI exceeded 10 events/h for more than several days, there was a provision to resume APAP for 3 nights to reassess the 95th percentile and reset the fixed PAP level. Close online surveillance, complemented by phone or in-person interaction with participants as required, was conducted to optimize PAP adherence and efficacy.
NDS therapy has been proposed as a control treatment for OSAH that they improve subjective sleep quality without effectively treating obstructive sleep disordered breathing (22). Recent data demonstrate no significant benefit of NDS therapy on OSAH severity in pregnancy (23, 24). NDS adherence was monitored by self-report and counting of NDSs at follow-up visits.
Study Protocol
Following randomization, participants underwent baseline measurements of 24-hour BP and arterial stiffness, a clinical assessment, and questionnaires evaluating subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]) (25) and daytime sleepiness (Epworth sleepiness score [ESS]) (26). These were repeated before delivery, targeting at least 4 weeks after the baseline measurements and within 4 weeks of the anticipated date of delivery. Some of the baseline data have been previously reported (6).
Study Measurements
PSG
In-home complete PSG was performed using the Embletta MPR with ST Proxy (Natus Inc.) (6). Signals included four electroencephalographic electrodes (C3, C4, F3, and F4); right and left electrooculograms; submental and bilateral tibialis anterior electromyograms; nasal pressure via cannula; rib cage, abdominal, and sum respiratory inductance plethysmography; pulse oximetry; body position; and snoring via microphone. A technician installed the equipment in the patient’s home and verified signal quality. Records were scored manually by a single certified PSG technologist. Sleep–wake state, arousals, and periodic limb movements were scored using current American Academy of Sleep Medicine criteria version 2.6 (27), while respiratory events were scored using the American Academy of Sleep Medicine research (Chicago) criteria (6, 28).
BP measurements
Twenty-four-hour BP was measured at baseline and before delivery. Measurements were made every 30 minutes during the daytime (6 a.m. to 11 p.m.) and every 1 hour at night (11 p.m. to 6 a.m.) (6, 29) using a validated device from Spacelabs Inc. Office BP was measured during the same study visits using a validated automated device (BpTRU; ManthaMed) using the average of the last five of six unattended measurements obtained 1 minute apart in the sitting or left lateral decubitus position (30). A secondary objective was to compare BpTRU measurements with 24-hour ambulatory BP values.
Arterial stiffness measurements
Participants underwent arterial stiffness measurement at the baseline and predelivery visits using applanation tonometry (SphygmoCor; ATCOR Medical) to obtain measurements of carotid–femoral pulse-wave velocity (central stiffness, the gold standard outcome measure of arterial stiffness), carotid–radial pulse-wave velocity (peripheral stiffness), wave reflection assessed by augmentation index and augmentation index adjusted for a heart rate of 75 beats/min, as well as central BP, pulse-pressure amplification (a measure of the progressive increase in pulse pressure from central to peripheral arteries), and subendocardial viability ratio (an index of myocardial oxygen supply and demand) using our established protocol (6, 31).
Maternal and fetal outcomes
Details of obstetrical history, physical examination, medications, and maternal and fetal well-being were obtained at baseline, during regular obstetrical visits and any hospitalizations or emergency department visits, at delivery, and at postpartum follow-up visits.
Adherence and efficacy
Average values from the first night of PAP use to the predelivery visit were obtained for adherence (h/night on nights used and on all nights; percentage of nights with ⩾4-h use, and percentage of nights with any use), leaks, and residual AHI. “Adequate adherence” was defined a priori as mean use ⩾4 h/night for at least 70% of nights. As an exploratory outcome, we assessed “acceptable adherence,” defined as any PAP use for >50% of nights. PAP participants completed a questionnaire assessing PAP side effects and satisfaction at the predelivery study visit.
For NDS therapy, adequate adherence was defined as use on >70% of nights and acceptable adherence as use on >50% of nights. NDS participants underwent a second in-home PSG study to evaluate effects on OSAH severity approximately 2 weeks after NDS initiation. These results will be reported separately (but no beneficial effect on OSAH severity or sleep characteristics was observed) (24).
Statistical Analysis
The pilot objectives were to demonstrate the feasibility of PAP treatment in patients with HDP, with the primary outcome measure being the proportion of participants demonstrating adequate adherence, and to obtain preliminary data on secondary outcome measures to plan a definitive, multicenter trial. Data analysis was therefore primarily descriptive.
Our sample size calculation was based on the primary pilot outcome measure of PAP adherence. Rates of adequate adherence vary considerably (46–83%) (32), and rates of 60–70% are not uncommon. We estimated that 35 participants per group (total n = 70) would be needed to observe an adequate adherence rate of PAP subjects (95% CI, 54–83%). Using a conservative 15% dropout rate, we planned to recruit a total of 80 subjects with OSAH. One HDP study showed an OSAH prevalence of 41% by PSG using conservative scoring criteria, with a prevalence of frequent snoring of 63% (33). We estimated that 50% of otherwise eligible patients with HDP would have OSAH, so we aimed to recruit 160 to undergo PSG. We calculated recruitment and study completion rates over the study period.
Continuous variables are reported as mean and standard deviation. Binary and categorical variables are summarized using frequency counts and percentages. Changes in 24-hour ambulatory BP at the baseline and predelivery visits were compared across groups using mixed-effects random-intercept linear regression models in which patient was considered to be the random element and the interaction of time of measurement with group as having fixed effects. This analysis was carried out using SPSS version 27 (IBM). Models were also run with adjustment for potential confounding by the number and defined daily dose (34) of antihypertensive drugs and by body mass index at baseline and before delivery. For the latter, mean values of systolic BP and diastolic BP and 95% CIs throughout the 24 hours in each period were estimated and displayed using margins and margins plots in Stata version 17 (StataCorp LLC).
Results
Study Participants
Two hundred eighty-nine potential participants were identified from our obstetrics clinics over 38 months (Figure 1). Of these, 184 women did not meet the eligibility criteria. During the recruitment phase, we screened 1.8 potential participants per month and identified a mean of 1.3 eligible patients per month. There were 38 potentially eligible women who declined participation. There were 67 potentially eligible participants who underwent PSG testing, of whom 56 (84%) tested positive for OSAH. Nineteen participants were excluded (5 participants with AHI < 5 events/h, 8 participants with AHI and ODI both ⩾30 events/h, and 6 participants who failed the first-night PSG and then refused to repeat). The remaining 48 participants were randomized to PAP (n = 27) or NDS (n = 21) therapy. Of these, 13 PAP and 8 NDS participants were lost to follow-up at the predelivery visit because of urgent delivery (19% vs. 14% for PAP vs. NDS therapy), PAP intolerance at initiation (19%), intolerable 24-hour BP measurements (11.1% vs. 9.5% for PAP vs. NDS therapy), or other reasons. There were 14 (52%) PAP and 13 (62%) NDS participants who completed all predelivery study measurements (Figure 1).
Figure 1.
Consolidated Standards of Reporting Trials flow diagram. AHI = apnea–hypopnea index; BP = blood pressure; CPAP = continuous positive airway pressure; ODI = oxygen desaturation index; OSAH = obstructive sleep apnea–hypopnea; PSG = polysomnography.
The baseline demographics and PSG characteristics of the 48 participants with HDP and OSAH are shown in Tables 1 and 2, respectively. Demographic characteristics, sleep quality, and OSA severity were similar for the PAP and NDS groups. A majority of participants had chronic hypertension (79.2%) and were receiving a single antihypertensive medication (64.6%) as well as aspirin (83.3%) to reduce preeclampsia risk. History of preeclampsia in a previous pregnancy was present in 31%. On average, patients reported mild excessive daytime sleepiness according to ESS score but overall poor subjective sleep quality according to the PSQI (Table 1). OSAH was moderate overall and characterized predominantly by obstructive hypopneas associated with microarousals, with relatively few events associated with arterial oxygen saturation reductions of ⩾4%. Values for the 27 participants who completed all study measures are shown in Tables E1 and E2 in the data supplement and are similar.
Table 1.
Participant characteristics
| Total (n = 48) | PAP (n = 27) | NDS (n = 21) | |
|---|---|---|---|
| Maternal age, yr | 36.5 ± 5.0 | 36.0 ± 4.3 | 37.2 ± 5.9 |
| Prepregnancy BMI, kg/m2 | 33.1 ± 7.5 | 32.9 ± 8.2 | 33.4 ± 6.7 |
| BMI at enrollment, kg/m2 | 35.1 ± 7.0 | 35.2 ± 7.5 | 34.9 ± 6.4 |
| Gestational weight gain, kg | 5.8 ± 5.9 | 6.9 ± 6.2 | 4.5 ± 5.3 |
| GA at BP assessment, wk | 28.0 ± 4.6 | 28.0 ± 4.6 | 27.9 ± 4.6 |
| GA at sleep study, wk | 25.2 ± 4.6 | 25.3 ± 4.8 | 25.1 ± 4.6 |
| ESS score | 9.5 ± 3.5 | 10.0 ± 3.9 | 9.0 ± 2.8 |
| PSQI score | 9.0 ± 3.5 | 8.7 ± 3.3 | 9.4 ± 3.7 |
| Parity | |||
| Nulliparous | 16 (33.3) | 8 (29.6) | 8 (38.1) |
| Multiparous | 32 (66.7) | 19 (70.4) | 13 (61.9) |
| Category of hypertension | |||
| Chronic hypertension | 38 (79.2) | 21 (77.8) | 17 (81.0) |
| Gestational hypertension | 10 (20.8) | 6 (22.2) | 4 (19.0) |
| Antihypertensive medications | |||
| Hydralazine | 1 (2.1) | 1 (3.7) | 0 |
| Methyldopa | 10 (20.8) | 4 (14.8) | 6 (28.6) |
| Labetalol | 32 (66.7) | 18 (66.7) | 14 (66.7) |
| Nifedipine | 25 (52.1) | 14 (51.9) | 11 (52.4) |
| Enalapril | 1 (2.1) | 1 (3.7) | 0 |
| Other medications | |||
| ASA | 40 (83.3) | 24 (88.9) | 16 (76.2) |
| Insulin | 7 (14.6) | 4 (14.8) | 3 (14.3) |
| Metformin | 4 (8.3) | 1 (3.7) | 3 (14.3) |
| Number of BP medications | |||
| 1 | 31 (64.6) | 19 (70.4) | 12 (57.1) |
| 2 | 14 (29.2) | 6 (22.2) | 8 (38.1) |
| ⩾3 | 3 (6.2) | 2 (7.4) | 1 (4.8) |
| Diabetes status | |||
| Gestational diabetes | 8 (16.7) | 6 (22.2) | 2 (9.5) |
| Preexisting diabetes | 5 (10.4) | 3 (11.1) | 2 (9.5) |
| Ethnicity | |||
| White | 25 (52.1) | 14 (51.9) | 11 (52.4) |
| African American | 10 (20.8) | 7 (25.9) | 3 (14.3) |
| Asian | 6 (12.5) | 2 (7.4) | 4 (19.0) |
| Hispanic | 7 (14.6) | 4 (14.8) | 3 (14.3) |
| Previous pregnancy with PrE | 15 (31.3) | 9 (33.3) | 6 (28.6) |
| Family history of CVD | 38 (79.2) | 21 (77.8) | 17 (81) |
| Severity of OSA | |||
| Mild | 18 (37.5) | 10 (37.0) | 8 (38.1) |
| Moderate | 23 (47.9) | 13 (48.1) | 10 (47.6) |
| Severe | 7 (14.6) | 4 (14.8) | 3 (14.3) |
Definition of abbreviations: ASA = acetylsalicylic acid; BMI = body mass index; BP = blood pressure; CVD = cardiovascular disease; ESS = Epworth sleepiness scale; GA = gestational age; NDS = nasal dilator strip; OSA = obstructive sleep apnea; PAP = positive airway pressure; PrE = preeclampsia; PSQI = Pittsburgh Sleep Quality Index.
Data are expressed as mean ± standard deviation or n (%).
Table 2.
Baseline polysomnography data
| Total (n = 48) | PAP (n = 27) | NDS (n = 21) | |
|---|---|---|---|
| Sleep efficiency, % | 80.2 ± 14.0 | 82.6 ± 11.0 | 77.0 ± 17.0 |
| Total sleep time, h | 6.2 ± 1.7 | 6.1 ± 1.7 | 6.3 ± 1.8 |
| Sleep stage | |||
| NREM 1, % | 17.7 ± 9.4 | 17.3 ± 10.1 | 18.2 ± 8.5 |
| NREM 2, % | 47.7 ± 8.9 | 46.7 ± 10.0 | 49.0 ± 7.2 |
| NREM 3, % | 17.2 ± 11.4 | 18.6 ± 13.8 | 15.4 ± 7.1 |
| REM, % | 17.4 ± 7.4 | 17.4 ± 8.9 | 17.4 ± 4.9 |
| Sleep onset latency, min | 13.5 ± 14.6 | 11.4 ± 10.3 | 16.5 ± 18.9 |
| WASO, min | 71.2 ± 58.6 | 56.5 ± 35.1 | 90.9 ± 76.9 |
| REM latency, min | 100.9 ± 53.4 | 106.8 ± 60.0 | 92.9 ± 43.0 |
| Microarousal index, events/h | 37.4 ± 15.8 | 36.4 ± 16.9 | 38.7 ± 14.5 |
| Total sleep time in supine, % | 22.4 ± 24.8 | 21.1 ± 24.1 | 24.2 ± 26.2 |
| AHI, events/h | 21.0 ± 15.3 | 22.1 ± 18.6 | 19.6 ± 10.0 |
| AI, events/h | 0.8 ± 1.5 | 0.9 ± 1.9 | 0.6 ± 0.7 |
| HI, events/h | 20.2 ± 14.5 | 21.2 ± 17.4 | 18.9 ± 9.7 |
| REM AHI, events/h | 39.3 ± 23.2 | 41.9 ± 26.6 | 36.0 ± 18.0 |
| NREM AHI, events/h | 16.9 ± 16.4 | 18.1 ± 19.7 | 15.2 ± 10.6 |
| Supine AHI, events/h | 32.5 ± 25.1 | 37.4 ± 30.8 | 26.6 ± 14.9 |
| Nonsupine AHI, events/h | 18.4 ± 14.2 | 19.7 ± 17.6 | 16.7 ± 8.5 |
| Respiratory arousal index, events/h | 16.8 ± 15.4 | 18.0 ± 18.5 | 15.3 ± 10.0 |
| 4% ODI, events/h | 3.6 ± 5.1 | 3.2 ± 4.4 | 4.1 ± 6.1 |
| Mean SpO2 during sleep, % | 96.0 ± 1.4 | 95.9 ± 1.7 | 96.1 ± 1.0 |
| Nadir SpO2 during sleep, % | 88.6 ± 5.0 | 88.5 ± 6.0 | 88.7 ± 3.5 |
| TST < 90%, % | 0.3 ± 0.8 | 0.4 ± 1.0 | 0.1 ± 0.2 |
Definition of abbreviations: AHI = apnea–hypopnea index; AI = apnea index; HI = hypopnea index; NDS = nasal dilator strip; NREM = non–rapid eye movement; ODI = oxygen desaturation index; PAP = positive airway pressure; REM = rapid eye movement; SpO2 = oxygen saturation; TST < 90% = total sleep time with oxygen saturation < 90%; WASO = wake after sleep onset.
Data are expressed as mean ± standard deviation.
Adherence Data
PAP data are shown in Table 3. Of the 27 participants randomized to PAP, 5 dropped out before any PAP use (Figure 1). Of the remaining 22 participants, 6 (27%) achieved adequate PAP adherence (⩾4 h/night for >70% of nights) over the treatment period, which rose to 7 participants (32%) during the final 2 weeks before the predelivery assessment; 10 participants (45%) achieved acceptable adherence (any PAP use for >50% of nights) over the treatment period. Among the 14 PAP participants completing all study measurements, mean PAP use was 3.1 ± 2.5 h/night over the 9.6 ± 4.0 week treatment period (Table 3). Overall, OSAH was well controlled, with acceptable leak measurements and a residual AHI of 0.5 ± 0.6 events/h. Most participants used nasal masks; a slight majority of remained in APAP mode. Symptoms associated with PAP intolerance included nasal congestion (50%), claustrophobia (21%), insomnia (7%), mask leaks (14%), and nocturnal choking (7%). In exploratory analyses, nasal congestion and claustrophobia were negatively correlated with PAP adherence. We also found a positive correlation between PAP adherence and 4% ODI but no other relationships between PAP use and demographics, sleep characteristics, OSAH severity, mask type, or PAP download parameters.
Table 3.
Download parameters of PAP therapy
| All CPAP (n = 27) | Any PAP Use (n = 22) | Completed Follow-Up (n = 14) | |
|---|---|---|---|
| Treatment period, d | 40.7 ± 31.9 | 50.0 ± 27.8 | 67.2 ± 28.4 |
| Days used ⩾4 h, % | 33.0 ± 34.4 | 40.4 ± 33.8 | 38.4 ± 33.7 |
| Average daily use, h/night | 2.6 ± 2.4 | 3.2 ± 2.3 | 3.1 ± 2.5 |
| Apnea–hypopnea index, events/h | 0.4 ± 0.5 | 0.4 ± 0.5 | 0.5 ± 0.6 |
| Apnea index, events/h | 0.3 ± 0.4 | 0.3 ± 0.4 | 0.4 ± 0.5 |
| Hypopnea index, events/h | 0.1 ± 0.1 | 0.1 ± 0.1 | 0.1 ± 0.1 |
| Median leak, L/min | 2.2 ± 4.2 | 2.4 ± 4.3 | 3.3 ± 5.3 |
| 95th percentile leak, L/min | 9.4 ± 9.0 | 10.2 ± 9.1 | 11.9 ± 10.3 |
| Mode of PAP therapy | |||
| Fixed-pressure mode | 10 (37.0) | 9 (40.9) | 6 (42.9) |
| APAP mode | 17 (63.0) | 13 (59.1) | 8 (57.1) |
| PAP setting | |||
| Pmin in APAP mode, cm H2O | 4.6 ± 1.0 | 4.7 ± 1.1 | 4.8 ± 1.4 |
| Pmax in APAP mode, cm H2O | 16.9 ± 3.1 | 16.5 ± 3.2 | 16.9 ± 3.7 |
| Median pressure, cm H2O | 6.7 ± 3.1 | 6.9 ± 3.1 | 6.5 ± 2.7 |
| 95th percentile pressure, cm H2O | 8.6 ± 3.3 | 8.8 ± 3.3 | 8.4 ± 2.8 |
| Fixed pressure, cm H2O | 9.0 ± 3.1 | 9.8 ± 1.8 | 9.5 ± 1.5 |
| Mask type | |||
| Nasal mask | 24 (88.9) | 19 (86.4) | 12 (85.7) |
| Full-face mask | 3 (11.1) | 3 (13.6) | 2 (14.3) |
Definition of abbreviations: APAP = autotitrating positive airway pressure; CPAP = continuous positive airway pressure; PAP = positive airway pressure; Pmax = maximum pressure; Pmin = minimum pressure.
Data are expressed as mean ± standard deviation or n (%).
In the NDS group, 7 of 21 participants demonstrated no NDS use (Figure 1), while the remaining 14 used NDSs on 80 ± 26% of nights over 8.0 ± 3.3 weeks, with 11 participants using NDSs >70% of nights and 13 using NDSs >50% of nights. Further data on side effects and participant satisfaction are provided in the data supplement (see Tables E3A–E3C).
Secondary Outcomes
Data for 24-hour BP are shown in Table 4 and Figures 2 and E1. On average, participants had normal 24-hour BP at baseline in both the PAP and NDS groups. Mean BP values increased slightly from the baseline to the predelivery visit in both groups, as expected, during the third trimester (35). There were no notable differences between the groups for BP profiles for either the baseline or the predelivery visit (Table 4 and Figures 2 and E1). The 24-hour BP pattern was not significantly affected by PAP treatment in mixed-effects linear regression models in unadjusted analysis (Figure 2) or after adjustment for the change in number and dose of antihypertensive medications (expressed as defined daily dose) and weight gain during pregnancy (see Figure E1).
Table 4.
Twenty-four-hour blood pressure outcomes
| BP | PAP
(n = 14) |
NDS
(n = 13) |
||||
|---|---|---|---|---|---|---|
| Baseline | Predelivery | Change | Baseline | Predelivery | Change | |
| 24-h systolic BP, mm Hg | 117.2 ± 7 | 126.1 ± 10.5 | 8.9 ± 10.9 | 119.5 ± 6.9 | 122.4 ± 9.4 | 2.8 ± 8.0 |
| 24-h diastolic BP, mm Hg | 68.9 ± 8.7 | 78.0 ± 9.7 | 9.1 ± 9.5 | 70.2 ± 6.1 | 73.2 ± 6.4 | 3.1 ± 5.3 |
| 24-h mean arterial pressure, mm Hg | 84.8 ± 7.7 | 94.4 ± 10.2 | 9.6 ± 9.6 | 86.2 ± 5.4 | 89.5 ± 7.3 | 3.4 ± 5.9 |
| Daytime systolic BP, mm Hg | 119.6 ± 6.9 | 127.9 ± 10.5 | 8.3 ± 11.1 | 121.8 ± 6.0 | 124.8 ± 10.0 | 2.9 ± 9.1 |
| Daytime diastolic BP, mm Hg | 71.3 ± 9.0 | 80.1 ± 9.4 | 8.8 ± 9.2 | 71.7 ± 5.7 | 75.6 ± 6.9 | 3.9 ± 5.8 |
| Daytime mean arterial pressure, mm Hg | 87.6 ± 7.6 | 96.4 ± 9.6 | 8.8 ± 8.9 | 88.3 ± 4.9 | 92.2 ± 8.0 | 3.9 ± 6.8 |
| Nighttime systolic BP, mm Hg | 110.8 ± 8.2 | 121.6 ± 10.2 | 10.8 ± 10.3 | 113.7 ± 10.5 | 116.7 ± 10.6 | 3.0 ± 11.3 |
| Nighttime diastolic BP, mm Hg | 62.6 ± 9.7 | 73.1 ± 12.6 | 10.4 ± 12.5 | 66.0 ± 8.3 | 66.9 ± 7.6 | 0.9 ± 8.7 |
| Nighttime mean arterial pressure, mm Hg | 78.0 ± 8.7 | 90.1 ± 13.9 | 12.1 ± 14.6 | 81.1 ± 8.6 | 83.1 ± 7.3 | 2.0 ± 8.7 |
Definition of abbreviations: BP = blood pressure; NDS = nasal dilator strip; PAP = positive airway pressure.
Data are expressed as mean ± standard deviation.
Figure 2.
Comparison of 24-hour blood pressure (BP) at baseline and predelivery visit between positive airway pressure therapy (gray lines) and nasal dilator strip (black lines) groups. Points represent the mean values of BP at each time point.
BpTRU measurements are shown in Table E4. BP changes mirrored those seen with 24-hour BP and were not notably different between the two groups from baseline to follow-up.
Arterial stiffness measurements are shown in Table 5. On average, participants had arterial stiffness measures that were within the normal range at baseline. The changes in arterial stiffness measures between the baseline and predelivery visits were similar for the PAP and NDS groups. Exploratory analyses including only completers with adequate or acceptable adherence did not demonstrate any evident effect of PAP on hemodynamic variables, though subject numbers were small. There were also no notable differences between fixed PAP and APAP treatment.
Table 5.
Arterial stiffness outcomes
| Arterial Stiffness | PAP
(n = 14) |
NDS
(n = 13) |
||||
|---|---|---|---|---|---|---|
| Baseline | Predelivery | Change | Baseline | Predelivery | Change | |
| Carotid femoral pulse-wave velocity, m/s | 7.2 ± 1.0 | 7.4 ± 1.4 | 0.3 ± 1.4 | 7.2 ± 1.3 | 7.1 ± 1.2 | −0.1 ± 1.3 |
| Carotid radial pulse-wave velocity, m/s | 7.8 ± 1.0 | 8.3 ± 2.1 | 0.5 ± 1.3 | 7.9 ± 1.6 | 8.7 ± 0.8 | 0.8 ± 1.4 |
| AI, % | 11.7 ± 5.7 | 12.4 ± 7.7 | 0.7 ± 7.6 | 15.7 ± 9.9 | 14.3 ± 11.0 | −1.3 ± 4.9 |
| AI corrected for HR 75 beats/min, % | 16.6 ± 8.0 | 18.4 ± 5.8 | 1.8 ± 6.6 | 19.3 ± 8.1 | 19.1 ± 9.7 | −0.2 ± 3.9 |
| Subendocardial viability ratio, % | 115.2 ± 18.0 | 116.2 ± 24.0 | 1.0 ± 17.8 | 117.8 ± 12.6 | 128.7 ± 16.0 | 10.9 ± 21 |
| Pulse pressure amplification, mm Hg | 1.6 ± 0.1 | 1.5 ± 0.3 | −0.1 ± 0.3 | 1.5 ± 0.2 | 1.4 ± 0.2 | −0.1 ± 0.2 |
| Central systolic blood pressure, mm Hg | 97.3 ± 11.9 | 103.6 ± 11.8 | 6.4 ± 10.7 | 103.0 ± 6.6 | 105.0 ± 7.3 | 2.0 ± 7.5 |
| Central diastolic blood pressure, mm Hg | 71.6 ± 7.7 | 75.9 ± 9.0 | 4.3 ± 7.5 | 75.0 ± 6.3 | 77.7 ± 5.7 | 2.7 ± 8.1 |
| Peripheral systolic blood pressure, mm Hg | 109.7 ± 7.1 | 114.3 ± 8.2 | 4.6 ± 9.4 | 114.0 ± 8.0 | 111.8 ± 21.8 | −2.2 ± 20.3 |
| Peripheral diastolic blood pressure, mm Hg | 69.8 ± 7.3 | 73.6 ± 9.0 | 3.8 ± 6.8 | 73.2 ± 5.6 | 72.6 ± 11.3 | −0.6 ± 12.3 |
Definition of abbreviations: AI = augmentation index; HR = heart rate; NDS = nasal dilator strip; PAP = positive airway pressure.
Data are expressed as mean ± standard deviation.
Maternal and neonatal outcomes for completers are shown in Table 6 and for all participants and those with adequate adherence in Table E5. Complications were similar in the two groups, with no evident benefit conferred by PAP treatment, while rates for preeclampsia and urgent delivery were somewhat higher for the PAP group.
Table 6.
Maternal and neonatal outcomes in participants who completed all study measures
| PAP (n = 14) | NDS (n = 13) | |
|---|---|---|
| Maternal complications | ||
| Preeclampsia | 5 (35.7) | 1 (7.7) |
| Eclampsia | 0 | 1 (7.7) |
| Postpartum hemorrhage | 1 (7.1) | 1 (7.7) |
| Urgent delivery | 7 (50.0) | 3 (23.1) |
| Medication during pregnancy | ||
| Magnesium (intravenous) | 0 | 1 (7.7) |
| Dexamethasone (intravenous) | 0 | 1 (7.7) |
| Maternal length of stay, d | 2.0 ± 0.8 | 3.2 ± 1.7 |
| Participants who increased antihypertensive medications | 4 (28.6) | 6 (46.2) |
| Participants who decreased antihypertensive medications | 2 (7.4) | 0 |
| Neonatal complications | ||
| Respiratory distress | 2 (14.3) | 0 |
| Hypoglycemia | 6 (42.9) | 5 (38.5) |
| Neonatal jaundice | 1 (7.1) | 1 (7.7) |
| NICU admission | 1 (7.1) | 0 |
| Required noninvasive/invasive ventilation | 0 | 2 (14.3) |
| Apgar score at 1 min | 8.1 ± 1.9 | 8.7 ± 0.9 |
| Apgar score at 5 min | 8.5 ± 1.0 | 8.6 ± 1.4 |
| Neonatal length of stay, d | 2.0 ± 1.6 | 2.4 ± 1.0 |
| Birth weight, g | 3,334 ± 511.0 | 3,248 ± 304.0 |
| Small for gestational age | 0 | 0 |
| Gestational age at delivery, wk | 38.6 ± 0.9 | 38.4 ± 0.8 |
| Preterm | 0 | 0 |
| Late preterm | 0 | 0 |
| Early preterm | 9 (64.3) | 8 (61.5) |
| Full term | 5 (35.7) | 5 (38.5) |
Definition of abbreviations: NICU = neonatal intensive care unit; NDS = nasal dilator strip; PAP = positive airway pressure.
Data are expressed as n (%) or mean ± standard deviation.
As shown in Table 7, a more notable improvement was seen in ESS score in the PAP group compared with the NDS group, while PSQI scores improved only slightly in both groups.
Table 7.
Subjective sleep outcomes in participants who completed all study measures
| Outcome | PAP
(n = 14) |
NDS
(n = 13) |
||||
|---|---|---|---|---|---|---|
| Baseline | Predelivery | Change | Baseline | Predelivery | Change | |
| Epworth sleepiness scale score | 11.0 ± 4.1 | 8.5 ± 4.3 | −2.5 ± 4.3 | 9.0 ± 3.2 | 9.3 ± 3.9 | 0.3 ± 3.6 |
| Pittsburgh Sleep Quality Index score | 9.1 ± 3.4 | 7.2 ± 3.1 | −1.9 ± 2.3 | 9.5 ± 3.0 | 8.3 ± 5.0 | −1.2 ± 4.3 |
Definition of abbreviations: NDS = nasal dilator strip; PAP = positive airway pressure.
Data are expressed as mean ± standard deviation.
Discussion
The primary objective of this pilot study was to evaluate rates of recruitment, study completion, and adequate adherence to PAP therapy (the primary outcome). We did not attain our target sample size. Despite efforts to reduce participation burden (e.g., synchronizing study visits with clinical visits, performing in-home PSG), there were still considerable demands on participants, which we believe affected recruitment. This argues for a pragmatic approach with a lower study burden for future larger scale RCTs. The coronavirus disease (COVID-19) pandemic was also a major barrier during the final year of the study.
We found a high prevalence of OSA among eligible patients who underwent PSG (84%; Figure 1). However, 8 of 56 OSAH-positive patients (15%) were excluded, as they exceeded our OSAH severity threshold. Severe OSAH would likely confer greater vascular risk (6) and thus potentially demonstrate greater treatment response. Given current equipoise surrounding cardiovascular outcomes in the nonpregnant, nonsleepy OSA population (36), consideration should be given to including more severe patients in future RCTs of HDP, with appropriate risk mitigation strategies.
The rate of completion of all study measurements was only slightly higher in the NDS group (62%) than the PAP group (52%) (Figure 1). Thus, factors other than PAP treatment per se affected study completion. There was loss of participants from both study groups because of emergency delivery in the context of preeclampsia. Although small single-night studies of preeclampsia have shown reduced nocturnal BP (19) and improved cardiac output with PAP (15), further studies are needed to better assess the impact of acute PAP in late pregnancy preeclampsia. However, these will require a different methodologic approach.
In that almost 80% of women recruited to our study had chronic hypertension, earlier recruitment and initiation of PAP therapy to promote adaptation, improved adherence, and enhanced retention should be considered in future studies. Earlier initiation/longer duration of treatment could enhance treatment effects, as OSA-related changes in arterial stiffness heralding later onset of preeclampsia (7) may occur relatively early in the second trimester (7, 8, 18).
In nonpregnant individuals, education regarding OSAH and PAP, together with monitoring and troubleshooting, increases PAP adherence (37). Given the known challenges of PAP treatment in pregnancy (10, 38, 39), we incorporated education and close follow-up by experienced study personnel. However, even PAP participants who completed all study measurements used treatment for a mean of only 3.1 h/night (Table 3). Although this is similar to adherence in recent larger OSA cardiovascular RCTs in nonpregnant individuals (40, 41), it is well below the target and leaves substantial residual OSAH. Further research is needed to identify strategies to optimize PAP adherence during pregnancy. We recently demonstrated that mandibular advancement splint (MAS) therapy was well tolerated during pregnancy (42) and, although less efficacious in reducing AHI than is typical for PAP, showed better adherence rates. One single-night study showed no effect on BP with MAS treatment in patients with HDP (43). However, in the general population, MAS may improve BP (44) and could be an option in future HDP studies. To ultimately demonstrate “real world” benefit of OSAH treatment on HDP outcomes, large pragmatic trials conducted at diverse tertiary and community centers, integrated into routine obstetrical care, and evaluating standard clinical outcome measures will be needed. Inclusion of a diversity of treatment approaches according to patient preference and choice may be the strategy most likely to yield effective OSAH treatment in this context (36).
Strengths and Limitations
Our study had several limitations. These included the small sample size due to the pilot nature of the trial and the recruitment challenges discussed above. We were therefore not adequately powered to detect significant changes in BP (even adjusted for medication change) or other secondary outcomes. Suboptimal PAP adherence was another limitation that may have attenuated potential benefit (37). The exclusion of patients with severe OSAH and/or sleepiness who potentially could have experienced greater benefit from PAP is another limitation. Last, BP was maintained within normal limits for most of our HDP participants, which may have attenuated potential PAP effects on BP. One possible approach for future studies could be to attempt systematic withdrawal of BP medications in patients with well-controlled BP during PAP treatment.
Conclusions
Challenges to recruitment and retention observed in this pilot study will need to be addressed to ensure feasibility in future large-scale trials. Improved strategies to enhance PAP adherence, together with alternate treatment approaches including MAS, need to be explored. Although there was a lack of evident PAP benefit on secondary outcomes in this pilot trial, given the observational evidence linking these two disorders, further adequately powered RCTs are warranted to evaluate the impact of effective OSAH treatment on maternal and fetal outcomes in patients with HDP.
Footnotes
Supported by Canadian Institutes of Health Research grant PJT-148763. In-kind support (positive airway pressure machines and masks) was provided by ResMed Inc. P.P. received salary support from the Faculty of Medicine, Prince of Songkla University. S.P., S.S.D., R.G, N.D., and A.B. received salary support from the Fonds de Recherche du Québec - Santé.
Author Contributions: Conception and design: R.J.K. Acquisition of data: P.P., N.G., A.O., and K.R. Analysis and interpretation of data: P.P., S.L.G., A.B., and R.J.K. Drafting the manuscript: P.P. and R.J.K. Critical revision for intellectual content and final approval of the version to be published: P.P., S.P., S.S.D., R.G., N.D., A.B., and R.J.K.
A data supplement for this article is available via the Supplements tab at the top of the online article.
Author disclosures are available with the text of this article at www.atsjournals.org.
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