Effect of continuous positive airway pressure on umbilical artery pH during scheduled cesarean delivery in individuals with class III obesity: A randomized controlled trial

Abstract

Objective

To evaluate the effect of continuous positive airway pressure (CPAP) on umbilical artery pH when utilized intraoperatively during scheduled cesarean delivery in individuals with class III obesity, defined as a body mass index (BMI) ≥ 40 kg/m².

Study design

This was a randomized controlled study of individuals with class III obesity and singleton pregnancy who underwent scheduled cesarean delivery. Subjects were randomized to receive the institutional standard of care consisting of oxygen 2 liters per minute (L/min) via nasal cannula or CPAP containing oxygen supplementation of 2 L/min during cesarean delivery. The primary outcome was umbilical artery pH. Secondary outcomes included umbilical venous blood gas values, maternal venous blood gas values, neonatal and maternal outcomes, intraoperative parameters, and maternal satisfaction.

Results

Of 65 subjects, 33 were randomized to CPAP and 32 to oxygen 2 L/min via nasal cannula. A total of 12 participants in the CPAP group were unable to tolerate the device for the planned duration and subsequently received 2 L/min of oxygen via nasal cannula. Modified intention to treat analysis showed no difference in the mean umbilical arterial pH between the CPAP and routine management groups (7.18 vs. 7.19; p = 0.61). Similarly, there was no difference in the proportion of arterial pH < 7.1 between the CPAP and routine management groups (12.1% vs. 12.1%; p = 1.00). There was no difference in other secondary outcomes.

Conclusion

Compared to routine oxygen supplementation, CPAP was not associated with improved umbilical artery pH in individuals with class III obesity undergoing scheduled cesarean delivery.

Trial Registration

ClinicalTrials.gov Identifier: NCT04993651

1. INTRODUCTION

Maternal obesity, especially class III obesity (body mass index [BMI] $\ge$40 kg/m²), is associated with lower umbilical artery pH and an increased risk of fetal acidosis at the time of non‐emergent, prelabor cesarean delivery [1, 2]. As maternal BMI increases, umbilical artery pH decreases, and risk of fetal acidosis increases [1, 3]. Even a short period of fetal acidemia is associated with an increased risk of adverse neonatal outcomes regardless of the type of acidosis (respiratory or metabolic) [3]. These findings are observed despite reassuring preoperative fetal monitoring, suggesting that intraoperative events play a role in the development of fetal acidemia.

There are multiple factors during cesarean delivery that have the potential to affect fetal‐maternal gas exchange. The surgical neuraxial blockade affects respiratory function, inducing sensory anesthesia up to T4 and resulting in paralysis of abdominal and intercostal muscles [4, 5]. While all individuals exhibit mild impairment of respiratory function after spinal anesthesia at the time of cesarean delivery, this effect is more pronounced in obese individuals [4]. Further, individuals with class III obesity are at high risk of obstructive sleep apnea (OSA) as high as 24% [6]. A brief alteration of maternal respiratory status could result in impaired oxygenation and carbon dioxide retention that could disrupt fetal acid–base status.

Continuous positive airway pressure (CPAP), a form of noninvasive positive pressure ventilation (NPPV), improves alveolar ventilation and maintains upper‐airway patency, thereby improving the exchange of carbon dioxide and oxygen. It additionally decreases the muscle load required for each breath and has been used in pregnant individuals [7, 8, 9, 10]. We hypothesized that neonates born to mothers with class III obesity wearing CPAP during the cesarean delivery would have a higher umbilical artery pH compared to routine airway management using nasal cannula (NC). We aimed to evaluate the effect of CPAP on fetal acid–base status in individuals with class III obesity at the time of scheduled cesarean delivery. We also examined the risk factors of neonatal acidosis in our cohort.

2. MATERIALS AND METHODS

This was a randomized controlled trial designed to compare the effect of two oxygen administration strategies—institutional standard of care with NC versus CPAP—on fetal umbilical arterial pH during scheduled, nonemergent cesarean delivery in individuals with class III obesity. Subjects were enrolled between October 2021 and April 2023. Institutional Review Board approval was obtained prior to study initiation, and the trial was registered at ClinicalTrials.gov (Identifier: NCT04993651). Manuscript preparation followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines [11].

Clinical records were reviewed for all pregnant individuals with BMI greater than 40 kg/m² receiving prenatal care or admitted for delivery at our institution. Those who met inclusion criteria of BMI 40 kg/m² or greater at their last prenatal visit before scheduled delivery, age 18–45 years, singleton gestation, scheduled for cesarean delivery from 37 and 0 weeks gestation to 41 and 0 weeks gestation were approached for participation. Subjects were excluded if their pregnancy was complicated by fetal growth restriction, active pulmonary disease (pneumonia, moderate or severe asthma, pulmonary hypertension), suspected placenta accreta, active maternal infection (pyelonephritis, urinary tract infections, suspected intra‐amniotic infection), fetus with aneuploidy or major anomaly (neural tube defect, diaphragmatic hernia, congenital heart disease, gastroschisis, or omphalocele). In concordance with hospital policy, all participants were screened for SARS‐CoV‐2. Individuals were excluded if they tested positive for SARS‐CoV‐2 within the previous 10 days, displayed ongoing SARS‐CoV‐2 symptoms (cough, fever, shortness of breath) with a positive test more than 10 days prior, or had a recent hospitalization for SARS‐CoV‐2 infection.

2.1. Randomization and allocation

On hospital admission, external fetal heart rate (FHR) monitoring was performed. Subjects remained eligible for participation if Category I FHR tracing was demonstrated [12]. After confirmation of a Category I FHR tracing, randomization was conducted using a computer‐generated randomization table in REDCap, with a 1:1 allocation ratio. Due to increasing risk of fetal acidosis with increasing BMI, randomization was stratified by maternal BMI less than 50 kg/m² or greater than or equal to 50 kg/m² [1, 3].

2.2. Intervention

Our exposure was an oxygen delivery device (CPAP or NC). For individuals who were assigned to CPAP, the face mask was applied with AUTO 5–20 cm H₂O and oxygen flow of 2 L/min, titrated as needed to maintain SpO₂ ≥ 95%. If the participant requested mask removal or experienced nausea, discomfort, or anxiety, the CPAP was discontinued, and an NC was used instead. For individuals who were assigned to NC. In accordance with institutional standard for obese patients undergoing cesarean delivery, NC was applied following the completion of neuraxial anesthesia, and oxygen flow of 2 L/min was increased if necessary to maintain SpO₂ ≥ 95%. Following neonatal delivery and blood sample collection, the CPAP mask or NC was removed based on the patient and anesthesia provider's discretion.

2.3. Study procedure

At the time of enrollment, screening for obstructive sleep apnea was performed using a STOP‐Bang score [6, 13, 14]. A maternal venous blood gas sample was obtained to assess maternal pH, oxygen, and carbon dioxide levels on admission. Standard institutional protocol for neuraxial anesthesia was utilized:

In most cases, a spinal block was performed (1.5–1.6 mL of 0.75% bupivacaine in 8% dextrose, 0.15 mg preservative‐free morphine, and 15 µg fentanyl); alternatively, a combined spinal‐epidural was allowed at the anesthesiologist's discretion. Inability to achieve adequate neuraxial anesthesia, requiring conversion to general anesthesia, led to study withdrawal. Blood pressure management included a 500‐mL lactated Ringer's bolus administered preoperatively, followed by phenylephrine infusion (50 µg/min) titrated to maintain mean arterial pressure within 20% of baseline.

2.4. Outcomes

The primary outcome was umbilical artery pH. Secondary outcomes included umbilical venous blood gas values, maternal venous blood gas values, neonatal and maternal outcomes, intraoperative parameters, and maternal satisfaction. Trained research staff obtained and immediately analyzed umbilical artery and venous blood samples after 30 s of delayed cord clamping. As part of the study protocol, maternal venous blood gas sample was also obtained within 2 min of neonatal delivery to explore for any interval change in maternal venous blood gas parameters. Prior to hospital discharge, patients in the CPAP group completed a satisfaction survey regarding comfort and tolerability. The questionnaire was completed any time prior to hospital discharge at the participants’ convenience; a research team member followed up with subjects to solicit any questions and collect the completed survey. The questionnaire asked patients to rate the following discomforts associated with CPAP use and cesarean delivery on a 5‐point Likert scale: Nausea/vomiting, dry mouth or nose, facial discomfort, difficulty speaking or hearing, difficulty breathing, shortness of breath, and claustrophobia. Subjects were additionally asked if they would be willing to use a CPAP device again in the future. Additional variables (maternal vital signs, ICU admissions, need for postoperative respiratory support, neonatal APGAR scores, NICU admissions, neonatal respiratory support, intubation, and lengths of stay) were collected from the electronic medical record.

2.5. Statistics

A power analysis was based on previously published data, which suggested an average umbilical artery pH of 7.22 (standard deviation 0.07) in individuals with class III obesity undergoing non‐emergent cesarean delivery [1, 15]. Detecting a 0.05 difference in umbilical artery pH with 80% power at a two‐sided α of 0.05 required a total of 64 participants.

We analyzed the data per modified intention to treat, given that this represents the true clinical scenario in which some individuals may not tolerate CPAP. A secondary, per protocol analysis was performed after excluding individuals who did not tolerate CPAP for the entire duration.

Descriptive statistics were utilized to assess baseline demographics. We used Fisher's exact test for categorical variables and student t‐test or Mann–Whitney U test for numerical variables. Normality was examined using skewness and kurtosis tests. Secondary analysis was performed to identify risk factors for neonatal acidosis defined as umbilical artery cord pH < 7.1, we conducted a simple logistic regression to calculate odds ratios (OR) with 95% confidence intervals (95%CI). All statistical tests were 2‐sided, and the statistical significance level was α = 0.05. All statistical analysis will be performed using Stata18 (StataCorp, College Station, TX).

3. RESULTS

A total of 1090 individuals were screened for eligibility (Figure 1). Of these, 85 met initial inclusion criteria and were enrolled. However, 19 were excluded at the time of hospital admission due to failing secondary screening criteria, leaving 66 participants. These 66 participants were randomized in a 1:1 ratio to receive either CPAP (n = 33) or NC (n = 33). In the routine airway group, one participant was excluded from the final analysis due to the inability to establish neuraxial anesthesia. Enrollment concluded upon reaching the target sample size of 64 analyzed participants.

FIGURE 1.

Study flow diagram.

Baseline demographics were similar in both groups (Table 1). The mean BMI was 49.4 kg/m² in the CPAP group and 49.4 kg/m² in the NC group (p = 0.94). Mean gestational age at delivery was 39.4 weeks in the CPAP group and 38.4 weeks in the NC group (p = 0.04). There was no difference in the duration of time from completion of neuraxial anesthesia to the delivery of the neonate in the groups (CPAP median 32 min [IQR 28–37] minutes and NC median 32 min [IQR 30‐40].

TABLE 1.

Demographics.

	CPAP (n = 33)	Routine (n = 32)	p value
Age (years)	30.5 (± 5.1)	30.7 (± 5.4)	0.858
Body mass index (kg/m2)	49.4 (± 7.3)	49.4 (± 9.1)	0.988
Gestational age	39.4 (± 2.5)	38.4 (± 1.0)	0.045
Race			0.738
White	7 (21.2)	10 (31.2)
Black	24 (72.7)	21 (65.6)
Asian	1 (3.0)	0 (0.0)
Hispanic	1 (3.0)	1 (3.1)
Other	1 (3.0)	1 (3.1)	1.00
Parity	2.0 (1.0–2.0)	1.0 (1.0–2.0)	0.495
Chronic hypertension	8 (24.2)	17 (53.1)	0.023
Pre‐gestational diabetes	2 (6.1)	7 (21.9)	0.082
Obstructive sleep apnea	0 (0.0)	2 (6.2)	0.238
STOP‐Bang Score	3.0 (3.0–4.0)	4.0 (3.0–5.0)	0.113
Hypertensive disorder of pregnancy	3 (9.1)	9 (28.1)	0.061
Gestational diabetes	5 (15.2)	5 (15.6)	1.00

Note: Numbers are shown as n (%), mean (± SD), or median (25th–75th percentile).

Table 2 summarizes the umbilical cord gas results. No significant difference in mean umbilical arterial pH was found between the CPAP and NC groups (7.18 vs. 7.19, respectively; p = 0.61). The proportion of neonates with an umbilical artery pH < 7.1 (12.1% vs. 12.9%; p = 1.00) or < 7.0 (6.1% vs. 6.5%; p = 1.00) did not differ between groups.

TABLE 2.

Umbilical cord gas results.

	CPAP (n = 33)	Nasal Cannula (n = 32)	p value
Umbilical artery
pH	7.18 (± 0.10) 7.18 (0.10)	7.19 (± 0.11)	0.613
PO2	13.9 (± 4.6)	14.0 (± 4.7)	0.957
PCO2	69.9 (± 14.9)	66.0 (± 12.0)	0.264
HCO3	25.9 (± 1.6)	25.6 (± 2.6)	0.519
Base deficit	1.81 (± 2.55)	2.14 (± 3.58)	0.682
pH < 7.1	4 (12.1)	4 (12.5)	1.00
pH < 7.0	2 (6.1)	2 (6.2)	1.00
Umbilical vein
pH	7.26 (± 0.09)	7.26 (± 0.09)	0.845
PO2	20.8 (± 5.9)	22.5 (± 7.4)	0.307
PCO2	55.9 (± 14.6)	52.6 (± 12.8)	0.34
HCO3	24.0 (± 1.6)	23.7 (± 2.0)	0.55
Base deficit	2.36 (± 3.30)	2.63 (± 3.61)	0.757

Neonatal APGAR scores at 1 min (median 8 [IQR 8–8] vs. 8 [IQR 7–8], p = 0.13) and at 5 min (9 vs. 9, p = 0.88) were comparable. The need for neonatal respiratory support (27.3% vs. 37.5%; p = 0.43) and NICU admission rates for ongoing respiratory support (9.1% vs. 19.4%; p = 0.30) were also similar between CPAP and NC groups (Table 3).

TABLE 3.

Neonatal outcomes.

	CPAP (n = 33)	Nasal Cannula (n = 32)	p value
Neonatal Outcomes
Apgar 1 min	8.0 (8.0–8.0)	8.0 (7.0–8.0)	0.128
Apgar 5 min	9.0 (8.0–9.0)	9.0 (8.0–9.0)	0.865
Need for respiratory support (Nasal Cannula, NIV, endotracheal tube)	9 (27.3)	12 (37.5)	0.43
Intubation	0 (0.0)	1 (3.1)	0.492
NICU admission	3 (9.1)	6 (18.8)	0.30
Duration of Hospitalization	2.0 (2.0–3.0)	2.0 (2.0–3.0)	0.387

Abbreviations: NICU, neonatal intensive care unit; NIV, noninvasive ventilation.

Twelve participants in the CPAP group could not tolerate the device for the planned duration (mean duration of use = 2 min), and subsequently received 2 L/min of oxygen via NC. A secondary, per‐protocol analysis excluded these 12 individuals. Among those who completed the study according to randomization and tolerated CPAP until delivery, there were no significant differences in umbilical arterial pH (7.18 vs. 7.19, p = 0.78), nor in the rates of umbilical artery pH < 7.1 (14.3% vs. 11.6%; p = 1.00) or < 7.0 (4.8% vs. 7.0%; p = 1.00) (Table 4).

TABLE 4.

Umbilical cord gas results, per protocol.

	CPAP (n = 21)	Routine (n = 44)	p value
Umbilical artery
pH	7.18 (± 0.09)	7.19 (± 0.11)	0.783
PO2	14.4 (± 5.3)	13.7 (± 4.2)	0.593
PCO2	70.7 (± 13.2)	66.7 (± 13.8)	0.282
HCO3	26.0 (± 1.4)	25.6 (± 2.4)	0.436
Base deficit	1.71 (± 2.80)	2.10 (± 3.22)	0.644
pH < 7.1	3 (14.3)	5 (11.4)	0.706
pH < 7.0	1 (4.8)	3 (6.8)	1.000
Umbilical vein
pH	7.26 (± 0.1)	7.26 (± 0.1)	0.879
PO2	20.0 (± 5.3)	22.4 (± 7.2)	0.190
PCO2	56.1 (± 10.1)	53.4 (± 15.2)	0.451
HCO3	24.3 (± 1.5)	23.6 (± 2.0)	0.157
Base deficit	1.86 (± 2.99)	2.81 (± 3.61)	0.301

Maternal venous blood gases at delivery were available for 51 of the 64 participants; reasons for missing samples primarily related to difficulty obtaining blood within 2 min of delivery (Supplemental Table 1). Baseline maternal venous blood gas values were similar across groups. No significant differences were observed in maternal venous pH, pO₂, pCO₂, or HCO₃ at delivery. There were no adverse maternal outcomes to include ICU admission and respiratory complications.

Table 5 presents the risk factor analysis for neonatal acidosis (umbilical artery pH < 7.1). Simple logistic regression identified a significant association between later gestational age at delivery and lower likelihood of acidosis (OR 0.4, 95% CI 0.17–0.90). A greater decrease in mean arterial pressure relative to baseline following neuraxial anesthesia was associated with higher odds of neonatal acidosis (OR 1.03, 95% CI 1.00–1.07). Additionally, participants with a STOP‐BANG score ≥ 5 had an increased risk of neonatal acidosis (OR 9.21, 95% CI 1.67–50.96).

TABLE 5.

Odds of umbilical artery pH < 7.1.

	Odds Ratio (95% Confidence Interval)
Body mass index	0.98 (0.89–1.08)
Gestational age	0.40 (0.17–0.90)
Duration of time from anesthesia procedure start to delivery	0.92 (0.83–1.02)
Time from neuraxial anesthesia completion to delivery	0.94 (0.84–1.06)
Preoperative MAP	0.96 (0.90–1.03)
Preoperative SpO2	1.18 (0.69–2.02)
SpO2 intraoperative nadir	0.86 (0.74–1.01)
Preoperative maternal venous pH	670.97 (0.00 to 2.0e+11)
Preoperative maternal venous PCO2	0.97 (0.85–1.11)
Preoperative maternal venous PO2	1.02 (0.98–1.06)
Delta MAP average (Preoperative MAP − average intraoperative MAP)	1.03 (0.98–1.08)
Delta MAP maximum (Preoperative MAP − lowest intraoperative MAP)	1.03 (1.00–1.07)
Chronic hypertension	1.71 (0.39–7.58)
Pregestational diabetes	0.88 (0.09–8.09)
STOP‐BANG score of 5 or greater	9.21 (1.67–50.96)

Abbreviation: MAP, mean arterial pressure.

Survey data were available for 29 of the 33 individuals assigned to CPAP. Of these 29 subjects, 22 reported they would be willing to use CPAP during a future procedure or if recommended for treatment of OSA. The most commonly reported negative symptom was mask‐related claustrophobia, although most participants indicated minimal adverse effects overall (Figure 2). Finally, the information about the missing information is presented in Table S2. Overall, the proportion of missing information was low.

FIGURE 2.

Satisfaction survey results for individuals receiving CPAP.

3.1. Comment

3.1.1. Principal findings

In this randomized controlled trial of individuals with class III obesity undergoing scheduled cesarean delivery, there was no difference in umbilical artery pH between those who received CPAP and those who received 2 L/min oxygen via NC. However, only two‐thirds of participants assigned to CPAP were able to tolerate it from the completion of neuraxial anesthesia until neonatal delivery. The study was not powered for a per‐protocol analysis, therefore, the results are inconclusive when restricting analysis to those subjects who were able to tolerate the device for the prescribed duration.

CPAP is known to improve alveolar ventilation and upper‐airway patency by providing positive end‐expiratory pressure [7]. However, in this study, maternal venous blood gas values at delivery were comparable in both the CPAP and NC groups. While not powered specifically to detect rare adverse events, there were no reported maternal pulmonary complications or aspiration episodes. We demonstrate that CPAP can be administered to conscious, pregnant individuals undergoing cesarean delivery with appropriate patient selection and monitoring.

3.2. Results in the context of what is known

Prior literature indicates that supplemental oxygen at the time of cesarean delivery reduces maternal desaturation risk but does not necessarily improve neonatal acid–base status [16]. Previous studies in nonobese populations similarly demonstrated that supplemental oxygen did not significantly affect umbilical artery pH or APGAR scores [17, 18, 19]. Although all obstetric patients experience a degree of respiratory function impairment post‐spinal anesthesia, the effect is more pronounced in those with higher BMI [4, 5]. Despite CPAP's known benefits of improving ventilation and offloading the work of breathing [7], our findings did not show improved neonatal acid–base status in the obese population. This trial represents the first to evaluate intraoperative CPAP specifically in class III obesity during cesarean delivery, although several published case reports have described its intraoperative use during cesarean delivery in patients with super‐morbid obesity, asthma, and obstructive sleep apnea [10, 20, 21, 22, 23].

Neuraxial anesthesia management also impacts fetal acid–base balance. For example, prolonged intervals between neuraxial anesthesia placement and delivery have been associated with lower umbilical artery pH at scheduled cesarean delivery [24]. In this study, CPAP did not prolong the operative interval. Nonetheless, individuals with obesity often have greater hemodynamic variability and require higher vasopressor doses to prevent hypotension after neuraxial anesthesia [25, 26, 27]. A larger drop in mean arterial pressure (MAP) from baseline was associated with a higher risk of neonatal acidosis, emphasizing the importance of meticulous blood pressure control [28, 29].

OSA prevalence in pregnant individuals with class III obesity can be as high as 24% [6], yet only two participants in this trial had a documented OSA diagnosis. A STOP‐Bang score ≥ 5 is suggestive of a moderate OSA risk. This was associated with increased odds of neonatal acidosis, indicating the possible contribution of unrecognized or undertreated OSA to adverse neonatal outcomes in this high‐risk population [13].

3.3. Clinical implications

While one‐third of subjects randomized to CPAP did not tolerate the application of the device, limiting the potential clinical applicability for many patients, two‐thirds, or the majority, of subjects did tolerate the device. This demonstrates the practicality use of CPAP for awake pregnant individuals with airway‐protective reflexes. No adverse respiratory events occurred, supporting that noninvasive positive pressure ventilation can be integrated into obstetric anesthesia protocols for appropriately selected patients.

3.4. Research implications

Further research is needed to investigate the effects of oxygen supplementation at the time of cesarean delivery in the obese population. Specific high‐risk groups at increased risk of neonatal acidosis, such as those with fetal growth restriction, should be included as they may be the most susceptible to the effects. With low rates of OSA and familiarity with the CPAP device among our patient population, it's possible that improved compliance and effect may be seen in patients already using CPAP for OSA. Additionally, further research is needed to evaluate the respiratory effects of neuraxial anesthesia on the obese pregnant patient to best understand how to support these individuals.

3.5. Strengths and limitations

Our study has many strengths. The randomized control design makes two comparison groups similar except for the intervention. Additionally, our patient population with an average BMI of 49 kg/m², represents a high‐risk population with class III obesity. The average arterial pH of our control population is similar to that reported in the literature, indicating that our study is adequately powered to detect a significant difference in the primary outcome. We additionally were able to evaluate risk factors for neonatal acidosis in this population of pregnant subjects with morbid obesity undergoing scheduled cesarean delivery.

The most significant limitation of this study is the poor compliance with only two‐thirds of those subjects randomized to CPAP able to tolerate it for the prescribed duration. Rates of CPAP adherence are similarly poor when prescribed for the treatment of OSA [30]. Assessment of arterial blood gas values would have provided a more accurate assessment of maternal oxygenation and ventilation. However, the venous blood sample is more easily obtained and there is acceptable agreement between arterial and venous pH, pCO₂, and bicarbonate values [31]. Lastly, due to the nature of the intervention, this study was unblinded.

4. CONCLUSIONS

In conclusion, the use of CPAP during cesarean delivery in patients with class III obesity did not improve umbilical artery pH when compared to routine NC management. We demonstrate the practical use of CPAP intraoperatively for respiratory support in an obese population undergoing cesarean delivery. Future studies focusing on subgroups at heightened risk of neonatal acidosis and exploring respiratory dynamics in morbidly obese parturients under neuraxial anesthesia may further refine the role of CPAP in improving perinatal outcomes.

DISCLOSURE

T.D. is a military service member or federal/contracted employee of the United States government. This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that `copyright protection under this title is not available for any work of the United States Government.' Title 17 U.S.C. 101 defines a U.S. Government work as work prepared by a military service member or employee of the U.S. Government as part of that person's official duties. The views expressed in this article reflect the results of research conducted by the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.

The study protocol was approved by the Eastern Virginia Medical School Institutional Review Board in compliance with all applicable federal regulations governing the protection of human subjects.

Supporting information

Supporting Information

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.