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Published in final edited form as: Pregnancy Hypertens. 2022 Nov 2;30:215–220. doi: 10.1016/j.preghy.2022.10.013

Sleep disordered breathing and the risk of severe maternal morbidity in women with preeclampsia: a population-based study

Isabelle Malhamé 1,2, Margaret H Bublitz 3, Danielle Wilson 4, Laura Sanapo 3, Elizabeth Rochin 5, Ghada Bourjeily 3
PMCID: PMC9712248  NIHMSID: NIHMS1847949  PMID: 36343510

Abstract

Objective:

Obstructive sleep apnea (OSA) may exacerbate the widespread endothelial dysfunction seen in preeclampsia, potentially worsening clinical outcomes. We aimed to assess whether OSA is associated with an increased risk of severe maternal morbidity, cardiovascular morbidity, and healthcare utilization among women with preeclampsia.

Study Design:

We performed a retrospective cohort study utilizing data from the National Perinatal Information Center (2010–2014) in the United States. The cohort comprised women with preeclampsia. We estimated the association between OSA and the outcomes using logistic regression analyses and determined odds ratio adjusted for demographic factors and comorbidities (ORadj) and associated 95% confidence intervals (CI).

Main outcome measures:

The primary outcome was a composite of mortality and severe maternal morbidity comprising intensive care unit (ICU) admission, acute renal failure, pulmonary edema, pulmonary embolism, congestive heart failure, cardiomyopathy, and stroke. Secondary outcomes comprised the subset of cardiovascular events, as well as increased healthcare utilization (including Cesarean delivery, preterm birth, ICU admission, and prolonged length of hospital stay).

Results:

In total, 71,159 women had preeclampsia, including 270 (0.4%) with OSA. Women with preeclampsia and OSA were more likely to experience severe maternal morbidity than women without OSA (ORadj 2.65, 95% CI [1.94–3.61]). Moreover, women with concomitant OSA had more severe cardiovascular morbidity than women without OSA (ORadj 5.05, 95% CI [2.28–11.17]). Accordingly, OSA was associated with increased healthcare utilization in women with preeclampsia (ORadj. 2.26, 95% CI [1.45–3.52]).

Conclusion:

In women with preeclampsia, OSA increases the risk for severe maternal morbidity, cardiovascular morbidity, and healthcare utilization.

Keywords: obstructive sleep apnea, OSA, preeclampsia, pregnancy, postpartum, peripartum, maternal morbidity, sleep disordered breathing

INTRODUCTION

Sleep disordered breathing describes a group of conditions involving abnormal respiratory patterns during sleep, with the spectrum ranging from snoring to complete obstruction of the upper airway and hypoventilation. In obstructive sleep apnea (OSA), recurrent episodes of airway obstruction may be associated with oxygen desaturation or arousal from sleep, along with acute changes in heart rate and blood pressure. (1) This cyclical pattern has been associated with sympathetic activation, oxidative stress, and elevations in proinflammatory cytokines as well as endothelial dysfunction. (2–5) Accordingly, in the non-pregnant population, OSA is consistently linked to hypertension, (6) cardiovascular diseases, (7–9) and metabolic dysfunction. (10)

In pregnancy, OSA and preeclampsia have been shown to be strongly associated. (11–15) Common risk factors – including obesity, diabetes mellitus, chronic hypertension, and maternal age over 35 years – may partially explain the inter-relation between these two conditions. (16) OSA may also contribute to increased peripheral vascular resistance and hypertension through lack of normal vascular reactivity of the maternal uterine arteries, increased sympathetic activation, and anti-angiogenic factor release. (16, 17) As a result, OSA may induce or possibly further exacerbate the widespread endothelial dysfunction seen in preeclampsia, (16, 18, 19) potentially leading to an increased risk of adverse outcomes. Accordingly, OSA is associated with an increased risk of severe maternal morbidity, including cardiovascular complications such as pulmonary edema and acute heart failure. (11, 12, 20)

Although several studies have estimated the incidence and the risk of preeclampsia among pregnant women with snoring and OSA, (11–14, 16) two studies, with limited sample sizes, have reported inconsistent findings of the effect of OSA on maternal morbidity outcomes among women with hypertensive disorders of pregnancy. (21, 22) In the first study (n=85), OSA was not associated with increased blood pressure severity or worsened anti-angiogenic profile in pregnant participants with hypertensive disorders (21). In the second study (n=100), the severity of OSA among participants with gestational hypertension and preeclampsia was correlated with blood pressure values, independently from maternal weight (22). Therefore, the impact of OSA on severe maternal morbidity, and specifically severe cardiovascular morbidity, among women with preeclampsia remains unclear. Our aim was to assess whether OSA is associated with an increased risk of severe maternal morbidity, and in particular severe cardiovascular morbidity, in a large population-based cohort of women with preeclampsia. In addition, since maternal morbidity can lead to increased healthcare resource requirements, we sought to assess the impact of OSA on healthcare utilization among women with preeclampsia. We hypothesized that women with preeclampsia and concomitant OSA had a higher risk of severe maternal morbidity, severe cardiovascular morbidity, and healthcare utilization than those without OSA.

MATERIALS AND METHODS

Data source

We used data from the National Perinatal Information Center (NPIC), containing 1,312,681 maternal records for deliveries from hospitals between 2010 and 2014. Only the first pregnancy episode of women in the cohort was captured in the dataset during the study period (i.e., the first pregnancy episode captured in the dataset may be a woman’s second pregnancy). NPIC is a membership organization consisting of perinatal centers from across all geographic census divisions of the United States (as defined by the American Hospital Association), that submit clinical and financial information for participation in the Perinatal Center Database (PCDB), as previously described. (11) The database comprises diagnosis and procedure codes based on the International Classification of Diseases, 9th Revision (ICD-9). A standardized data validation process involving the PCDB and individual participating hospitals is routinely performed and has been described elsewhere. (11, 23)

The study was reviewed and approved by institutional review boards of the Rhode Island Hospital (IRB#881483), and the Women & Infants Hospital (IRB#894311), and consent was waived.

Study population

All women admitted for delivery with diagnostic codes for preeclampsia/eclampsia (ICD-9 codes 642.4, 642.5, 642.6) were identified from the larger dataset. Demographic characteristics included age and race/ethnicity, and use of tobacco, alcohol, or drug. Baseline comorbidities included obesity, chronic hypertension, pre-pregnancy diabetes (type 1 or type 2), gestational diabetes, chronic renal disease, dyslipidemia, adrenal disorders, and hypothyroidism (Details of Codes in Table S1 of the Supplementary Appendix).

Exposure definition

The exposure was OSA, as defined by ICD-9 codes 780.53, 780.57, 780.51, 327.2, and 327.23.

Outcomes definition

The primary outcome was a composite of severe maternal morbidity events occurring during delivery hospitalization, including intensive care unit (ICU) admission, acute renal failure, pulmonary edema, pulmonary embolism, congestive heart failure, cardiomyopathy, stroke, and death. The secondary outcome of severe cardiovascular morbidity was a subset of the main composite outcome. It included congestive heart failure, cardiomyopathy, pulmonary edema, and stroke during delivery hospitalization. Additionally, we examined a secondary outcome of healthcare utilization including Cesarean delivery, preterm birth, ICU admission, and prolonged length of hospital stay (>90th percentile for length of stay for vaginal or Cesarean delivery. (24) All outcome events were observed during delivery hospitalization, and as such complicated the index pregnancy.

Statistical Analyses

Baseline demographic and clinical characteristics were described using proportions or means and standard deviations, as appropriate. To estimate the association between OSA and the primary outcome, we ran crude and adjusted logistic regression analyses to determine odds ratio (OR), and their associated 95% confidence intervals (CI). Adjusted analyses included the following confounders based on published research on OSA and adverse maternal outcomes: (11, 12) maternal age, race, parity, obesity, chronic hypertension, pre-pregnancy diabetes, gestational diabetes, chronic renal disease, dyslipidemia, hypothyroidism, adrenal disorders, and tobacco, alcohol, or drug use. Since Cesarean delivery was on the potential causal pathway between OSA and the primary outcome, this variable was not included as a confounder. Moreover, given the nature of our dataset, it was not possible to determine whether cardiac diseases predated the occurrence of the outcome. As such, cardiac diseases were not included as confounders. Results were considered statistically significant for p value ≤0.05. Statistical analyses were performed using SPSS IBM version 25.

RESULTS

Of 1,312,681 women with obstetric deliveries, 71,159 had preeclampsia, including 270 (0.4%) with concomitant OSA. Mean age of participants at delivery was 29 ± 6 years. About a quarter of the cohort was primiparous, and mean gravida was 2 ± 2. Women with preeclampsia and concomitant OSA were on average older, and they had more comorbidities including obesity, chronic hypertension, pre-existing and gestational diabetes, and dyslipidemia (Table 1). There was no difference in gravidity or incidence of chronic renal disease between the two groups. Women with preeclampsia and OSA had more reported drug and tobacco use than women without OSA (Table 1).

Table. 1.

Baseline demographic and clinical characteristics of the study population

Preeclampsia N=71159 Preeclampsia Without OSA N=70889 Preeclampsia With OSA N=270 p value
Maternal age, mean±SD 29±6 29±6 31±6 <0.001
 Maternal age above 35, n (%) 14366 (20%) 14285 (20%) 81 (30%) <0.001
Gravida, mean±SD 2±2 2±2 2±2 0.24
Race/Ethnicity 0.05
 Non-Hispanic Black (%) 16629 (29) 16549 (23) 80 (30)
 Non-Hispanic White (%) 30467 (53) 30349 (43) 118 (44)
 Hispanic (%) 5051 (9) 5040 (7) 11 (4)
 Other (%) 5396 (9) 5378 (8) 18 (7)
Drug use, n (%) 1135 (2) 1126 (2) 9 (3) 0.02
Alcohol use, n (%) 85 (0.1) 85 (0.1) 0 (0) 0.57
Tobacco use, n (%) 2672 (4) 2649 (4) 23 (9) <0.001
Pre-pregnancy diabetes, n (%) 2553 (4) 2521 (4) 32 (12) <0.001
Gestational diabetes, n (%) 7431 (10) 7376 (10) 55 (20) <0.001
Chronic renal disease, n (%) 513 (0.7) 510 (0.7) 3 (1) 0.45
Dyslipidemia, n (%) 171 (0.2) 167 (0.2) 4 (1) <0.001
Adrenal disorders, n (%) 36 (0.05) 36 (0.05) 0 (0) 0.71
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OSA = Obstructive sleep apnea

In total, 8371 (11.8%) women with preeclampsia experienced severe maternal morbidity, including 399 (0.6%) with severe cardiovascular morbidity (Table 2). Women with preeclampsia and OSA were more likely to develop severe maternal morbidity than women without OSA (OR 2.59, 95% CI [1.97–3.41]; ORadj 2.65, 95% CI [1.94–3.61]) (Figure 1). The increase in severe maternal morbidity was mostly driven by the incidence of pulmonary edema (1.1% vs. 0.2%), cardiomyopathy (1.1% vs. 0.2%), stroke (0.4% vs. <0.1%), and ICU admission (24.1% vs. 10.8%, Table 3). Accordingly, women with preeclampsia and OSA were more likely to experience the composite outcome of severe cardiovascular morbidity than women without OSA (OR 5.50, 95% CI [2.71–11.20], ORadj 5.05, 95% CI [2.28–11.17]) (Figure 1).

Table 2.

Frequency of composite outcomes in women with preeclampsia with and without obstructive sleep apnea

Preeclampsia N=71159 Preeclampsia without OSA N=70889 Preeclampsia with OSA N=270 p value
Composite severe maternal morbidity1, n (%) 8371 (11.8) 8302 (11.7) 69 (25.6) <0.001
Composite severe cardiovascular morbidity2, n (%) 399 (0.6) 391 (0.6) 8 (3.0) <0.001
Composite increased healthcare utilization3, n (%) 53151 (74.7) 52917 (74.6) 234 (86.7) <0.001
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OSA = Obstructive sleep apnea

1

Comprised ICU admission, acute renal failure, pulmonary edema, pulmonary embolism, congestive heart failure, cardiomyopathy, stroke, and death.

2

Comprised congestive heart failure, cardiomyopathy, pulmonary edema, and stroke.

3

Comprised Cesarean delivery, preterm birth, ICU admission, and prolonged length of hospital stay

Figure 1.

Figure 1.

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The association between obstructive sleep apnea and composite maternal outcomes in women with preeclampsia.

CI = Confidence Interval; OR = Odds Ratio

Table 3.

Frequency of individual components of the composite outcomes in women with preeclampsia with and without obstructive sleep apnea

Preeclampsia N=71159 Preeclampsia without OSA N=70889 Preeclampsia with OSA N=270
Acute Renal Failure, n (%) 668 (0.9) 665 (0.9) 3 (1.1)
Pulmonary Edema, n (%) 139 (0.2) 136 (0.2) 3 (1.1)
Pulmonary Embolism, n (%) 5 (<0.1) 5 (<0.1) 0 (0)
Congestive Heart Failure, n (%) 160 (0.2) 159 (0.2) 1 (0.4)
Cardiomyopathy, n (%) 167 (0.2) 164 (0.2) 3 (1.1)
Stroke, n (%) 33 (<0.1) 32 (<0.1) 1 (0.4)
ICU admission, n (%) 7737 (10.9) 7672 (10.8) 65 (24.1)
Prolonged length of stay1 n (%) 25020 (35.2) 24952 (35.2) 68 (25.2)
Cesarean delivery, n (%) 38271 (53.8) 38067 (53.7) 204 (75.6)
Preterm birth (< 37 weeks), n (%) 16209 (22.8) 16139 (22.8) 70 (25.9)
Maternal death, n (%) 13 (<0.1) 13 (<0.1) 0 (0)
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ICU = Intensive care unit; OSA = Obstructive sleep apnea

1

>90th percentile for length of stay for vaginal or Cesarean delivery

Women with preeclampsia and OSA required more healthcare utilization than women without OSA (OR 2.21, 95% CI [1.55–3.14], ORadj. 2.26, 95% CI [1.45–3.52]) (Figure 1). The increase in healthcare utilization was explained by more ICU admissions (24.1% vs. 10.8%) and Cesarean delivery (75.6% vs. 53.7%) in women with concomitant OSA (Table 3).

DISCUSSION

We compared the incidence of severe maternal morbidity and severe cardiovascular morbidity, as well as healthcare utilization in women with preeclampsia with and without concomitant OSA. Women with preeclampsia and OSA were twice more likely to develop severe maternal morbidity, and five times more likely to experience severe cardiovascular morbidity compared to women with preeclampsia without OSA. In addition, women with preeclampsia and OSA had increased healthcare utilization. Thus, OSA may be a predictor of adverse maternal outcomes, and an important risk marker to address when caring for pregnant women with preeclampsia.

The association between OSA and maternal morbidity outcomes among women with hypertensive disorders has previously been examined in two studies. (21, 22) In the first (n=85), OSA was not associated with increased blood pressure severity or worsened anti-angiogenic profile in pregnant participants with hypertensive disorders. (21) Conversely, in the second (n=100), the severity of OSA among participants with gestational hypertension and preeclampsia was correlated with blood pressure values, independently from maternal weight.(22) The populations in the two studies differed in several ways, including pre-pregnancy body-mass index (BMI), matching for BMI, and distinct geographic settings. (21, 22) Moreover, discrepant findings may have been partially explained by the fact that the first study considered OSA as a dichotomous variable, irrespective of OSA severity, whereas the latter considered the spectrum of OSA severity as a continuous variable. As such, the effect of OSA on preeclampsia-related outcomes may only be seen with more severe forms of OSA. The prevalence of OSA among women with preeclampsia in our cohort was 0.4%, which is much lower than the prevalence reported in prospective studies specifically designed to detect OSA, (12, 25) but higher than the 0.12% prevalence of OSA in the larger dataset that this subset originated from. (11) Indeed, mild OSA affected ~15% of pregnant women with obesity in the second trimester, (26) and at least 50% of some populations at high-risk for OSA. (27) Moreover, OSA occurred in 52.5% of women with hypertensive disorders of pregnancy, compared to 37.5% of women with normotensive pregnancies matched on BMI. (28) Thus, OSA is likely to have been largely under-diagnosed and under-reported in our cohort, and women with an established diagnosis in our cohort may represent a subgroup with known severe, symptomatic OSA. The observed impact of OSA on preeclampsia-related outcomes, contrasting with previous findings, (21) may reflect underlying greater OSA severity captured by our dataset.

Women with preeclampsia and concomitant OSA experienced more severe maternal morbidity than women without OSA, even after adjustment for confounders. Mechanistic pathways examining the association of OSA and preeclampsia are scarce. Since the degree of angiogenic imbalance in preeclampsia has been correlated with severe manifestations, (29, 30) a potential greater angiogenic imbalance in the women with OSA in our cohort may partially explain the observed association between OSA and severe maternal morbidity, though this hypothesis was not tested. Indeed, the imbalance between circulating pro-angiogenic placental growth factor (PlGF) and anti-angiogenic soluble Fms-like tyrosine 1 (sFlt-1) that characterizes preeclampsia, (31) was found to be more pronounced among pregnant women with OSA than those without OSA, even after adjusting for gestational age, BMI, and chronic hypertension. (32) While the treatment of OSA with continuous positive airway pressure has not yet been shown to result in long lasting improvement in measures of preeclampsia or preeclampsia severity, improvements in hemodynamic measures after one night of therapy and anti-angiogenic markers following weeks of therapy have previously been reported in small studies. (33–35) Hence, OSA may be a modifiable risk factor for hypertensive disorders of pregnancy and related maternal morbidity. In addition, women with preeclampsia and concomitant OSA may require closer peripartum follow-up to prevent severe maternal morbidity.

We report a strong association between OSA and severe cardiovascular morbidity, the leading cause of maternal mortality in North America. (36, 37) Since heart failure and stroke in pregnancy may be caused by severe hypertension, (38) optimization of blood pressure management among women with preeclampsia is key to prevention of severe cardiovascular morbidity. Continuous positive airway pressure has been associated with blood pressure reduction in small prospective studies of pregnant participants with hypertensive disorders. (34, 39) Moreover, the application of positive airway pressure in non-pregnant patients improved left ventricular ejection fraction and stroke outcomes in patients with heart failure and stroke, respectively. (40–42) As such, whether OSA treatment in preeclampsia can mitigate adverse cardiovascular outcomes needs to be determined.

The annual cost of preeclampsia care to the United States (US) healthcare systems was 2.18 billion dollars in 2012. (43) In our study, OSA among women with preeclampsia was associated with increased healthcare utilization. In the non-pregnant population, treatment of OSA with positive airway pressure led to favorable economic outcomes, and a consistent reduction in healthcare utilization. (44) Thus, reducing OSA-related adverse perinatal outcomes, possibly with the use of positive airway pressure therapy, may decrease some of the economic burden caused by preeclampsia.

Our study had several strengths. We used a large population-based sample that allowed us to observe rare outcomes in a geographically broad and diverse population. Moreover, by contributing evidence on OSA as a potentially treatable risk factor for severe maternal morbidity in a high-risk population, we addressed a clinically relevant knowledge gap. We had several limitations. The administrative dataset used had inherent limitations, including some missing medical record level clinical information such as OSA and preeclampsia severity, treatment for OSA, and indications for Cesarean delivery, as well as important parameters such as weight, BMI, and biomarker levels. Maternal comorbidities assessed at delivery hospitalization may have been under-reported. (45) However, as is the case with studies conducted in administrative datasets, (46) granular details about when events were first observed (i.e., during delivery hospitalization or at a previous point in time) could not be ascertained. However, since indicators composing the outcome represented acute conditions, outcomes are unlikely to have reflected chronic conditions preceding the exposure. Differential reporting of OSA among women with and without severe maternal morbidity could have introduced an observation bias. Despite these limitations, administrative datasets remain an effective data source to study severe maternal morbidity in epidemiologic studies given the relative rarity of this outcome. (47) Study findings must be interpreted with caution, given that the size and the number of outcome events of the exposed group was relatively limited. Nevertheless, our cohort of women with OSA was much larger than cohorts of previous studies conducted on the topic of OSA among women with preeclampsia. (21, 22) While we adjusted for multiple potential confounders, matching was not performed, and residual confounding by unmeasured covariates could have occurred. Moreover, the associations described may not have been causal, as we were not able to explore potential causal mechanisms in this epidemiological design that may link OSA and severe maternal morbidity in women with preeclampsia.

CONCLUSIONS

We found that OSA was a predictor of severe maternal morbidity, and mainly severe cardiovascular morbidity, in women with preeclampsia, even after adjustment for comorbid conditions. In addition to determining whether the treatment of OSA could prevent the development of preeclampsia, further research is required to explore mechanistic pathways underlying this association and to determine whether treatment of OSA in women with established preeclampsia could mitigate adverse maternal and perinatal outcomes.

Supplementary Material

1

HIGHLIGHTS.

  • Severe maternal morbidity was more common when OSA was present with preeclampsia.

  • In preeclampsia, women with OSA had five-fold increased risk of cardiovascular morbidity.

  • OSA was associated with increased healthcare utilization in women with preeclampsia.

ACKNOWLEDGEMENTS

Funding:

This study was partially funded by Women’s Medicine Collaborative Seed Funding at The Miriam Hospital. GB is funded by National Heart Lung and Blood Institute (NHLBI) R01HL130702 and National Institute for Child Health and Human Development (NICHD) R01HD078515. MB received funding from the National Institute of General Medical Sciences P20 GM103652 and National Heart Lung and Blood Institute (NHLBI) R01HL157288. The sponsors had no role in the study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication.

List of Abbreviations:

BMI

body-mass index

CI

confidence intervals

ICU

intensive care unit

ICD-9

International Classification of Diseases, 9th Revision

NPIC

National Perinatal Information Center

OSA

obstructive sleep apnea

OR

odds ratio

PCDB

Perinatal Center Database

PlGF

placental growth factor

sFlt −1

soluble Fms-like tyrosine 1

US

United States

Footnotes

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Summary conflict of interest statements: The authors report no conflicts of interest.

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NIHMS1847949-supplement-1.pdf (73.3KB, pdf)

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