Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and metaanalysis




Objective


Symptoms of sleep-disordered breathing (SDB) are increased in pregnancy compared to the nongravid state. Maternal SDB may be associated with adverse pregnancy outcomes, but this is still under investigation. We performed a systematic literature review, and where feasible, a metaanalysis, to evaluate whether women with SDB in pregnancy have a higher risk of specific adverse pregnancy outcomes compared with women without SDB.


Study Design


Original studies published until June 2012 evaluating the association between gestational hypertension/preeclampsia, gestational diabetes, low birthweight infants, and maternal SDB, defined either by symptoms or the reference standard polysomnography, were identified from PubMed, EMBASE, and Web of Science. Data were extracted on study design and outcome estimates. When appropriate, effect estimates from each study were pooled using a random-effects model.


Results


Of the 4386 studies identified, 31 met the defined criteria. Twenty-one studies, all observational in design, reported dichotomous outcomes; 9 of these adjusted for potential confounders. Maternal SDB was significantly associated with gestational hypertension/preeclampsia (pooled adjusted odds ratio [aOR], 2.34; 95% confidence interval [CI], 1.60–3.09; 5 studies), and gestational diabetes (pooled aOR, 1.86; 95% CI, 1.30–2.42; 5 studies).


Conclusion


Based on published observational studies to date, maternal SDB is associated with an increased risk of gestational hypertension and gestational diabetes after adjusting for potential confounders. However, large-scale, prospective cohort, and interventional studies are needed to further elucidate the relationship between maternal SDB and adverse pregnancy outcomes.





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Sleep-disordered breathing (SDB) refers to a group of disorders characterized by breathing pauses during sleep and is associated with microarousals, oxygen desaturations, and/or hemodynamic changes. In the nonpregnant population, SDB has been associated with several adverse cardiometabolic outcomes, including hypertension, cardiovascular disease, stroke, and altered glucose and lipid metabolism.


In pregnancy, symptoms of SDB are common and worsen with gestational age, with 14-35% of pregnant women reporting habitual snoring in the third trimester. The potential mechanisms contributing to SDB in pregnancy include gestational weight gain, edema, and hormonal influences. However, the true prevalence of SDB in pregnancy is unknown because the majority of studies have relied on symptom-based diagnosis rather than objective polysomnographic (PSG) recordings.


SDB is associated with sleep disruption and intermittent hypoxia-reoxygenation, which may lead to increased sympathetic activity, oxidative stress, and inflammation. During pregnancy, these disturbances could contribute to maternal cardiometabolic derangements such as gestational hypertension and diabetes and to impairment of placental function, resulting in poor fetal outcomes such as intrauterine growth restriction. Establishing a causal link between maternal SDB and adverse pregnancy outcomes could therefore have important implications for prenatal care. Several recent studies have investigated whether symptom-based or PSG-based definitions of SDB are associated with maternofetal complications. However, because the results have been conflicting, there is a clear need for a systematic review and metaanalysis of the available literature in summarizing the current evidence.


Objective


Our objective was to conduct a systematic review and, where feasible, metaanalysis to evaluate whether pregnant women with SDB have a higher risk of adverse pregnancy outcomes, which we defined as gestational hypertension/preeclampsia, gestational diabetes, or the delivery of low-birthweight infants, compared with pregnant women without SDB.




Methods for Review


We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement as the template for reporting the review.


Search strategy and study selection


We searched for citations on the association between SDB and pregnancy in the following 3 electronic databases published up until June 2012: PubMed, EMBASE, and Web of Science. All citations were then combined and the duplicates were excluded.


Search terms in PubMed included the following MeSH terms for SDB exposure: snoring; sleep apnea syndromes; and sleep apnea, obstructive. For adverse pregnancy outcomes, the following MeSH terms were used: pregnancy; hypertension, pregnancy induced; pregnancy complications, cardiovascular; pregnancy outcome; and diabetes, gestational. Text terms used were sleep, sleep apnea, and pregnancy. Terms were combined using the Boolean operator, or, within each category, and the Boolean operator, and, when combining between exposure and outcome.


In EMBASE, the EMTREE search terms for SDB exposure were sleep, sleep apnea syndrome, or snoring. For adverse pregnancy outcomes, the terms used were as follows: pregnancy, pregnancy complications, or text word pregnancy. The search strategy in Web of Science was sleep apnea or snoring and pregnant*. The search was not restricted by language. Studies were excluded if they were conference abstracts, reviews, or case reports. The bibliographies of 3 review papers were manually searched for potentially relevant citations that were not detected by the electronic search.


Studies were included if they assessed for an association between SDB in pregnancy and adverse pregnancy outcomes. We did not narrow our initial search to include the specific adverse pregnancy outcomes of interest (eg, gestational hypertension, gestational diabetes, and low-birthweight infants) because we postulated that some citations may not include these actual outcomes in the title but rather only in the abstract or full text. Instead, we eliminated articles that did not include at least 1 of these 3 outcomes when reviewing citations at the full text article stage of the review.


Studies were included only if there was a comparison group so that we could calculate odds ratios and mean differences in the outcomes between groups. We included all citations in the qualitative review that described an association between SDB and adverse pregnancy outcomes, including those that exclusively reported continuous data.


Data extraction and consensus


Two reviewers (S.P. and L.M.P.) independently screened the titles for potential relevance. Only titles that were mutually agreed upon as being not relevant were excluded. The 2 reviewers then screened abstracts and full-text articles for inclusion/exclusion criteria. At these stages, if there was disagreement between the 2 reviewers, a final decision was made based on consensus.


Once the final articles were identified after the full-text review, the 2 investigators independently reviewed the papers and extracted information on the following information: year and country of the study, study population, study design, number of exposed/unexposed or cases/controls, definitions, and criteria used for SDB and each of the adverse pregnancy outcomes, timing of exposure measurement, effect estimates or continuous data, and where applicable, adjusted variables. Study quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.


Definitions of SDB and adverse pregnancy outcomes


For the purpose of this review, SDB was defined according to the reference diagnostic standard, PSG demonstrating obstructive sleep apnea-hypopnea, or presumed/probable obstructive sleep apnea (OSA) based on reported symptoms of snoring, nocturnal choking/gasping, witnessed apneas, or simplified sleep recordings showing evidence of upper airway obstruction (inspiratory flow limitation) and/or repetitive oxygen desaturations.


In studies that presented more than 1 category of SDB (eg, none, mild, moderate, or severe), if the categories were mutually exclusive, we combined numbers to provide an effect estimate for any SDB compared with none. If the categories were not mutually exclusive, then we chose the more severe category of SDB and compared it with no SDB.


For the outcome of gestational hypertension/preeclampsia, if a study presented numbers for gestational hypertension and preeclampsia separately, we combined them as long as they were mutually exclusive. Gestational diabetes was defined by the presence or absence of the diagnosis by clinical criteria that were specified by the authors of each study. Finally, for infants with low birthweight, we chose the definition as being less than the 10th percentile to ensure consistency between studies.


Data analysis


We classified studies based on whether continuous data or categorical data were reported and also by adverse pregnancy outcome. Within each group of studies classified by adverse pregnancy outcome, heterogeneity of the effect estimates was assessed by calculating the I 2 statistic for both the crude effect estimates and the adjusted effect estimates. Crude and/or adjusted effect estimates were pooled only for studies that did not show significant heterogeneity, defined as I 2 of 75% or greater.


A metaanalysis was performed using a Der Simonian and Laird random-effects model to account for the variability across studies and to derive conservative assessments of the uncertainty in the estimates. The Mantel-Haenszel method was used for pooling crude effect estimates across studies. Studies were excluded if no subjects with the outcome of interest were observed in either exposure group. For the adjusted odds ratios, pooling was performed using the inverse variance method. We pooled adjusted odds ratios, even when these were adjusted for different variables, because adjusted effect estimates are likely to be more representative of the true measure of effect than the crude ratios. Continuous data, weighted by sample size, were pooled if there was no significant heterogeneity among the mean difference in effect size estimates across studies.




Methods for Review


We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement as the template for reporting the review.


Search strategy and study selection


We searched for citations on the association between SDB and pregnancy in the following 3 electronic databases published up until June 2012: PubMed, EMBASE, and Web of Science. All citations were then combined and the duplicates were excluded.


Search terms in PubMed included the following MeSH terms for SDB exposure: snoring; sleep apnea syndromes; and sleep apnea, obstructive. For adverse pregnancy outcomes, the following MeSH terms were used: pregnancy; hypertension, pregnancy induced; pregnancy complications, cardiovascular; pregnancy outcome; and diabetes, gestational. Text terms used were sleep, sleep apnea, and pregnancy. Terms were combined using the Boolean operator, or, within each category, and the Boolean operator, and, when combining between exposure and outcome.


In EMBASE, the EMTREE search terms for SDB exposure were sleep, sleep apnea syndrome, or snoring. For adverse pregnancy outcomes, the terms used were as follows: pregnancy, pregnancy complications, or text word pregnancy. The search strategy in Web of Science was sleep apnea or snoring and pregnant*. The search was not restricted by language. Studies were excluded if they were conference abstracts, reviews, or case reports. The bibliographies of 3 review papers were manually searched for potentially relevant citations that were not detected by the electronic search.


Studies were included if they assessed for an association between SDB in pregnancy and adverse pregnancy outcomes. We did not narrow our initial search to include the specific adverse pregnancy outcomes of interest (eg, gestational hypertension, gestational diabetes, and low-birthweight infants) because we postulated that some citations may not include these actual outcomes in the title but rather only in the abstract or full text. Instead, we eliminated articles that did not include at least 1 of these 3 outcomes when reviewing citations at the full text article stage of the review.


Studies were included only if there was a comparison group so that we could calculate odds ratios and mean differences in the outcomes between groups. We included all citations in the qualitative review that described an association between SDB and adverse pregnancy outcomes, including those that exclusively reported continuous data.


Data extraction and consensus


Two reviewers (S.P. and L.M.P.) independently screened the titles for potential relevance. Only titles that were mutually agreed upon as being not relevant were excluded. The 2 reviewers then screened abstracts and full-text articles for inclusion/exclusion criteria. At these stages, if there was disagreement between the 2 reviewers, a final decision was made based on consensus.


Once the final articles were identified after the full-text review, the 2 investigators independently reviewed the papers and extracted information on the following information: year and country of the study, study population, study design, number of exposed/unexposed or cases/controls, definitions, and criteria used for SDB and each of the adverse pregnancy outcomes, timing of exposure measurement, effect estimates or continuous data, and where applicable, adjusted variables. Study quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.


Definitions of SDB and adverse pregnancy outcomes


For the purpose of this review, SDB was defined according to the reference diagnostic standard, PSG demonstrating obstructive sleep apnea-hypopnea, or presumed/probable obstructive sleep apnea (OSA) based on reported symptoms of snoring, nocturnal choking/gasping, witnessed apneas, or simplified sleep recordings showing evidence of upper airway obstruction (inspiratory flow limitation) and/or repetitive oxygen desaturations.


In studies that presented more than 1 category of SDB (eg, none, mild, moderate, or severe), if the categories were mutually exclusive, we combined numbers to provide an effect estimate for any SDB compared with none. If the categories were not mutually exclusive, then we chose the more severe category of SDB and compared it with no SDB.


For the outcome of gestational hypertension/preeclampsia, if a study presented numbers for gestational hypertension and preeclampsia separately, we combined them as long as they were mutually exclusive. Gestational diabetes was defined by the presence or absence of the diagnosis by clinical criteria that were specified by the authors of each study. Finally, for infants with low birthweight, we chose the definition as being less than the 10th percentile to ensure consistency between studies.


Data analysis


We classified studies based on whether continuous data or categorical data were reported and also by adverse pregnancy outcome. Within each group of studies classified by adverse pregnancy outcome, heterogeneity of the effect estimates was assessed by calculating the I 2 statistic for both the crude effect estimates and the adjusted effect estimates. Crude and/or adjusted effect estimates were pooled only for studies that did not show significant heterogeneity, defined as I 2 of 75% or greater.


A metaanalysis was performed using a Der Simonian and Laird random-effects model to account for the variability across studies and to derive conservative assessments of the uncertainty in the estimates. The Mantel-Haenszel method was used for pooling crude effect estimates across studies. Studies were excluded if no subjects with the outcome of interest were observed in either exposure group. For the adjusted odds ratios, pooling was performed using the inverse variance method. We pooled adjusted odds ratios, even when these were adjusted for different variables, because adjusted effect estimates are likely to be more representative of the true measure of effect than the crude ratios. Continuous data, weighted by sample size, were pooled if there was no significant heterogeneity among the mean difference in effect size estimates across studies.




Results


General characteristics of included studies


Using our search strategy for electronic databases and manual citation searches, we identified and screened 4386 citations. Figure 1 outlines the selection process for the final 31 studies included in the qualitative analysis. Characteristics of the 31 studies are summarized in Table 1 . Twenty-nine of these studies were observational in design and the remaining 2 were small-scale interventional studies in which participants were randomized to continuous positive airway pressure (CPAP) or standard treatment.




Figure 1


PRISMA flow diagram

PRISMA flow diagram for inclusion of the studies examining the association between maternal SDB and adverse pregnancy outcomes.

SBD , sleep-disordered breathing.

Pamidi. Maternal sleep apnea and adverse pregnancy outcomes. Am J Obstet Gynecol 2014 .


Table 1

Summary of the 31 studies examining the association between maternal SDB and GHTN/PE, GDM, and low infant birthweight










































































































































































































































































































































































































































































































Study Country, population Participants, n Study design Exposure to SDB Reporting of adverse pregnancy outcomes Continuous data reported b
Measurement and definition Timing Crude effect estimates Adjusted variables Pooled in metaanalysis a
GHTN GDM LBW GHTN GDM LBW
Ayrlm et al, 2011 Turkey; hospital 41 snorers, 159 nonsnorers Cross-sectional Snoring questionnaire During labor None Birthweights
Bachour et al, 2008 Finland; cases: hospital, controls: home 17 PE, 15 controls Case-control 1. Oximetry/nasal pressure cannula
2. Snoring questionnaire (for effect estimate)
Third TM None AHI, ODI, flow limitation
Blyton et al, 2004 Australia; hospital 24 PE; 15 controls RCT Full overnight PSGs pre-CPAP Second/third TM None AHI
Bourjeily et al, 2010 United States; hospital 1000 postpartum women from hospital Cross-sectional Index 1 of MAPI questionnaire c 24-48 h postpartum Age, DM, chronic HTN, renal disease, BMI at delivery, smoking, multifetal pregnancy None
Calaora-Tournadre et al, 2006 France; hospital 20 GHTN/PE, 418 controls Case-control Snoring questionnaire Postpartum None None
Champagne et al, 2009 Canada; cases: hospital, cases: clinics 17 GHTN, 33 frequency-matched controls Case-control Overnight unattended portable PSG >20 wks GA, 1 mo postpartum Maternal age, gestational age, prepregnancy BMI, previous pregnancy, previous live birth AHI, ODI
Chen et al, 2012 Taiwan; population-based data sets 791 with OSA diagnostic codes, 4746 controls Case-control ICD diagnostic codes for OSA after PSG Variable Maternal education, marital status, GDM, GHTN, other comorbidities, obesity, geographic region, paternal age, infants age, parity Birthweights
Connolly et al, 2001 Ireland; antenatal clinic and ward 15 PE, 15 controls from each trimester Case-control In-hospital overnight limited PSG Variable None AHI, flattening index, flow limitation
Edwards et al, 2000 Australia; cases: hospital controls: clinics 25 PE, 17 controls Case-control Full overnight PSG Controls: third TM, Cases: unclear None RDI
Facco et al, 2010 United States; clinics 202 nulliparous women Prospective cohort Snoring questionnaire 6-20 wks and third TM Age, ethnoracial status, BMI, and short sleep duration 1 h mean OGTT
Facco et al, 2012 United States; hospital database 145 pregnant who had PSG Retrospective (cross-sectional) Full in-lab PSG Variable None None
Franklin et al, 2000 Sweden; hospital 518 women Cross-sectional Snoring questionnaire Delivery day Age at delivery, smoking, weight before delivery None
Higgins et al, 2011 United States; hospital 1343 (+) Berlin, 2731 (–) Berlin Prospective cohort Berlin Questionnaire Delivery day None Birthweights
Izci et al, 2005 Scotland; clinics 82 PE, 167 controls Case-control Snoring questionnaire Third TM None None
Izci et al, 2003 Scotland; cases: hospital, controls: clinic 37 PE, 50 controls Case-control Snoring questionnaire Third TM None None
Jniene et al, 2010 Morocco; hospital 144 women after delivery Cross-sectional Self-reported snoring Within 24 after delivery None None
Koken et al, 2007 Turkey; prenatal clinics 40 snorers,43 nonsnorers Prospective cohort Snoring: Berlin Questionnaire Second/third TM None Birthweights
Loube et al, 1996 United States; prenatal clinics 49 frequent snorers, 301 nonsnorers Prospective cohort Snoring: Hawaii Scale Questionnaire Second/third TM None Birthweights
Louis et al, 2010 United States; tertiary prenatal clinics 57 with OSA, 114 obese and normal-weight controls Retrospective cohort PSG-confirmed OSA Before and during pregnancy None for adverse pregnancy outcomes of interest c Birthweights
Micheli et al, 2011 Greece; population-based cohort 48 severe snorers, 151 occasional snorers, 892 nonsnorers Prospective cohort Snoring, computer-assisted interview Third TM Maternal age, education, prepregnancy BMI, smoking Birthweights
Olivarez et al, 2010 United States; admitted to antepartum service 20 OSA, 80 no OSA Prospective cohort PSG-confirmed OSA GA ≥26 wks None None
Perez-Chada et al, 2007 Argentina; hospital 156 snorers, 291 never-snorers Cross-sectional Snoring frequency, witnessed sleep apnea, questionnaire Delivery day Maternal age, prepregnancy BMI, weight gain, neck circumference, smoking, alcohol (for GHTN/PE outcome only) Birthweights
Poyares et al, 2007 Brazil; obstetrics clinic with preexisting HTN All chronic snorers: 7 CPAP, 9 no CPAP RCT 8 wks of CPAP; PSG only in those treated with CPAP Initiated first few weeks of pregnancy None Birthweights
Qiu et al, 2010 United States; prenatal clinics 89 snorers, 1169 nonsnorers Prospective cohort Self-reported snoring frequency, Interview <20 wks Maternal age, ethnicity, stratified by BMI (overweight vs lean) None
Reid et al, 2011 Canada; obstetrical ward with GHTN 34 GHTN, 26 controls with PSG Cross-sectional PSG-confirmed OSA Third TM None AHI, RERA index, RDI, ODI
Reutrakul, et al, 2011 United States; women with routine OGTT 26 GDM, 116 NGT Case-control ESS, Berlin, frequent snoring, questionnaires Second TM BMI None
Sahin et al, 2008 Turkey; prenatal clinics 4 OSA, 31 non-OSA Prospective cohort PSG-confirmed OSA Third TM None Birthweights
Tauman et al, 2011 Israel; medical ward 48 habitual snorers, 74 nonsnorers Cross-sectional Self-reported snoring, questionnaire Delivery room None Birthweights
Ursavas et al, 2008 Turkey; third trimester, prenatal clinics 55 habitual snorers, 414 nonhabitual snorers Prospective cohort Self-reported snoring Third TM None None
Yin et al, 2008 United Kingdom; clinics and wards 150 pregnant women with oximetry obtained Cross-sectional 1. Snoring: questionnaires (effect estimates)
2. Overnight oximetry
Third TM None None
Yinon et al, 2006 Israel; cases: Department of Obstetrics and Gynecology, controls: advertising 17 PE, 25 matched controls Case-control Nocturnal sleep study: Watch-PAT100 Third TM None RDI by Watch-PAT

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