maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and...

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OBSTETRICS

Maternal sleep-disordered breathing and adverse pregnancyoutcomes: a systematic review and metaanalysisSushmita Pamidi, MD; Lancelot M. Pinto, MD, MSc; Isabelle Marc, MD; Andrea Benedetti, PhD;Kevin Schwartzman, MD, MPH; R. John Kimoff, MD

OBJECTIVE: Symptoms of sleep-disordered breathing (SDB) are RESULTS: Of the 4386 studies identified, 31 met the defined criteria.
increased in pregnancy compared to the nongravid state. MaternalSDB may be associated with adverse pregnancy outcomes, but thisis still under investigation. We performed a systematic literaturereview, and where feasible, a metaanalysis, to evaluate whetherwomen with SDB in pregnancy have a higher risk of specific adversepregnancy outcomes compared with women without SDB.
STUDY DESIGN: Original studies published until June 2012 evaluatingthe association between gestational hypertension/preeclampsia,gestational diabetes, low birthweight infants, and maternal SDB,defined either by symptoms or the reference standard poly-somnography, were identified from PubMed, EMBASE, and Web ofScience. Data were extracted on study design and outcome estimates.When appropriate, effect estimates from each study were pooled usinga random-effects model.

From the Respiratory Division and Sleep Laboratory (Drs Pamidi, Pinto, Schwand the Respiratory Epidemiology and Clinical Research Unit and DepartmeBiostatistics, and Occupational Health (Drs Benedetti and Schwartzman), MCenter, Montreal, and the Department of Pediatrics, Centre Hospitalier de l’UnCity (Dr Marc), QC, Canada.

Received April 19, 2013; revised June 9, 2013; accepted July 31, 2013.

The authors report no conflict of interest.

Presented in part at the annual International Conference of the American ThoPhiladelphia, PA, May 17-22, 2013.

Reprints: Sushmita Pamidi, MD, McGill University Health Centre, Respiratory687 Pine Ave. W, Montreal, Quebec, Canada H3A 1A1. sushmita.pamidi@m

0002-9378/$36.00 � ª 2014 Mosby, Inc. All rights reserved. � http://dx.doi.org/10.1

See related editorial, page 3

See Journal Club, page 87

52.e1 American Journal of Obstetrics & Gynecology JANUARY 2014

Twenty-one studies, all observational in design, reported dichotomousoutcomes; 9 of these adjusted for potential confounders. Maternal SDBwas significantly associated with gestational hypertension/pre-eclampsia (pooled adjusted odds ratio [aOR], 2.34; 95% confidenceinterval [CI], 1.60e3.09; 5 studies), and gestational diabetes (pooledaOR, 1.86; 95% CI, 1.30e2.42; 5 studies).

CONCLUSION: Based on published observational studies to date,maternal SDB is associated with an increased risk of gestational hy-pertension and gestational diabetes after adjusting for potential con-founders. However, large-scale, prospective cohort, and interventionalstudies are needed to further elucidate the relationship betweenmaternal SDB and adverse pregnancy outcomes.

Key words: adverse pregnancy outcomes, gestational diabetes,gestational hypertension, low birthweight infants, sleep apnea

Cite this article as: Pamidi S, Pinto LM, Marc I, et al. Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review andmetaanalysis. Am JObstet Gynecol 2014;210:52.e1-14.

leep-disordered breathing (SDB)
S refers to a group of disorders char-acterized bybreathing pausesduring sleepand is associated with microarousals, ox-ygen desaturations, and/or hemodynamicchanges.1 In the nonpregnant population,SDB has been associated with several ad-verse cardiometabolic outcomes, includ-ing hypertension, cardiovascular disease,
stroke, and altered glucose and lipidmetabolism.In pregnancy, symptoms of SDB are

common and worsen with gestationalage,2 with 14-35% of pregnant womenreporting habitual snoring in the thirdtrimester.3-5 The potential mechanismscontributing to SDB in pregnancyinclude gestational weight gain, edema,

artzman, and Kimoff)nt of Epidemiology,cGill University Healthiversité Laval, Quebec

racic Society,

Division, Room L4.05,ail.mcgill.ca.

016/j.ajog.2013.07.033

and hormonal influences.6 However, thetrue prevalence of SDB in pregnancy isunknown because themajority of studieshave relied on symptom-based diagnosisrather than objective polysomnographic(PSG) recordings.

SDB is associated with sleep disruptionand intermittent hypoxia-reoxygenation,which may lead to increased sympa-thetic activity, oxidative stress, and in-flammation. During pregnancy, thesedisturbances could contribute to ma-ternal cardiometabolic derangementssuch as gestational hypertension anddiabetes and to impairment of placentalfunction, resulting in poor fetal out-comes such as intrauterine growth re-striction. Establishing a causal linkbetween maternal SDB and adversepregnancy outcomes could thereforehave important implications for prenatalcare. Several recent studies have investi-gated whether symptom-based or PSG-based definitions of SDB are associatedwith maternofetal complications. How-ever, because the results have been

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conflicting, there is a clear need for asystematic review and metaanalysis ofthe available literature in summarizingthe current evidence.

OBJECTIVE

Our objective was to conduct a systematicreview and, where feasible, metaanalysisto evaluate whether pregnant womenwith SDB have a higher risk of adversepregnancy outcomes, which we definedas gestational hypertension/preeclampsia,gestational diabetes, or the delivery oflow-birthweight infants, compared withpregnant women without SDB.

METHODS FOR REVIEW

We used the Preferred Reporting Itemsfor Systematic Reviews and Meta-Analysis statement7 as the template forreporting the review.

Search strategy and study selectionWe searched for citations on the associ-ation between SDB and pregnancy in thefollowing 3 electronic databases pub-lished up until June 2012: PubMed,EMBASE, and Web of Science. All cita-tions were then combined and theduplicates were excluded.

Search terms in PubMed included thefollowing MeSH terms for SDB exposure:snoring; sleep apnea syndromes; and sleepapnea, obstructive. For adverse pregnancyoutcomes, the following MeSH termswere used: pregnancy; hypertension, pre-gnancy induced; pregnancy complica-tions, cardiovascular; pregnancyoutcome;and diabetes, gestational. Text terms usedwere sleep, sleep apnea, and pregnancy.Terms were combined using the Booleanoperator, or, within each category, and theBoolean operator, and, when combiningbetween exposure and outcome.

In EMBASE, the EMTREE searchterms for SDB exposure were sleep, sleepapnea syndrome, or snoring. For adversepregnancy outcomes, the terms usedwere as follows: pregnancy, pregnancycomplications, or text word pregnancy.The search strategy in Web of Sciencewas sleep apnea or snoring and preg-nant*. The search was not restricted bylanguage. Studies were excluded if theywere conference abstracts, reviews, orcase reports. The bibliographies of 3

review papers were manually searchedfor potentially relevant citations thatwere not detected by the electronicsearch.8-10

Studies were included if they assessedfor an association between SDB in preg-nancy and adverse pregnancy outcomes.We did not narrow our initial search toinclude the specific adverse pregnancyoutcomes of interest (eg, gestational hy-pertension, gestational diabetes, andlow-birthweight infants) because wepostulated that some citations may notinclude these actual outcomes in the titlebut rather only in the abstract or full text.Instead, we eliminated articles that didnot include at least 1 of these 3 outcomeswhen reviewing citations at the full textarticle stage of the review.Studies were included only if there was

a comparison group so that we couldcalculate odds ratios and mean differ-ences in the outcomes between groups.We included all citations in the qualitativereview that described an association be-tween SDB and adverse pregnancy out-comes, including those that exclusivelyreported continuous data.

Data extraction and consensusTwo reviewers (S.P. and L.M.P.) inde-pendently screened the titles for poten-tial relevance. Only titles that weremutually agreed upon as being notrelevant were excluded. The 2 reviewersthen screened abstracts and full-text ar-ticles for inclusion/exclusion criteria. Atthese stages, if there was disagreementbetween the 2 reviewers, a final decisionwas made based on consensus.Once the final articles were identified

after the full-text review, the 2 in-vestigators independently reviewed thepapers and extracted information on thefollowing information: year and countryof the study, study population, studydesign, number of exposed/unexposed orcases/controls, definitions, and criteriaused for SDB and each of the adversepregnancy outcomes, timing of exposuremeasurement, effect estimates or contin-uous data, and where applicable, adjustedvariables. Study quality was assessedusing the Strengthening the Reporting ofObservational Studies in Epidemiology(STROBE) checklist.11

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Definitions of SDB and adversepregnancy outcomesFor the purpose of this review, SDB wasdefined according to the reference diag-nostic standard, PSG demonstratingobstructive sleep apnea-hypopnea, orpresumed/probable obstructive sleepapnea (OSA) based on reported symp-toms of snoring, nocturnal choking/gasping, witnessed apneas, or simplifiedsleep recordings showing evidence ofupper airway obstruction (inspiratoryflow limitation) and/or repetitive oxygendesaturations.

In studies that presented more than1 category of SDB (eg, none, mild,moderate, or severe), if the categorieswere mutually exclusive, we combinednumbers to provide an effect estimatefor any SDB compared with none. Ifthe categories were not mutuallyexclusive, then we chose the more se-vere category of SDB and compared itwith no SDB.

For the outcome of gestationalhypertension/preeclampsia, if a studypresented numbers for gestational hy-pertension and preeclampsia separately,we combined them as long as they weremutually exclusive. Gestational diabeteswas defined by the presence or absenceof the diagnosis by clinical criteria thatwere specified by the authors of eachstudy. Finally, for infants with lowbirthweight, we chose the definition asbeing less than the 10th percentile toensure consistency between studies.

Data analysisWe classified studies based on whethercontinuous data or categorical data werereported and also by adverse pregnancyoutcome. Within each group of studiesclassified by adverse pregnancy outcome,heterogeneity of the effect estimates wasassessed by calculating the I2 statistic12

for both the crude effect estimates andthe adjusted effect estimates. Crude and/or adjusted effect estimates were pooledonly for studies that did not show sig-nificant heterogeneity, defined as I2 of75% or greater.12

A metaanalysis was performed using aDer Simonian and Laird random-effectsmodel to account for the variabilityacross studies and to derive conservative

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FIGURE 1PRISMA flow diagram

PRISMA7 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.

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assessments of the uncertainty in theestimates.13 TheMantel-Haenszel methodwas used for pooling crude effect estimatesacross studies.14 Studies were excluded ifno subjects with the outcome of interestwere observed in either exposure group.For the adjusted odds ratios, pooling wasperformed using the inverse variancemethod.15 We pooled adjusted odds ra-tios, even when these were adjusted fordifferent variables, because adjustedeffect estimates are likely to be morerepresentative of the true measure ofeffect than the crude ratios.16 Contin-uous data, weighted by sample size, werepooled if there was no significant het-erogeneity among the mean differencein effect size estimates across studies.

RESULTS

General characteristics of includedstudiesUsing our search strategy for electronicdatabases and manual citation searches,we identified and screened 4386 cita-tions. Figure 1 outlines the selectionprocess for the final 31 studies includedin the qualitative analysis. Characteris-tics of the 31 studies are summarized inTable 1. Twenty-nine of these studieswere observational in design3-5,17-42 andthe remaining 243,44 were small-scaleinterventional studies in which partici-pants were randomized to continuouspositive airway pressure (CPAP) orstandard treatment.

Among the observational studies, thedistribution of study designs was as fol-lows: 9 prospective cohorts, 1 cohort, 10case-control, and 9 cross-sectional. Nineof the 29 observational studies adjustedfor potential confounding variables,whereas the remaining studies presentedonly crude-effect estimates or continuousdata pertaining to the adverse pregnancyoutcomes of interest (Table 1). Twenty-one studies presented dichotomous out-comes that could be presented as effectestimates, but for 10 studies, only con-tinuous outcomes for the adverse preg-nancyoutcomes of interest were available.

Definition of exposure and outcomesThere was considerable heterogeneityin how SDB was defined and measuredin each study (Table 1). The majority of

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studies (n¼ 17) defined SDB accordingto self-reported snoring, although themethod of assessment (eg, interview vsquestionnaire), timing of exposurestatus ascertainment (ie, trimester), andthe ascertainment of details regardingthe actual frequency and loudness of thesnoring varied substantially betweenstudies. Other symptom-based defini-tions such as gasping, choking, or wit-nessed apneas were also used.3,34

Twelve studies included objective sleeprecordings and used the apnea-hypopnea index (AHI) criteria, therespiratory disturbance index (RDI), orairflow limitation to characterizeSDB.18,20-23,25,31,33,36,38,42,43

Of the studies that reported effect es-timates fromdichotomous outcomes, the

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association between maternal SDB andgestational hypertension/preeclampsiawas examined in 18 studies, gestationaldiabetes in 6 studies, and delivery of low-birthweight infants in 7 studies. Severalstudies examined more than one adversepregnancy outcome at a time (Table 1).Other adverse outcomes, such as lowApgar scores, cesarean section delivery,and premature delivery, were evaluatedin some studies but were not examined inour analysis because these were not theoutcomes of interest in our a prioridefined protocol.

Definitions of preeclampsia, gesta-tional hypertension, and gestational dia-betes conformed to standard guidelines(eg, the American Congress of Obstetricsand Gynecology, the American Diabetes

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TABLE 1Summary of the 31 studies examining the association between maternal SDB and GHTN/PE, GDM, and low infant birthweight

StudyCountry,population Participants, n

Studydesign

Exposure to SDB Reporting of adverse pregnancy outcomes

Continuousdatareportedb

Measurementand definition Timing

Crude effectestimates Adjusted

variables

Pooled inmetaanalysisa

GHTN GDM LBW GHTN GDM LBW

Ayrlm et al,201117

Turkey;hospital

41 snorers,159 nonsnorers

Cross-sectional Snoringquestionnaire

Duringlabor

� e e None e e e Birthweights

Bachouret al, 200818

Finland; cases:hospital, controls:home

17 PE, 15 controls Case-control 1. Oximetry/nasalpressure cannula2. Snoringquestionnaire (foreffect estimate)

Third TM � e e None e e e AHI, ODI,flowlimitation

Blytonet al, 200443

Australia;hospital

24 PE;15 controls

RCT Full overnight PSGspre-CPAP

Second/third TM

e e e None e e e AHI

Bourjeilyet al, 20103

United States;hospital

1000 postpartumwomen fromhospital

Cross-sectional Index 1 of MAPIquestionnairec

24-48 hpostpartum

� � � Age, DM, chronicHTN, renal disease,BMI at delivery,smoking, multifetalpregnancy

� � e None

Calaora-Tournadreet al, 200619

France;hospital

20 GHTN/PE,418 controls

Case-control Snoringquestionnaire

Postpartum � e e None e e e None

Champagneet al, 200920

Canada; cases:hospital, cases:clinics

17 GHTN, 33frequency-matchedcontrols

Case-control Overnightunattendedportable PSG

>20 wksGA, 1 mopostpartum

� e e Maternal age,gestational age,prepregnancy BMI,previous pregnancy,previous live birth

� e e AHI, ODI

Chen et al,201221

Taiwan;population-baseddata sets

791 with OSAdiagnostic codes,4746 controls

Case-control ICD diagnosticcodes for OSAafter PSG

Variable � � � Maternal education,marital status, GDM,GHTN, othercomorbidities,obesity,geographic region,paternal age, infantsage, parity

� � � Birthweights

Connollyet al, 200122

Ireland; antenatalclinic and ward

15 PE, 15 controlsfrom each trimester

Case-control In-hospitalovernight limitedPSG

Variable e e e None - - - AHI,flatteningindex, flowlimitation

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

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TABLE 1Summary of the 31 studies examining the association between maternal SDB and GHTN/PE, GDM, and low infant birthweight (continued)


Studydesign





variables



Edwardset al, 200023

Australia; cases:hospital controls:clinics

25 PE,17 controls

Case-control Full overnightPSG

Controls:thirdTM, Cases:unclear

e e e None e e e RDI

Facco et al,201024

United States;clinics

202 nulliparouswomen

Prospectivecohort

Snoringquestionnaire

6-20 wksand thirdTM

e � e Age, ethnoracialstatus, BMI, andshort sleep duration

e � e 1 h meanOGTT

Facco et al,201225

United States;hospital database

145 pregnantwho had PSG

Retrospective(cross-sectional)

Full in-lab PSG Variable � � e None e e e None

Franklinet al, 20004

Sweden; hospital 518 women Cross-sectional Snoringquestionnaire

Deliveryday

� e � Age at delivery,smoking, weightbefore delivery

� e � None

Higgins et al,201126

United States;hospital

1343 (þ) Berlin,2731 (e) Berlin

Prospectivecohort

BerlinQuestionnaire

Deliveryday

� e e None e e e Birthweights

Izci et al,200527

Scotland; clinics 82 PE, 167controls

Case-control Snoringquestionnaire

Third TM � e e None e e e None

Izci et al,200328

Scotland; cases:hospital, controls:clinic

37 PE, 50 controls Case-control Snoringquestionnaire

Third TM � e e None e e e None

Jniene et al,201029

Morocco; hospital 144 womenafter delivery

Cross-sectional Self-reportedsnoring

Within 24afterdelivery

� e e None e e e None

Koken et al,200730

Turkey;prenatal clinics


Prospectivecohort

Snoring: BerlinQuestionnaire

Second/third TM

e e e None e e e Birthweights

Loube et al,19965

United States;prenatal clinics

49 frequent snorers,301 nonsnorers

Prospectivecohort

Snoring: HawaiiScale Questionnaire

Second/third TM


Louis et al,201031

United States;tertiary prenatalclinics

57 with OSA,114 obese andnormal-weightcontrols

Retrospectivecohort

PSG-confirmedOSA

Beforeand duringpregnancy

� e � None for adversepregnancyoutcomesof interestc

e e e Birthweights


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TABLE 1Summary of the 31 studies examining the association between maternal SDB and GHTN/PE, GDM, and low infant birthweight (continued)


Studydesign





variables



Micheli et al,201132

Greece;population-basedcohort

48 severe snorers,151 occasionalsnorers, 892nonsnorers

Prospectivecohort

Snoring,computer-assistedinterview

Third TM e e � Maternal age,education,prepregnancyBMI, smoking

e e � Birthweights

Olivarezet al, 201033

United States;admitted toantepartum service

20 OSA, 80no OSA

Prospectivecohort

PSG-confirmedOSA

GA �26 wks � � e None e e e None

Perez-Chadaet al, 200734

Argentina; hospital 156 snorers,291 never-snorers

Cross-sectional Snoring frequency,witnessed sleepapnea, questionnaire

Deliveryday

� e � Maternal age,prepregnancy BMI,weight gain, neckcircumference,smoking, alcohol(for GHTN/PEoutcome only)

� e e Birthweights

Poyareset al, 200744

Brazil; obstetricsclinic withpreexisting HTN

All chronic snorers:7 CPAP, 9 no CPAP

RCT 8 wks of CPAP;PSG only in thosetreated with CPAP

Initiatedfirst fewweeks ofpregnancy


Qiu et al,201035

United States;prenatal clinics


Prospectivecohort

Self-reportedsnoring frequency,Interview

<20 wks e � e Maternal age,ethnicity, stratifiedby BMI (overweightvs lean)

e � e None

Reid et al,201136

Canada; obstetricalward with GHTN

34 GHTN, 26controls with PSG

Cross-sectional PSG-confirmedOSA

Third TM � e e None e e e AHI, RERAindex, RDI,ODI

Reutrakul,et al, 201137

United States;women withroutine OGTT

26 GDM, 116 NGT Case-control ESS, Berlin,frequent snoring,questionnaires

Second TM e � e BMI e � e None

Sahinet al, 200838

Turkey; prenatalclinics

4 OSA, 31 non-OSA Prospectivecohort

PSG-confirmedOSA

Third TM e e e None e e e Birthweights

Taumanet al, 201139

Israel; medical ward 48 habitual snorers,74 nonsnorers

Cross-sectional Self-reportedsnoring,questionnaire

Deliveryroom



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TABLE

1Sum

maryof

the31

studiesexam

iningtheassociationbetweenmaternalS

DBandGHTN

/PE,GDM,and

lowinfant

birthw

eight(continued)

Study

Country,

popu

lation

Participants,n

Study

design

Exposure

toSDB

Reporting

ofadversepregnancyoutcom

es

Continu

ous

data

reported

bMeasurement

anddefinition

Timing

Crude

effect

estimates

Adjusted

variables

Pooledin

metaanalysisa

GHTN

GDM

LBW

GHTN

GDM

LBW

Ursavas

etal,2008

40

Turkey;third

trimester,

prenatalclinics

55habitualsnorers,

414nonhabitual

snorers

Prospective

cohort

Self-reported

snoring

ThirdTM

�e

eNone

ee

eNone

Yinetal,

2008

41

UnitedKingdom

;clinicsandwards

150pregnant

wom

enwith

oximetryobtained

Cross-sectional

1.Snoring:

questionnaires

(effectestim

ates)

2.Overnight

oximetry

ThirdTM

�e

�None

ee

eNone

Yinonetal,

2006

42

Israel;cases:

Departmentof

Obstetricsand

Gynecology,controls:

advertising

17PE,25

matched

controls

Case-control

Nocturnalsleep

study:Watch-

PAT100

ThirdTM

ee

eNone

ee

eRDIby

Watch-PAT

AHI,apnea-hypopnea

index;BMI,body

massindex;CPAP,continuous

positiveairway

pressure;DM,diabetes

mellitus;ESS,EpworthSleepiness

Scale;GA,gestationalage;GDM,gestationaldiabetes;GHTN,gestationalhypertension;HTN,hypertension;LBW,

infantswith

lowbirthw

eight;MAPI,m

ultivariableapneapredictionindex;NGT,normalglucosetolerance;ODI,oxygen

desaturationindex;OGTT,1

houroralglucosetolerance;OSA,obstructivesleepapnea;PE,preeclampsia;PSG

,polysom

nogram

;RCT,random

ized

controlledtrial;RDI,respiratorydisturbanceindex;RERA,respiratoryefforterelatedarousal;TM

,trimester.

aReferstopoolingofcategoricaloutcom

esonly.PoolingofmeandifferenceofAHIinGHTN/PEvscontrolswas

also

performed

butdoesnotappearinthistable(Figure6);b

MAPIquestionnaireincludes

symptom

sofsnoringloudly,snortingorgasping,episodes

ofstoppedbreathing,orchokingepisodes;cAdjustmentsweremadeforotheroutcom

esbutnotforadversepregnancyoutcom

esofinterest.

Pamidi.Maternalsleep

apneaandadversepregnancyoutcom

es.A

mJObstetGynecol2014.


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Association, and the Canadian MedicalAssociation) when specified. Only 3 ofthe 18 studies examining the associationbetween maternal SDB and gestationalhypertension/preeclampsia did notspecify the exact diagnostic criteria forgestational hypertension/preeclampsiabut rather used chart-based diagnosesor diagnostic codes (Higgins et al,26

Chen et al,21 and Facco et al25). Forthe gestational diabetes outcome, onlyChen et al21 did not state the specificdefinition but rather used diagnosticcodes because those authors relied onpopulation-based datasets.

Effect estimates for adversepregnancy outcomesFor each adverse pregnancy outcome ofinterest, crude and adjusted effect esti-mates are outlined in Figures 2-4. Studieswere also subdivided according to themethod of assessment of SDB exposure(ie, symptom based or PSG based) withineach outcome. Heterogeneity of effect es-timates for a particular adverse pregnancyoutcome was higher for crude estimatescompared with adjusted estimates.

Among studies investigating the as-sociation between maternal SDB andgestational hypertension/preeclampsia,the between-study variance accountedfor 62.5% of the total variance in unad-justed analyses but only 29.8% of thetotal variance among adjusted estimates(Figure 2, A and B). Despite the hetero-geneity among the 18 crude-effect esti-mates, only 2 point estimates yieldedodds ratios (ORs) less than 1, both ofwhich had confidence intervals (CIs)that extended above 1.25,33 Thirteen ofthe 18 studies suggested an increased riskof gestational hypertension/preeclamp-sia in the presence of maternal SDB.Among the 12 studies that assessed SDBexposure based on symptoms in thecrude analyses, the pooled OR was 3.11(95% CI, 2.28e4.25), compared with apooled OR of 2.25 (95% CI, 1.13e4.52)in 6 studies that used PSG to measureSDB. Moreover, there were 5 studies thatadjusted for potential confounders, andthese demonstrated that the associationbetween SDB and gestational hyperten-sion/preeclampsia was preserved whencompared with crude risk estimates

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FIGURE 2Unadjusted and adjusted ORs for SDB and gestational hypertension orpreeclampsia

Forest plots showing A, unadjusted and B, adjusted ORs for SDB and gestational hypertension or

preeclampsia. Weights are from random-effects analysis and are shown by gray-shaded boxes.

OR, odds ratio; SBD, sleep-disordered breathing.



(pooled adjusted OR, 2.34; 95% CI1.60e3.09 vs pooled unadjusted OR,2.86; 95% CI, 2.17e3.78). Two of the5 studies that were adjusted for con-founders used PSG-based assessment ofSDB.20,21

In studies with gestational diabetesoutcomes, the between-study variancefor crude effect estimates was 53.3% ofthe total variance in comparison withnearly 0% when the analysis wasrestricted to adjusted estimates only.With the exception of 1 study with anORof less than 1,33 all other studies in theunadjusted analyses had ORs greaterthan 1 but with highly variable ORsranging from 0.61 to 4.33 (Figure 3, A).Because there were only 2 studies21,33

that used PSG-based assessment ofSDB, these were not pooled separately. Inthe 5 studies with adjusted analyses(Figure 3, B), all point estimates for ORswere greater than 1 with a pooled OR of1.86 (95% CI, 1.30e2.42) comparedwith an unadjusted pooled OR of 2.11(95% CI, 1.38e3.23). Only 1 study,Chen et al,21 used PSG-based assessmentfor SDB among the adjusted analyses.

In the 7 studies with unadjusted low-birthweight infant outcomes (Figure 4,A), there was negligible between-studyvariance and the pooled OR was 1.39(95% CI, 1.14e1.65). Despite the lowstatistical heterogeneity (I2 ¼ 0, P ¼ .6),the unadjusted ORs ranged from 0.88 to2.89. Two studies21,31 used PSG-basedassessment for SDB. Because adjustedORs for low-birthweight infant out-comes were available for only 3 stud-ies,4,21,32 pooling was not performed(Figure 4, B). Of the studies that adjustedfor confounders, only Chen et al21 reliedon the PSG-based assessment of SDB.

Studies with continuous datareportedTen of 31 studies reported only contin-uous outcomes, and 8 studies reportedboth continuous and dichotomous out-comes relating to the adverse pregnancyoutcomes of interest. The data availablewere for the following: (1) OSA severityamong pregnant women with vs withoutgestational hypertension/preeclampsia,and (2) infant birthweight amongwomenwith vs without SDB.

The mean AHI reported amongstudies examining gestational hyperten-sive/preeclamptic women comparedwith controls are shown in Table 2. With

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the exceptions of 2 studies in which theresults did not reach statistical signifi-cance,23,43 all studies reported signifi-cantly higher AHI in the gestational

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FIGURE 3Unadjusted and adjusted ORs for association between SDB andgestational diabetes

A, Unadjusted and B, adjusted ORs for the association between SDB and gestational diabetes.




hypertension/preeclampsia group com-pared with controls.

Inspiratory flow limitation is a markerof upper airway narrowing during sleepandmay represent a mild form of SDB.45

Although not quantified, Edwards et al23

reported that despite the similar AHI forthe 2 groups, the entire hypertensive

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group displayed evidence of inspiratoryflow limitation and snoring. Moreover,Connolly et al22 demonstrated that thepreeclamptic group spent 31 � 8.4% ofsleep time with inspiratory flow limita-tion, compared with only 15.5� 2.3% ofsleep time in the third trimester controlgroup (P¼ .001). Finally, Bachour et al18

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also showed that women with pre-eclampsia spent more time with flowlimitation compared with controls (21�18% vs 4 � 9%, P ¼ .01).

The mean differences in AHI amongpatients with gestational hypertension/preeclampsia and controls for PSGstudies are shown in Figure 5. Poolingwas not performed because of the het-erogeneity of effects across studies (I2 ¼90.7%). The weighted mean differenceranged from 0.8 to 20.4 across 6 studies.

The mean birthweights of infantsborn to women with SDB comparedwith women without SDB are displayedin Table 3. Only 2 studies reported asignificant difference in birthweightsbetween the 2 groups,26,31 and amongthese, 1 study26 reported higher birth-weights in the groupwith no exposure toSDB.

Poyares et al44 investigated chronicsnorers with preexisting hypertensiontreated with CPAP compared with noCPAP, but no significant difference wasnoted in birthweights. The mean differ-ences in birthweight among the studiesreporting continuous birthweight mea-sures are illustrated in Figure 6. Therewas significant heterogeneity in thesedifferences (I2 ¼ 75.5%) so pooling wasnot performed.

Quality analysisQuality assessment was performed usingthe STROBE checklist, and there wassubstantial heterogeneity in study qual-ity and design. Despite including onlystudies in which the comparison groupcomprised pregnant women, a selectionbias was possible, given the manner inwhich subjects and controls wererecruited. The timing of assessment forOSA varied across studies, ranging froma few years before and after pregnancy,during the course of the pregnancy, orduring the intra- and immediate post-partum periods (Table 1).

The methods used for the assessmentof SDB exposure were also heteroge-neous and included validated andunvalidated questionnaires, physician-reported International Classification ofDiseases (ICD) codes for OSA in acountrywide database,21 and objectivemeasures such as overnight oximetry,

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FIGURE 4Unadjusted and adjusted ORs for the association between SDB and lowinfant birthweights

A, Unadjusted and B, adjusted ORs for the association between SDB and low infant birthweights are

shown.




the Watch_PAT100 system,42 and unat-tended portable PSG. Seven studies re-ported the use of full overnight attendedPSGs to assess exposure, the methodpresently considered the reference stan-dard for the diagnosis of OSA. Among

studies that used PSG-based criteria forSDB that reported dichotomous out-comes, only Champagne et al,20 Olivarezet al,33 and Reid et al36 performed PSGson subjects after recruitment, ratherthan evaluating retrospective data.

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In addition, of these studies, the actualcutoffs forAHI, RDI, and airflow limitationvaried. For example, Champagne et al20

used an AHI of 15 or greater, Louis et al31

and Olivarez et al33 used an AHI of 5 orgreater, and Reid et al36 used a respiratorydisturbance index of 5 or greater. Chenet al21 used population-based data sets andspecific PSG diagnostic criteria were notspecified.

A majority of studies that reporteddichotomous outcomes did not reportconfounder-adjusted estimates, andoverall, only 7 studies specificallyadjusted for maternal weight or bodymass index (BMI).3,4,20,24,32,34,37 How-ever, Chen et al21 adjusted their analysesto a diagnosis of obesity in population-based data sets, and Qiu et al35 re-ported effect estimates stratified by BMI(overweight vs lean). Thus, all of theadjusted-effect estimates reported forgestational hypertension, gestationaldiabetes, and low-birthweight infants,adjusted for maternal obesity to somedegree.

COMMENT

Summary of findingsA systematic review of the literatureinvestigating the association betweenadverse pregnancy outcomes (ie, ges-tational hypertension/preeclampsia, ges-tational diabetes, and/or delivery oflow-birthweight infants) and maternalSDB yielded 21 studies that presentedeffect estimates, all of which were ob-servational in design. Studies that metcriteria for the metaanalysis demon-strated an increased risk of gestationalhypertension/preeclampsia and gesta-tional diabetes in pregnant women withSDB compared with those without SDB,even after adjustment for potential con-founders. Moreover, studies that re-ported outcomes in terms of AHIdemonstrated that women with gesta-tional hypertension/preeclampsia had asignificantly greater degree of SDB(ie, higher pooled mean AHI) thanwomen without gestational hyperten-sion/preeclampsia.

Delivery of low-birthweight infantswas associated with maternal SDBamong studies reporting crude ORs(pooled unadjusted OR of 1.39; 95%CI,

can Journal of Obstetrics & Gynecology 52.e10

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TABLE 2Mean AHI in gestational hypertension/preeclampsia vs controls

Study

Mean AHIin cases(events/h)

Mean AHIin controls(events/h) P value Comparison groups

Bachour et al,200818

1 � 0.9 0.2 � 0.5 .02 Preeclampsia vs controls

Blyton et al,200443

19 � 10(no-CPAP group)

9 � 4 NS Preeclamptics vs controls

Champagne et al,200920

38.6 � 36.7 18.2 � 12.2 .005 Gestational hypertensionvs controls

Edwards et al,200023

7.6 � 2.5 4.5 � 1 NS Preeclamptics vs controls

Reid et al,201136

3.1 � 6.2 0.5 � 1.3 .04 Gestational hypertensionvs controls

Yinon et al,200642

18.4 � 8.4 8.3 � 1.3 < .05 Preeclampsia vs controls

All data are presented as mean � SD.

AHI, apnea-hypopnea index; CPAP, continuous positive airway pressure; NS, not significant.



1.14e1.65). Adjusted ORs were avail-able for only 3 of these studies, makingpooling of these estimates inappro-priate. However, each of these studiesdemonstrated a significant relationship

FIGURE 5AHI for gestational hypertension or p

Mean difference in AHI for women with gestation

controls is shown.

AHI, apnea-hypopnea index.

Pamidi. Maternal sleep apnea and adverse pregnancy outcomes

52.e11 American Journal of Obstetrics & Gynecol

between maternal SDB and low infantbirthweight. The analysis of studies thatprovided continuous data revealed thatthe differences in birthweights of in-fants born to women with SDB

reeclampsia

al hypertension or preeclampsia compared with

. Am J Obstet Gynecol 2014.

ogy JANUARY 2014

compared with women without SDBwere too heterogeneous to permitinference.

Biological plausibilityIn nonpregnant populations, SDB hasbeen strongly linked with a variety ofcomplications, including hypertension,type 2 diabetes, and insulin resistance,independent of obesity and other riskfactors.46,47 Consequences of SDB, suchas intermittent hypoxia/reoxygenationand sleep fragmentation, can lead tosympathetic activation, oxidative stress,inflammation, and endothelial dys-function, which are key mechanismsunderlying adverse cardiometabolicoutcomes.46 Although the mechanismslinking SDB to adverse pregnancy out-comes have not yet been fully elucidated,it is highly plausible that SDB may leadto recurrent episodes of placental hyp-oxemia, changes in vascular tone andhemodynamic fluctuations that mayaffect maternal-fetal health. Althoughdata on these mechanisms are generallysparse in the literature on pregnantwomen, a recent study has linked endo-thelial dysfunction with both SDB andpreeclampsia.42 Also, rodent studieshave demonstrated that intermittenthypoxia during pregnancy leads toimpaired fetal growth and low birth-weight.48,49Although causality cannotyet be determined, some preliminaryinterventional studies have demon-strated blood pressure and hemody-namic improvements after treatingwomen with gestational hypertension/preeclampsia with CPAP.43,44,50

LimitationsThere are several important limitationsto this metaanalysis. First, because thepooled effect estimates were derivedfrom observational studies, susceptibil-ity to confounding is a concern. In fact,only some studies presenting effect esti-mates adjusted for potential con-founders, and among those that did,selection of confounding variables varied.Despite this, maternal obesity, a strongconfounder, given its association withboth SDB and adverse pregnancy out-comes, was adjusted for in varying degreesin the 9 studies that reported adjusted

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TABLE 3Mean birthweights in exposed vs nonexposed

Study

Meanbirthweightin exposedgroup, g

Meanbirthweightin nonexposedgroup, g P value Comparison groups

Ayrlm et al,201117

3332 � 102 3473 � 175 NS Snorers vs nonsnorers

Chen et al,201221

3063 � 584 3147 � 418 N/A Diagnostic codes for OSAvs no OSA

Higginset al, 2011,26

median (IQR)

3475 (3155e3780) 3374 (3085e3685) < .01 Positive vs negativeBerlin Questionnaire

Koken et al,200730


Loube et al,19965

3534 � 474 3450 � 652 NS Frequent snorers vsnonsnorers

Louis et al,201031

3013 � 968 3288 � 590 < .001 PSG-confirmed OSAvs obese controls

Micheli et al,201132

3039 � 527.5 3163 � 445.8 N/A Severe snorersvs nonsnorers

Perez-Chadaet al, 200734

3200 � 649 3211 � 606 NS Snorers vs never-snorers

Sahin et al,200838

2947 � 595.5 3383.9 � 394.2 NS PSG-confirmed OSAvs no OSA

Tauman et al,201139


All data are presented as mean � SD unless otherwise specified.

IQR, interquartile range; N/A, not available; NS, not significant; OSA, obstructive sleep apnea; PSG, polysomnogram.



effect estimates for all 3 adverse pregnancyoutcomes. Moreover, despite adjustmentfor BMI, maternal weight, or diagnosis ofobesity, the effect estimates remainedsignificant when compared with crudeORs (Figures 2, B, 3, B, and 4, B).

In addition, all except one21 of the 9studies adjusted for maternal age,another likely confounder in the rela-tionship between maternal SDB andadverse pregnancy outcomes. Othervariables that may potentially be con-founders but that were not routinelyadjusted for were maternal comorbid-ities, preexisting conditions, and smok-ing status. However, the influence ofthese confounders is more uncertain.

Another key limitation is the between-study variability present in definitionsand measurements of SDB, study design,and selection of study population, whichall likely contribute to the heterogeneity

of effect estimates. Among studiesadjusting for confounders, objectivesleep recordings for determining thepresence of SDB were used in only 2studies among those pooled for gesta-tional hypertension/preeclampsia20,21

and in only one of the studies pooledfor the gestational diabetes outcome,21

with most of the remaining studiesdefining SDB according to symptomssuch as snoring.The predictive value of snoring in

pregnant women is uncertain. The Ber-lin Questionnaire, which includes ques-tions on snoring symptoms, was foundto have a sensitivity and specificity forpredicting SDB in pregnancy of only35% and 63.8%, respectively, whencompared with PSG.33 However, evenamong the studies using objective sleeprecordings, traditional PSG scoringcriteria for hypopneas and apneas may

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not be sensitive enough to detect clini-cally relevant SDB that is manifested bymore subtle abnormalities, such asairflow limitation.18,22,44,50 Thus, furtherresearch needs to be done in the field tobetter understand the most sensitive andobjective way of evaluating SDB inpregnancy. For this reason, we believe itis important to include both subjectiveand objective measures of SDB inpregnancy.

The timing of the assessment of theexposure to SDB also varied betweenstudies and ranged from during preg-nancy to after delivery. Nonetheless,despite nondifferential misclassificationof exposure that would be expected toweaken the association between SDB andadverse pregnancy outcomes, we stillfound reasonably strong associationsbetween the following: (1) SDB andgestational hypertension/preeclampsia;(2) SDB and gestational diabetes; and (3)AHI and gestational hypertension.

Notwithstanding these limitations,the adjusted effect estimates for the as-sociation between SDB and both gesta-tional hypertension/preeclampsia andgestational diabetes exceeded 1 across allstudies, with only 1 study reporting aconfidence interval that included thenull (Qiu et al35; Figure 3, B), suggestinga consistently found significant associa-tion. Importantly, the finding that theAHI as measured by objective sleep re-cordings was significantly higher amongwomen with gestational hypertension/preeclampsia compared with controls isconsistent with the pooled effect esti-mates from the studies in whichsymptom-based diagnoses of SDB weremore commonly used.

ConclusionsThis systematic review of the literatureon associations between SDB andadverse pregnancy outcomes demon-strates that despite methodological lim-itations including variation in studydesign, SDB definition, and adjustmentfor confounders, there are significantassociations between SDB and gesta-tional hypertension/preeclampsia andSDB and gestational diabetes. An insuf-ficient number of adjusted studies were


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FIGURE 6Mean difference in infant birthweights in SDB compared with no SDB

Mean difference in infant birthweights born to women with SDB compared with women without SDB

is shown.

SBD, sleep-disordered breathing.



available for low-birthweight infants topermit a pooled estimate.

These findings have important po-tential implications for prenatal care andprovide a strong rationale for furtherinvestigation of the interaction betweenSDB and key pregnancy outcomes. Thiswill require larger observational cohortstudies with rigorous definitions ofobjectively documented SDB as well asrandomized, controlled interventionaltrials to determine the effects of SDBtreatment on pregnancy outcomes. -

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