SNORING DURING PREGNANCY AND DELIVERY OUTCOMES: A COHORT STUDY http://dx.doi.org/10.5665/sleep.3112

Snoring during Pregnancy and Delivery Outcomes: A Cohort Study

Louise M. O’Brien, PhD, MS1,2,4; Alexandra S. Bullough, MBChB, FRCA3; Jocelynn T. Owusu, MPH1; Kimberley A. Tremblay, MS1; Cynthia A. Brincat, MD, PhD4; Mark C. Chames, MD4; John D. Kalbfleisch, PhD5; Ronald D. Chervin, MD, MS1 Sleep Disorders Center, Department of Neurology, 2Department of Oral and Maxillofacial Surgery, 3Department of Anesthesiology, 4Department of Obstetrics and Gynecology, 5Department of Biostatistics, University of Michigan, Ann Arbor, MI 1

Study Objective: This cohort study examined the impact of maternal snoring on key delivery outcomes such as mode of delivery, infant birth centile, and small-for-gestational age. Design: Cohort study. Setting: A large tertiary medical center. Patients or Participants: Pregnant women in their third trimester were recruited between March 2007 and December 2010. Measurements and Results: Women were screened for habitual snoring, as a known marker for sleep disordered breathing. Outcome data were obtained from medical records following delivery and birth centiles were calculated. Of 1,673 women, a total of 35% reported habitual snoring (26% with pregnancy-onset snoring and 9% with chronic snoring). After adjusting for confounders, chronic snoring was associated with small-forgestational age (OR 1.65, 95%CI 1.02-2.66, P = 0.041) and elective cesarean delivery (OR 2.25, 95%CI 1.22-4.18, P = 0.008). Pregnancy-onset snoring was associated with emergency cesarean delivery (OR 1.68, 95%CI 1.22-2.30, P = 0.001). Conclusion: Maternal snoring during pregnancy is a risk factor for adverse delivery outcomes including cesarean delivery and small-for-gestational age. Screening pregnant women for symptoms of SDB may provide an early opportunity to identify women at risk of poor delivery outcomes. Clinical Trials Registration: Identifier: NCT01030003. Keywords: Sleep disordered breathing, small for gestational age, cesarean delivery, cord blood Citation: O’Brien LM; Bullough AS; Owusu JT; Tremblay KA; Brincat CA; Chames MC; Kalbfleisch JD; Chervin RD. Snoring during pregnancy and delivery outcomes: a cohort study. SLEEP 2013;36(11):1625-1632.

INTRODUCTION Emerging data now demonstrate that habitual snoring, as a risk factor for sleep disordered breathing, is particularly common in pregnant women,1,2 likely due to increased weight, edema, and nasal congestion. In cross-sectional studies, habitual snoring has been associated with adverse maternal outcomes such as gestational hypertension and preeclampsia3-7 as well as gestational diabetes.5,8 Of note, in a large longitudinal study, we have recently shown that new-onset snoring during pregnancy, rather than chronic snoring, plays an independent role in the association with gestational hypertension and preeclampsia.9 This suggests that a new insult during pregnancy may be of particular importance to maternal health compared to one where physiologic adaptation may have occurred. Despite increasing evidence to link snoring with adverse maternal outcomes, literature on associations with delivery and fetal outcomes is conflicted. Case reports suggest that maternal SDB is a risk factor for intrauterine growth restriction (IUGR) or small for gestational age (SGA),10-12 and some crosssectional studies support this.3,4 One prospective cohort study found an adjusted relative risk for IUGR of 2.0 ([1.0-3.8).13 Nonetheless, other studies have failed to support these findings.2,5,14-16 However, the potential role of maternal SDB in fetal outcomes is likely complex, since the known consequences of

SDB include both hypertension and metabolic dysregulation, which may have opposing impact on the fetus. Should maternal SDB be implicated in adverse fetal outcomes, the potential public health impact would be immense. Billions of healthcare dollars are spent on operative deliveries, care for preterm infants, and those admitted to the neonatal intensive care unit (NICU). An urgent need exists to understand these potential associations in large longitudinal studies. Therefore, the goal of the current study was to determine whether habitual snoring during the last trimester of pregnancy is associated with adverse delivery outcomes. A secondary aim was to compare effects of pregnancy-onset snoring to that of chronic snoring.

Submitted for publication November, 2012 Submitted in final revised form March, 2013 Accepted for publication March, 2013 Address correspondence to: Louise M. O’Brien, PhD, MS, Michael Aldrich Sleep Disorders Laboratory, C728 Med Inn, Box 5845, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0845; Tel: (734) 647-9064; Fax: (734) 647-9065; E-mail: [email protected]

Habitual Snoring

SLEEP, Vol. 36, No. 11, 2013 1625 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1625/2558938 by guest on 19 February 2018

METHODS Participants Pregnant women were recruited from prenatal clinics within the University of Michigan between March 2007 and December 2010 by trained research assistants, and were eligible if they were ≥ 18 years old and ≥ 28 weeks pregnant with a single fetus. There were no other exclusion criteria. Written informed consent was obtained. This study was approved by the University of Michigan Institutional Review Board. Data Collection Pregnant women were queried about the presence of habitual snoring and whether they had stopped breathing/gasped for air at night. Habitual snoring was defined as snoring either “3-4 times per week” or “almost every day.” Enquiry was made about its timing to identify incident cases. Pregnancy-onset snoring was considered present when habitual snoring began during Maternal Snoring and Delivery Outcomes—O’Brien et al

pregnancy. Chronic snoring was defined as habitual snoring both before and during pregnancy. A question item about snoring was chosen instead of a multi-item SDB questionnaire for several reasons: one question is strongly and reliably associated with the overnight polysomnogram (PSG)-derived apnea-hypopnea index (AHI, number of apneic events per hour of sleep)17,18; in women, a report of “often” or “usually (always or almost always)” snoring is associated with PSG-confirmed SDB with respective odds ratios of 3.8 and 16.317; this provides an approach easily and immediately translated into clinical settings. Similarly, we used one question about self-reported apnea (“stopped breathing or gasped for air”). Women received a $10 gift card for participating. Other Variables

Following delivery, medical records were accessed to ascertain key variables including demographics, height, weight at each visit, total amount of weight gained, gravidity, parity, gestational age at delivery, duration of labor, mode of delivery, infant gender, birth weight, Apgar scores, and any NICU admission. The major study outcomes included infant birth centile, mode of delivery, cord blood gases, and newborn transfer. Customized infant birth centiles were calculated based on the recommendation from Gardosi et al.,19 using the Gestation Related Optimal Weight (GROW) software,20 which optimizes birth centile based on maternal height, maternal weight, ethnic origin, parity, infant gender, gestational age, and birth weight. Such centiles, based on individual fetal growth potential, enhance the ability to differentiate between physiological and pathological smallness21,22 and are able to identify substantially more pregnancies at a risk for adverse outcome than the currently used national standard for fetal growth.23 These centiles represent the optimal growth potential expected under ideal circumstances and are not based on the population average, which includes pregnancies with risk factors for low birth weight, such as smoking.21 Data were also collected on previous or family history of gestational hypertension or preeclampsia, smoking status, a diagnosis of chronic hypertension, gestational hypertension, preeclampsia, or gestational diabetes. The latter diagnoses were obtained from medical coding using the International Classification of Diseases, Ninth Revision (ICD-9) and were cross-checked with careful review of all medical records. In reporting this study, guidelines from Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) group24 were followed. Statistics Sample size was calculated based on available literature at the time of study design. We predicted that the frequency of snoring would be 25%,1-3 and approximately 2% of women without snoring would deliver an SGA infant, compared to an estimated 8% of infants born to snoring women.3 A sample size ≥ 1,400 pregnant women would have power of ~99% to detect this difference with a 2-tailed significance level of 5%. With this sample size, we would retain 82% power to detect a difference even if the proportion of SGA infants increased to 3% in non-snoring women and decreased to 7% of snoring women. As BMI is strongly associated with SDB, and BMI changes across pregnancy, pre-pregnancy or early first trimester BMI was categorized according to Institute of Medicine (IOM) recommendations.25 Subjects were classified as underweight SLEEP, Vol. 36, No. 11, 2013 1626 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1625/2558938 by guest on 19 February 2018

(BMI < 18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), or obese (BMI ≥ 30.0 kg/ m2). Absolute weight gain was determined, and subjects were classified according to whether they exceeded the IOM recommendations for gestational weight gain; 28-40 lb for underweight women, 25-35 lb for normal weight women, 15-25 lb for overweight women, and 11-20 lb for obese women. All data obtained were double-entered into a database and analyzed with SPSS (version 19.0, IBM). Histograms, boxplots, and descriptive methods were used to examine data for errors and outliers. Between-group comparisons of continuous variables (maternal age, BMI, and gestational age, birth centile) were conducted with t-tests (snoring vs no snoring) and ANOVA (chronic snoring, pregnancy-onset snoring, and no snoring). Dichotomized variables were compared with χ2 tests. Logistic regression was used to determine associations between snoring and delivery/infant outcomes after adjusting for potential covariates where appropriate (including maternal age, race, pre-pregnancy BMI, weight gain in excess of IOM recommendations, gravidity, smoking, educational level, previous or family history of gestational hypertension/preeclampsia, previous cesarean delivery). Odds ratios (OR) and 95% confidence intervals (CI) were calculated. A p-value < 0.05 was considered statistically significant. RESULTS Of the 2,038 pregnant women invited to participate, 1,689 (83%) consented. There were no statistically significant differences in maternal age, gestational age, parity, or BMI between women who did or did not participate. Five women were subsequently excluded because they were < 28 weeks’ gestation, and 2 women were excluded because they were < 18 years. In addition, 9 women delivered at another hospital, so no delivery records were available. Thus, the total sample of women who provided data for analysis was 1,673. Table 1 shows the demographics of the sample. The vast majority of women had bed partners (94%), and only 2% of partners complained about snoring when women reported nonsnoring. Since this did not alter any findings, all analyses were performed with maternal self-report of snoring. Overall, 35% of women reported snoring; 65% were non-snorers at both pre-pregnancy and in the 3rd trimester; 26% started snoring during pregnancy; and 9% reported chronic snoring (before and during pregnancy). Chronic snorers had higher pre-pregnancy BMI compared to both pregnancy-onset and non-snorers (31.7 ± 8.9 kg/m2 vs 28.3 ± 7.6 kg/m2 vs 25.0 kg/m2, respectively, P < 0.001) as well as a higher 3rd trimester BMI (35.4 ± 8.2 kg/ m2 vs 33.4 ± 7.2 kg/m2 vs 29.8 ± 6.1 kg/m2, P < 0.001). Delivery and infant outcomes for each snoring group are shown in Table 2. Duration of labor was not included in the analyses because the majority of first stage of labor durations were not recorded (81.7%); therefore, we could not confirm the true time of labor onset. Delivery Outcomes Infant Birth Centiles

The mean birth centile for each snoring group is shown in Figure 1. Overall, 12.5% of infants were born < 10th centile and Maternal Snoring and Delivery Outcomes—O’Brien et al

Table 1—Demographic data for the whole sample

Age, years

Pregnant Women (n = 1,673) 29.8 ± 5.8

Baseline BMI, kg/m2

26.5 ± 7.2

3rd trimester BMI, kg/m2

31.3 ± 7.0

Racial Background, % Caucasian African American Asian Multi-racial/Other

70.9 14.7 7.3 7.2

Educational Level, % < 12th grade ≥ 12th grade Some college 4-year college Postgraduate

8.0 20.7 22.0 38.4 10.9

Gestational Age at Enrollment, weeks

34.2 ± 3.7

Nulliparous, %

44.2

Gestational Hypertension, %

6.4

Figure 1—Mean birth centiles: snoring group. Mean birth centiles for infants of non-snoring, pregnancy-onset snoring, and chronic snoring women.

13.1% were born ≥ 90th centile. Table 2 shows the proportions of SGA and large-for-gestational-age (LGA) infants in each snoring group. For each snoring group, Figures 2A-C illustrate the proportion of infants born in each 10th-centile bin. Of note, in non-snoring women the distribution of the birth centiles demonstrates an almost equal distribution, with small peaks at either extreme, i.e., SGA and LGA infants (Figure 2A). In contrast, the infants born to chronic snoring women tended to cluster around the lower centiles, and there were significantly more infants < 10th centile (P = 0.027, Figure 2C). There was more variability in birth centile in infants born to women with pregnancy-onset snoring, although there were no significant differences in the distribution compared to the non-snoring women (Figure 2B). In unadjusted analyses, chronic snoring was associated with < 10th birth centile (OR 1.73, 95%CI 1.09-2.74, P = 0.02) but pregnancy-onset snoring was not. A logistic regression model that controlled for presence of preeclampsia and maternal smoking (but not maternal factors that had already been accounted for in the customized birth centile calculations) found an independent association between chronic snoring and < 10th birth centile (OR 1.65, 95%CI 1.02-2.66, P = 0.041).

of dilation, arrest of descent, failure of descent, n = 126; 38.8%), fetal heart rate concerns/intolerance of labor (n = 124; 38.2%), failed induction (n = 20; 6.2%), maternal conditions (n = 11; 3.4%), unsuccessful vaginal birth after cesarean, n = 6; 1.8%), severe preeclampsia (n = 5; 1.5%), placental conditions (n = 3; 0.9%), cephalopelvic disproportion (n = 2; 0.6%), and other, not defined (n = 28; 8.6%). Indications for elective cesarean included the following: previous cesarean section (n = 181; 59.3%), breech position/fetal malpresentation (n = 49; 16.1%), maternal condition (n = 19; 6.2%), fetal macrosomia (n = 8; 2.6%), placenta previa/vasa previa (n = 7; 2.3%), fetal anomaly (n = 6; 2.0%), fetal heart rate concerns (n = 5; 1.6%), maternal request (n = 1; 0.3%), other, not defined (n = 29; 9.5%). Both chronic and pregnancy-onset snoring were associated with elective cesarean delivery in unadjusted analyses (OR 2.00, 95%CI 1.33-3.04, P = 0.001 and OR 1.43, 95%CI 1.06-1.92, P = 0.021, respectively), whereas only pregnancy-onset snoring was associated with emergency cesarean delivery (OR 1.66, 95%CI 1.25-2.20, P < 0.001). In a logistic regression model that controlled for potential covariates (those not included in the customized birth centile calculations) such as maternal education level, presence of preeclampsia, presence of gestational diabetes, previous cesarean delivery, and birth centile, both chronic and pregnancy-onset snoring remained independently associated with elective cesarean delivery (OR 2.25, 95%CI 1.22-4.18, P = 0.006, and OR 1.70, 95%CI 1.13-2.57, P = 0.012, respectively). In a separate logistic regression model that controlled for maternal education level, presence of preeclampsia, presence of gestational diabetes, birth centile, and induction of labor, pregnancy-onset snoring remained independently associated with emergency cesarean delivery (OR 1.68, 95%CI 1.222.30, P = 0.001).

Mode of Delivery

Cord Blood Gases

Preeclampsia, %

10.0

Diabetes Mellitus, %

14.9

Gestational Diabetes, %

17.0

Smoker, %

12.6

Habitual Snoring, %

35.0

Data shown as mean ± standard deviation, or proportion as appropriate. BMI, body mass index.

Overall, 19.4% of women had an emergency cesarean delivery and 18.2% had an elective cesarean delivery. Indications for emergency cesarean included: arrest disorders (arrest SLEEP, Vol. 36, No. 11, 2013 1627 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1625/2558938 by guest on 19 February 2018

Cord blood gas values by maternal snoring group are provided in Table 2. Significantly more infants born to women with pregnancy-onset snoring, compared to non-snoring women, had Maternal Snoring and Delivery Outcomes—O’Brien et al

Table 2—Comparison of pregnancy outcomes in women with and without habitual snoring

Anesthesia, % None Morphine Epidural Spinal Epidural/spinal combination General anesthesia

Snoring (n = 586)

Chronic Snoring (n = 151)

Pregnancy-Onset Snoring (n = 435)

Non-Snoring (n = 1,087)

8.9* 0 70.0* 17.3 2.0 1.8

10.9 0 69.4 15.0 1.4 3.4

8.2** 0 70.3* 18.1 2.2 1.2

15.4 0.7 64.1 15.5 2.2 2.2

Induced labor, %

39.3

42.6§

38.1

34.6

Mode of delivery, % Vaginal Elective C/S Emergency C/S

55.3*** 21.7** 23.0**

53.7** 26.8** 19.5

55.9*** 19.9 24.2**

66.1 16.4 17.5

Gestational age at delivery, days < 37 weeks’ gestation

271.1 ± 14.6 15.5

270.0 ± 14.2 17.4

271.5 ± 14.5 14.8 7.25 ± 0.07***

272.1 ± 14.4 13.0

Umbilical artery pH

7.26 ± 0.07

7.26 ± 0.06

Umbilical artery PO2

15.42 ± 9.44*

15.27 ± 7.14*

15.50 ± 10.18*

17.22 ± 13.29

7.27 ± 0.07

Umbilical artery PCO2

57.65 ± 11.03**

58.39 ± 10.12**

57.35 ± 11.35*

55.77 ± 10.05

Umbilical vein pH

7.36 ± 0.77

7.33 ± 0.06

7.37 ± 0.91

7.33 ± 0.11

Umbilical vein PO2

25.20 ± 7.63*

25.60 ± 7.16*

25.04 ± 7.79**

26.14 ± 7.32

Umbilical vein PCO2

45.05 ± 8.20**

44.98 ± 7.62**

45.08 ± 8.41**

43.90 ± 7.62

Birth weight, g < 10th birth centile, % ≥ 90th birth centile, % Male, % 1-minute Apgar 1-minute Apgar < 7, %

3291.0 ± 649.5 13.6 13.2 50.4 7.5 ± 1.9 19.4*

3240.5 ± 588.6 19.9* 10.3 46.3 7.4 ± 1.9 19.7*

3313.5 ± 672.2 14.0 14.3 51.8 7.5 ± 2.0 20.0*

3276.1 ± 609.3 12.5 13.1 51.9 7.6 ± 1.9 15.6

5-minute Apgar

8.6 ± 1.1

8.6 ± 1.2

8.7 ± 1.0

8.7 ± 0.9

5-minute Apgar < 7, %

4.0

4.9

3.7

3.2

Data shown as mean ± standard deviation, or proportion as appropriate. *P < 0.05, **P < 0.01, ***P < 0.001 for comparisons with non-snoring controls. § P = 0.08 for comparisons with non-snoring controls.

Figure 2—Distribution of birth centiles from non-snoring women. Distribution of birth centiles in 10-centile bins of infants born to women with no snoring (A); pregnancy-onset snoring (B), and chronic snoring (C). SLEEP, Vol. 36, No. 11, 2013 1628 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1625/2558938 by guest on 19 February 2018

Maternal Snoring and Delivery Outcomes—O’Brien et al

Table 3—Reasons for newborn transfer PregnancyNon-Snoring Onset Snoring (n = 1,087) (n = 435) Clinician discretion 0.3% 0.8% Fetal anomaly 3.4% 2.3% Evaluation and echo 0.1% – Gestation < 37 weeks 5.2% 7.8% Resuscitation 0.9% 0.8% Observation 2.2% 2.5% Respiratory status 0.9% 0.5% Low Apgar 0.1% 0.3% Sepsis workup 4.5% 6.3% Meconium aspiration 0.1% – Polycystic kidney 0.1% – Required oxygen – 0.5% Gastroschisis – 0.3% Hypoplastic left heart – – syndrome

Chronic Snoring (n = 151) – 4.0% – 7.7% 1.4% 4.9% 1.4% – 3.5% – – 1.4% – 0.7%

umbilical arterial pH values < 7.20 (18.0% vs 11.9% P = 0.015). Infants of chronic snorers were no more likely to have arterial pH values < 7.20 compared to either non-snorers or pregnancyonset snorers (10.8% vs 11.9%, P = 0.82 and 10.8% vs 18.0%, P = 0.11, respectively). The number of infants who were classified as having metabolic acidosis, defined as umbilical arterial pH < 7.00 and base deficit ≥ 12.0 mmol/L,26 was n = 2; therefore, no further analysis could be conducted. Newborn Transfer Following delivery, 19.3% of infants were taken to the treatment room, triage, or admitted to the NICU. By maternal snoring status this comprised 17.9% of infants born to nonsnoring women, 21.1% of infants of pregnancy-onset snorers, and 24.6% of infants of chronic snorers. The proportion of transferred infants born to chronic snorers compared to nonsnorers did not quite reach statistical significance (P = 0.06). The indications for transfer are given in Table 3. Overall, 8.6% of infants were admitted to the NICU. By maternal snoring group, 8.3% of infants born to non-snoring women, 8.4% of infants born to pregnancy-onset snorers, and 11.3% of infants born to chronic snorers were admitted to the NICU. Although a greater proportion of infants of chronic snorers were admitted to the NICU compared to both other groups, this did not reach statistical significance (P = 0.30). “Stopped Breathing/Gasped for Air” (Self-Reported Apnea) In total 3.1% of women reported that they had stopped breathing/gasped for air at night. Interestingly, infants of women who reported apnea were more likely than others to have a larger mean birth centile (61.2 vs 48.5, P < 0.001; Figure 3) and be born ≥ 90th centile (22.4% vs 12.8%, P = 0.049). Figures 4A-B illustrate the distribution of birth centiles for infants born to selfreported non-apneic and apneic women. Notably, women with reported apnea were more likely than others to have diabetes mellitus (26.9% vs 14.2%, P = 0.016). However, in unadjusted SLEEP, Vol. 36, No. 11, 2013 1629 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1625/2558938 by guest on 19 February 2018

Figure 3—Mean birth centiles; apnea. Mean birth centiles for infants of women with and without reported apnea.

logistic regression analyses, self-reported apnea was not associated with infants ≥ 90th birth centile (OR 1.6, 95%CI 0.7-3.9, P = 0.29). Similarly, in a logistic regression that adjusted for diabetes mellitus, gestational diabetes, and maternal smoking (but not variables included in the customized birth centile calculation), only diabetes mellitus was an independent predictor of infants ≥ 90th centile (OR 4.6, 95%CI 2.3-9.1, P < 0.001) with smoking demonstrating an inverse relationship (OR 0.3, 95%CI 0.1-0.7, P = 0.008). Furthermore, infants of self-reported apneic women were more likely than non-apneic women to have 1-min Apgar scores < 7 (35.3% vs 16.7%, P = 0.002), although there was no difference in the proportion of infants who had 5-min Apgar scores < 7 (4.0% vs 3.6%, P = 0.89). However, the absolute number of infants in the maternal apnea group was too small to conduct meaningful logistic regression. DISCUSSION These novel findings, from the largest prospective study to date designed to investigate delivery outcomes in pregnant women with habitual snoring, show that snoring—and in particular chronic snoring—is independently associated with SGA as well as cesarean delivery. Previously we have shown that new-onset maternal snoring during pregnancy is associated with gestational hypertension and preeclampsia.9 By contrast, it is chronic maternal snoring that is associated with SGA even after accounting for other known risk factors. These data may help address conflicting findings in the literature regarding fetal effects of maternal SDB, since none of the previously reported studies on pregnancy outcomes differentiated between chronic and new-onset symptoms.2-5,13,27 The findings of an increased frequency of SGA in women with chronic snoring may at first appear counterintuitive, since the chronic snorers had the highest BMI. Both overweight and obesity are reported risk factors for LGA infants,28,29 likely related to gestational diabetes.30 Indeed, a population-based cohort of 167,750 women in Sweden reported that higher pre-pregnancy maternal weight was a protective factor against SGA.31 Maternal Snoring and Delivery Outcomes—O’Brien et al

Figure 4—Distribution of birth centiles from non-apneic women. Distribution of birth centiles in 10-centile bins of infants born to pregnant women without reported apnea (A) and with reported apnea (B).

However, SGA infants are so-defined against a population standard, which clearly includes physiological variation in size as well as pathological variables that will affect size, such as maternal smoking, hypertension, and diabetes. This generic standard fails to address the growth potential of the fetus in the absence of pathological factors. Use of customized birth centiles in recent years has called into question the association between high maternal BMI and macrosomic infants.22 Customized birth weight centiles have been shown in multiple studies around the world to be superior to population-based standards for studies of the association with pregnancy complications, as well as outcomes including SGA, stillbirth, and perinatal death.22,32,33,23,34-36 Of note, large studies now demonstrate that high maternal BMI is associated with a higher risk for SGA based on customized birth centiles.19,22 These obese women have a higher perinatal mortality rate, which is associated with a higher proportion of SGA identified using the customized centile method but not the standard population centile method.22 Moreover, an additional 49% of mothers with elevated perinatal mortality risk were identified using the customized centile method compared to the standard population centile method.22 Our current findings, therefore, suggest that habitual snoring, as a pathological maternal variable, may affect fetal growth and infant birth weight. Potential mechanisms relating maternal sleep and poor pregnancy outcomes may include inflammatory cascades and placental dysfunction. Inflammation, oxidative stress, and endothelial dysfunction are all implicated not only in SDB37 but also in adverse pregnancy outcomes.38,39 A recent hypothesis paper40 postulated that disturbed sleep during early pregnancy—as likely occurs in chronic snorers—contributes to an increased inflammatory response that may disrupt the normal remodeling of maternal blood vessels that perfuse the placenta. Uteroplacental hypoperfusion, with consequent compromised placental blood flow to the fetus, could ensue,41 leading to a higher risk of SGA. SLEEP, Vol. 36, No. 11, 2013 1630 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1625/2558938 by guest on 19 February 2018

Another novel finding from this cohort is that habitual snoring was associated with SGA infants, while reported apnea was associated with LGA infants. However, regression models demonstrated that only maternal diabetes, and not maternal apnea, was independently associated with LGA infants. One possible mechanism could be the impact of diabetic insults on placental development,42 whereby the duration or extent of hyperglycemia, hyperinsulinemia, or dyslipidemia exceeds the capacity of the placenta to maintain a buffer response and excess fetal growth occurs. No previous study has reported associations between maternal SDB and cord blood gases. Umbilical cord pH at delivery is a crucial measure of intrapartum fetal monitoring for the identification and prevention of fetal acidemia. A recent meta-analysis demonstrated that low arterial cord pH showed strong and consistent associations with clinically relevant adverse neonatal outcomes such as intraventricular hemorrhage, seizures, hypoxic-ischemic encephalopathy, cerebral palsy, and mortality.43 Current findings that more infants of mothers with pregnancy-onset snoring had umbilical arterial pH values < 7.20 merits further investigation in large epidemiological samples. Our sample size was too small to investigate a pH < 7.0, which is the consensus threshold for ascribing cerebral palsy to intrapartum hypoxia.26 Sleep deprivation and fatigue have been reported to increase the incidence of cesarean delivery,44-46 although none of these studies reported maternal snoring. One retrospective study of 57 women with obstructive sleep apnea diagnosed prior to pregnancy found that they were at higher risk of cesarean delivery.4 A newly published prospective study from the same group found that risk for cesarean delivery among obese women was higher in those with obstructive sleep apnea.47 Our finding that maternal snoring increased the incidence of both elective and emergency cesarean deliveries, after adjustment for other known risk factors, is novel. Furthermore, Maternal Snoring and Delivery Outcomes—O’Brien et al

while pregnancy-onset snoring increased the risk for cesarean delivery in general, chronic snoring was associated only with elective delivery. One possible reason for the latter association is that there may be a low threshold for elective delivery in growth restricted fetuses48 in order to avoid added stresses on an already compromised fetus. However, there were multiple reasons for elective delivery and thus any associations remain speculative. With respect to emergency delivery, it is plausible that poor sleep may lead to physiologic changes that might be predictive of dysfunctional labor.44,45 Indeed, SDB is associated with fatigue, which could result in maternal exhaustion with subsequent prolongation of labor and operative delivery. The increased incidence of newborn transfer (to triage, treatment room, or the NICU) in infants of chronic snorers has not been previously reported. The reasons for transfer were varied and the proportion of infants transferred for any given indication was small, precluding meaningful analysis. However, there was no significant difference in the proportion of infants who were admitted to the NICU between snoring groups. Nonetheless, it is noteworthy that a larger proportion of infants of snoring women were born < 37 weeks, despite this not being statistically significant. However, we are unable to address reports that maternal SDB may be related to preterm delivery4 since this study was designed to recruit third-trimester women only, and a large proportion had reached 37 weeks at recruitment. Future longitudinal studies of sleep across pregnancy are required to address the public health issue of preterm delivery. This study has a number of strengths including a large, well-characterized sample size from a tertiary referral center, prospective design, high response rate, and use of customized birth centiles. Nonetheless, a weakness is the lack of objective measures of SDB. However, the overall goal of the study was to determine whether report of snoring is a predictor of infant outcome, since objective measures of SDB are not readily available in an obstetric setting and are labor-intensive and expensive. Furthermore, self-report of snoring has been strongly and reliably associated with objective measures of SDB in general17 and more specifically in a pregnant population.49 Without objective measures, however, we cannot determine the severity of underlying SDB. An additional limitation is the potential for recall bias when women were asked about snoring prior to pregnancy. However, our data are remarkably similar to reports from non-pregnant women or those during early pregnancy,8,9,50 which suggests that recall bias is likely minimal. Data obtained from ICD-9 coding may be considered a limitation since these codes are used primarily for billing purposes. However, all records were individually reviewed to ensure that no pertinent information was missed, so we do not believe that the integrity of our data has been compromised. While the sample demographics reflect that of the local Ann Arbor area, it is possible that our findings may not be generalizable to other health systems. In summary, maternal snoring during pregnancy, particularly chronic snoring that began prior to pregnancy, is independently associated with adverse delivery outcomes. A simple screen for symptoms of SDB at obstetric visits may have clinical utility in helping to predict and perhaps lower the prevalence of cesarean delivery and SGA. Potential effects of SDB severity and therapeutic intervention during pregnancy on infant outcomes clearly merit further research. SLEEP, Vol. 36, No. 11, 2013 1631 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1625/2558938 by guest on 19 February 2018

ACKNOWLEDGMENTS The authors thank the pregnant women who participated in this study; the medical, nursing, and clinic staff who supported this study; Ken Piehl for assistance with data extraction; and we are indebted to research assistants Fatema Arastu, BA, Sierra Casper, BA, Meghan Hewlett, BA, Meredith Hall, PA-C, MD, and to Lori A. Kempf, BA, CCRP, research coordinator, at the University of Michigan for dedicated assistance with subject recruitment. DISCLOSURE STATEMENT This was not an industry supported study. This project was supported by the Gene and Tubie Gilmore Fund for Sleep Research, the University of Michigan Institute for Clinical and Health Research (MICHR) grant UL1RR024986, MICHR seed pilot grant F021024, and the National Heart, Lung, and Blood Institute (R21 HL089918). Dr. O’Brien was also supported by a career grant from the National Heart, Lung, and Blood Institute (K23 HL095739) and in part by R21 HL087819. Dr. O’Brien has received equipment support from Philips Respironics Inc. and is an advisory board member for the non-profit Star Legacy Foundation. Dr. Chames participates in a study that receives equipment from Cura Surgical. Dr. Chervin receives educational grants from Philips Respironics Inc., Fisher Paykel Inc., receives honoraria as section editor for UpToDate, receives fees for technology licensed by Zansors Inc., is an advisory board member for the non-profit Sweet Dreamzzz Inc., is named in patents owned by the University of Michigan for signal analysis diagnostic algorithms and hardware relevant to the assessment and treatment of sleep disorders, and serves on the Board of Directors of the American Academy of Sleep Medicine, American Board of Sleep Medicine, American Sleep Medicine Foundation, and the International Pediatric Sleep Association. The other authors have indicated no financial conflicts of interest. REFERENCES

1. Izci B, Martin SE, Dundas KC, Liston WA, Calder AA, Douglas NJ. Sleep complaints: snoring and daytime sleepiness in pregnant and pre-eclamptic women. Sleep Med 2005;6:163-9. 2. Loube DI, Poceta JS, Morales MC, Peacock MD, Mitler MM. Selfreported snoring in pregnancy. Association with fetal outcome. Chest 1996;109:885-9. 3. Franklin KA, Holmgren PA, Jonsson F, Poromaa N, Stenlund H, Svanborg E. Snoring, pregnancy-induced hypertension, and growth retardation of the fetus. Chest 2000;117:137-41. 4. Louis JM, Auckley D, Sokol RJ, Mercer BM. Maternal and neonatal morbidities associated with obstructive sleep apnea complicating pregnancy. Am J Obstet Gynecol 2010;202:261 e261-5. 5. Bourjeily G, Raker CA, Chalhoub M, Miller MA. Pregnancy and fetal outcomes of symptoms of sleep-disordered breathing. Eur Respir J 2010;36:849-55. 6. Perez-Chada D, Videla AJ, O’Flaherty ME, et al. Snoring, witnessed sleep apnoeas and pregnancy-induced hypertension. Acta Obstet Gynecol Scand 2007;86:788-92. 7. Ursavas A, Karadag M, Nalci N, Ercan I, Gozu RO. Self-reported snoring, maternal obesity and neck circumference as risk factors for pregnancyinduced hypertension and preeclampsia. Respiration 2008;76:33-9. 8. Facco FL, Grobman WA, Kramer J, Ho KH, Zee PC. Self-reported short sleep duration and frequent snoring in pregnancy: impact on glucose metabolism. Am J Obstet Gynecol 2010;203:142 e141-5. 9. O’Brien LM, Bullough AS, Owusu JT, et al. Pregnancy-onset habitual snoring, gestational hypertension, and pre-eclampsia: prospective cohort study. Am J Obstet Gynecol 2012;207:e1-9

Maternal Snoring and Delivery Outcomes—O’Brien et al

10. Schoenfeld A, Ovadia Y, Neri A, Freedman S. Obstructive sleep apnea (OSA)-implications in maternal-fetal medicine. A hypothesis. Med Hypotheses 1989;30:51-4. 11. Roush SF, Bell L. Obstructive sleep apnea in pregnancy. J Am Board Fam Pract 2004;17:292-4. 12. Charbonneau M, Falcone T, Cosio MG, Levy RD. Obstructive sleep apnea during pregnancy. Therapy and implications for fetal health. Am Rev Respir Dis 1991;144:461-3. 13. Micheli K, Komninos I, Bagkeris E, et al. Sleep patterns in late pregnancy and risk of preterm birth and fetal growth restriction. Epidemiology 2011;22:738-44. 14. Hedman C, Pohjasvaara T, Tolonen U, Suhonen-Malm AS, Myllyla VV. Effects of pregnancy on mothers’ sleep. Sleep Med 2002;3:37-42. 15. Tauman R, Sivan Y, Katsav S, Greenfeld M, Many A. Maternal snoring during pregnancy is not associated with fetal growth restriction. J Matern Fetal Neonatal Med 2012;25:1283-6. 16. Ayrim A, Keskin EA, Ozol D, Onaran Y, Yiidirim Z, Kafali H. Influence of self-reported snoring and witnessed sleep apnea on gestational hypertension and fetal outcome in pregnancy. Arch Gynecol Obstet 2011;283:195-9. 17. Bliwise DL, Nekich JC, Dement WC. Relative validity of self-reported snoring as a symptom of sleep apnea in a sleep clinic population. Chest 1991;99:600-8. 18. Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000;283:1829-36. 19. Gardosi J, Francis A. A customized standard to assess fetal growth in a US population. Am J Obstetr Gynecol 2009;201:25 e21-7. 20. Customised Weight Centile Calculator - GROW-Centile v.5.12/6.2. Gestation Network; 2009. http://www.gestation.net. 21. Gardosi J, Figueras F, Clausson B, Francis A. The customised growth potential: an international research tool to study the epidemiology of fetal growth. Paediatr Perinat Epidemiol 2011;25:2-10. 22. Gardosi J, Clausson B, Francis A. The value of customised centiles in assessing perinatal mortality risk associated with parity and maternal size. BJOG 2009;116:1356-63. 23. Odibo AO, Francis A, Cahill AG, Macones GA, Crane JP, Gardosi J. Association between pregnancy complications and small-for-gestationalage birth weight defined by customized fetal growth standard versus a population-based standard. J Matern Fetal Neonatal Med 2011;24:411-7. 24. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007;370:1453-7. 25. Rasmussen KM, Yaktine AL, eds. Committee to Reexamine IOM Pregnancy Weight Guidelines, Food and Nutrition Board, Board on Children, Youth and Families, Institute of Medicine, National Research Council. Weight Gain During Pregnancy: Reexamining the Guidelines. Washington, DC: The National Academies Press; 2009. 26. MacLennan A. A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999;319:1054-9. 27. Facco FL, Kramer J, Ho KH, Zee PC, Grobman WA. Sleep disturbances in pregnancy. Obstet Gynecol 2010;115:77-83. 28. Driul L, Cacciaguerra G, Citossi A, Martina MD, Peressini L, Marchesoni D. Prepregnancy body mass index and adverse pregnancy outcomes. Arch Gynecol Obstetr 2008;278:23-6. 29. Khashan AS, Kenny LC. The effects of maternal body mass index on pregnancy outcome. Eur J Epidemiol 2009;24:697-705.

SLEEP, Vol. 36, No. 11, 2013 1632 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1625/2558938 by guest on 19 February 2018

30. Fadl HE, Ostlund IK, Magnuson AF, Hanson US. Maternal and neonatal outcomes and time trends of gestational diabetes mellitus in Sweden from 1991 to 2003. Diabet Med 2010;27:436-41. 31. Cnattingius S, Bergstrom R, Lipworth L, Kramer MS. Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 1998;338:147-52. 32. Clausson B, Gardosi J, Francis A, Cnattingius S. Perinatal outcome in SGA births defined by customised versus population-based birthweight standards. BJOG 2001;108:830-4. 33. Figueras F, Figueras J, Meler E, et al. Customised birthweight standards accurately predict perinatal morbidity. Arch Dis Child Fetal Neonatal Ed 2007;92:F277-280. 34. McCowan LM, Harding JE, Stewart AW. Customized birthweight centiles predict SGA pregnancies with perinatal morbidity. BJOG 2005;112:1026-33. 35. Mongelli M, Figueras F, Francis A, Gardosi J. A customized birthweight centile calculator developed for an Australian population. Aust N Z J Obstet Gynaecol 2007;47:128-31. 36. Zhang X, Platt RW, Cnattingius S, Joseph KS, Kramer MS. The use of customised versus population-based birthweight standards in predicting perinatal mortality. BJOG 2007;114:474-7. 37. Lavie L. Oxidative stress inflammation and endothelial dysfunction in obstructive sleep apnea. Front Biosci (Elite Ed) 2012;4:1391-403. 38. Pennington KA, Schlitt JM, Jackson DL, Schulz LC, Schust DJ. Preeclampsia: multiple approaches for a multifactorial disease. Dis Model Mech 2012;5:9-18. 39. Gargano JW, Holzman C, Senagore P, et al. Mid-pregnancy circulating cytokine levels, histologic chorioamnionitis and spontaneous preterm birth. J Reprod Immunol 2008;79:100-10. 40. Okun ML, Roberts JM, Marsland AL, Hall M. How disturbed sleep may be a risk factor for adverse pregnancy outcomes. Obstet Gynecol Surv 2009;64:273-80. 41. Edwards N, Sullivan CE. Sleep-disordered breathing in pregnancy. Sleep Med Clin 2008;3:81-95. 42. Desoye G, Hauguel-de Mouzon S. The human placenta in gestational diabetes mellitus. The insulin and cytokine network. Diabetes Care 2007;30 Suppl 2:S120-6. 43. Malin GL, Morris RK, Khan KS. Strength of association between umbilical cord pH and perinatal and long term outcomes: systematic review and meta-analysis. BMJ 2010;340:c1471. 44. Lee KA, Gay CL. Sleep in late pregnancy predicts length of labor and type of delivery. Am J Obstet Gynecol 2004;191:2041-6. 45. Chien LY, Ko YL. Fatigue during pregnancy predicts caesarean deliveries. J Adv Nurs 2004;45:487-94. 46. Wangel AM, Molin J, Ostman M, Jernstrom H. Emergency cesarean sections can be predicted by markers for stress, worry and sleep disturbances in first-time mothers. Acta Obstetr Gynecolog Scand 2011;90:238-44. 47. Louis JM, Auckley D, Miladinovic B, et al. Perinatal outcomes associated with obstructive sleep apnea in obese pregnant women. Obstet Gynecol 2012;120:1085-92. 48. Mari G, Hanif F. Intrauterine growth restriction: how to manage and when to deliver. Clin Obstet Gynecol 2007;50:497-509. 49. O’Brien LM, Bullough AS, Hewlett MM, et al. Associations between habitual snoring and PSG-defined SDB in pregnant women. Sleep 2011;34(Abstract Supplement):A320. 50. Pien GW, Fife D, Pack AI, Nkwuo JE, Schwab RJ. Changes in symptoms of sleep-disordered breathing during pregnancy. Sleep 2005;28:1299-305.

Maternal Snoring and Delivery Outcomes—O’Brien et al