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Adverse infant outcomes among women with sleep apnea or insomnia during pregnancy: A retrospective cohort study

  • Jennifer N. Felder
    Correspondence
    Corresponding author: Jennifer N. Felder, PhD, Osher Center for Integrative Health, University of California, San Francisco, UCSF Box 1726, San Francisco, CA 94143, USA
    Affiliations
    Osher Center for Integrative Health, University of California, San Francisco, San Francisco, California, USA

    Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, California, USA
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  • Rebecca J. Baer
    Affiliations
    Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, California, USA

    UCSF California Preterm Birth Initiative, University of California, San Francisco, San Francisco, California, USA

    Department of Pediatrics, University of California, San Diego, San Diego, California, USA
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  • Larry Rand
    Affiliations
    Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, California, USA

    UCSF California Preterm Birth Initiative, University of California, San Francisco, San Francisco, California, USA
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  • Kelli K. Ryckman
    Affiliations
    Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa, USA
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  • Laura Jelliffe-Pawlowski
    Affiliations
    UCSF California Preterm Birth Initiative, University of California, San Francisco, San Francisco, California, USA

    Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, California, USA
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  • Aric A. Prather
    Affiliations
    Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, California, USA

    Center for Health and Community, University of California, San Francisco, San Francisco, California, USA
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Open AccessPublished:November 10, 2022DOI:https://doi.org/10.1016/j.sleh.2022.09.012

      Abstract

      Objective

      To evaluate whether sleep apnea or insomnia among pregnant people is associated with increased risk for adverse infant outcomes.

      Design

      Retrospective cohort study

      Setting

      California

      Participants

      The sample included singleton live births. Sleep apnea and insomnia were defined based on ICD-9 and -10 codes. A referent group was selected using exact propensity score matching on maternal characteristics, obstetric factors, and infant factors among individuals without a sleep disorder.

      Measurements

      Adverse infant outcomes were obtained from birth certificate, hospital discharge, and death records (eg, Apgar scores, neonatal intensive care unit (NICU) stay, infant death, long birth stay, etc.). Logistic regression was used to calculate odds of an adverse infant outcome by sleep disorder type.

      Results

      Propensity-score matched controls were identified for 69.9% of the 3371 sleep apnea cases and 68.8% of the 3213 insomnia cases. Compared to the propensity-matched referent group, individuals with a diagnosis of sleep apnea (n = 2357) had infants who were more likely to have any adverse outcome, low 1-min Apgar scores, NICU stay, and an emergency room visit in the first year of life. Infants born to mothers with a diagnosis of insomnia (n = 2212) were at increased risk of few negative outcomes relative to the propensity matched referent group, with the exception of an emergency room visit.

      Conclusions

      In unadjusted analyses, infants born to individuals with a diagnosis of sleep apnea or insomnia were at increased risk of several adverse outcomes. These were attenuated when using propensity score matching, suggesting these associations were driven by other comorbidities.

      Keywords

      Introduction

      Sleep disturbance is common among pregnant people, with nearly half experiencing poor sleep quality.
      • Sedov ID
      • Cameron EE
      • Madigan S
      • Tomfohr-Madsen LM.
      Sleep quality during pregnancy: a meta-analysis.
      More concerning is that a sizeable subset of pregnant people experience more severe and impairing presentations warranting a sleep disorder diagnosis. For example, meta-analytic findings show that sleep apnea occurs in 15% of pregnant people
      • Liu LN
      • Su G
      • Wang SL
      • Zhu BQ.
      The prevalence of obstructive sleep apnea and its association with pregnancy-related health outcomes: a systematic review and meta-analysis.
      and insomnia symptoms occur in 38% of pregnant people.
      • Sedov ID
      • Anderson NJ
      • Dhillon AK
      • Tomfohr-Madsen LM.
      Insomnia symptoms during pregnancy: a meta-analysis.
      Sleep disorders during pregnancy can have significant consequences for both the pregnant person and their infant.
      • Okun ML
      • O'Brien LM.
      Concurrent insomnia and habitual snoring are associated with adverse pregnancy outcomes.
      For example, sleep apnea is associated with increased risk of gestational hypertension and diabetes, preterm birth, congenital anomaly, resuscitation at birth, intubation at birth, neonatal intensive care unit (NICU) admission, and longer hospital stay.
      • Liu LN
      • Su G
      • Wang SL
      • Zhu BQ.
      The prevalence of obstructive sleep apnea and its association with pregnancy-related health outcomes: a systematic review and meta-analysis.
      ,
      • Bourjeily G
      • Danilack VA
      • Bublitz MH
      • Muri J
      • Rosene-Montella K
      • Lipkind H.
      Maternal obstructive sleep apnea and neonatal birth outcomes in a population based sample.
      • Felder JN
      • Baer RJ
      • Rand L
      • Jelliffe-Pawlowski LL
      • Prather AA.
      Sleep disorder diagnosis during pregnancy and risk of preterm birth.
      • Pamidi S
      • Pinto LM
      • Marc I
      • Benedetti A
      • Schwartzman K
      • Kimoff RJ.
      Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and meta-analysis.
      In contrast, little is known about the impact of maternal insomnia on pregnancy and infant outcomes. We know, for example, that pregnant people with an insomnia diagnosis are 70% more likely (odds ratio [OR] = 1.7, 95% confidence interval [CI] 1.1-2.6) to have an infant born early preterm (<34 weeks gestation) relative to propensity score matched pregnant people without an insomnia diagnosis
      • Felder JN
      • Baer RJ
      • Rand L
      • Jelliffe-Pawlowski LL
      • Prather AA.
      Sleep disorder diagnosis during pregnancy and risk of preterm birth.
      (this is consistent with several smaller studies suggesting associations between sleep disturbance and preterm birth)
      • Blair LM
      • Porter K
      • Leblebicioglu B
      • Christian LM.
      Poor sleep quality and associated inflammation predict preterm birth: Heightened risk among African Americans.
      ,
      • Okun ML
      • Schetter CD
      • Glynn LM.
      Poor sleep quality is associated with preterm birth.
      ; however, whether insomnia impacts infant outcomes more broadly is unclear.
      The aim of the present study was to investigate associations between a diagnosis of sleep apnea or insomnia in pregnant people and a wide spectrum of infant outcomes in a large cohort of nearly 3 million pregnant people and their newborns. We hypothesized that pregnant people with a sleep apnea or insomnia diagnosis would be more likely to give birth to an infant with an adverse outcome than people without a sleep disorder diagnosis. We also examined whether links between sleep disorders and adverse infant outcomes remained after matching on maternal characteristics, obstetric factors, gestational age, and birthweight.

      Methods

      This was a retrospective cohort sample drawn from all California live born infants between January 1, 2011 and December 31, 2017 (n = 3,448,707). Birth and death certificates, maintained by California Vital Statistics, were linked to hospital discharge, emergency department, and ambulatory surgery records maintained by the California Office of Statewide Health Planning and Development. This administrative database includes detailed information on maternal and infant characteristics, diagnoses at hospital discharge, and procedures that occurred as early as one year prior to delivery for the mother and as late as one year post-delivery for the parent and infant. Data files provided diagnoses and procedure codes based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9)
      American Medical Association
      International Classification of Diseases, 9th Revision, Clinical Modification.
      and International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10).
      World Health Organization
      International Statistical Classification of Diseases and Related Health Problems, 10th Revision.
      The sample was restricted to singleton births with gestations between 22 and 44 weeks with linked birth certificate and hospital discharge records (n = 3,066,016; Fig. 1). This study sample was restricted to infants without ICD codes for chromosomal abnormalities or major structural birth defects on their birth admission or any readmissions during the first year of life and to infants born to mothers with no recorded sleep disorder or only those with insomnia or sleep apnea (n = 2,977,048). Structural birth defects for the study were considered “major” if determined by clinical review as causing major morbidity and mortality or leading to hospitalization during the first year of life.
      • Baer RJ
      • Norton ME
      • Shaw GM
      • et al.
      Risk of selected structural abnormalities in infants after increased nuchal translucency measurement.
      Finally, to remove infants with implausible birthweight and gestational age combinations, infants with birthweights more than 3 standard deviations from the mean were excluded (final sample n = 2,959,204).
      • Talge NM
      • Mudd LM
      • Sikorskii A
      • Basso O.
      United States birth weight reference corrected for implausible gestational age estimates.
      Sleep apnea or insomnia diagnosis was defined as an ICD-9 or ICD-10 diagnostic code in the delivery hospital discharge record (Appendix). Other sleep disorders, such as sleep-related movement disorder, occurred so infrequently in the hospital record that meaningful analyses of those data were not possible. Because this analysis was limited to hospital discharge data, information was unavailable about how or when sleep disorders were diagnosed.
      Adverse infant outcomes included 1- and 5-minute Apgar score <7, respiratory distress syndrome, NICU admission, hypoglycemia, infant death, long hospital stay (>2 days for vaginal delivery, >4 days for cesarean delivery), emergency department visit prior to 3 months of age and in the first year of life, hospital admission prior to 3 months of age and in the first year of life, and a composite binary measure indicating whether or not the infant had any adverse outcome. Birthweight and obstetric estimate of gestational age were obtained from birth certificate records. Respiratory distress syndrome and hypoglycemia data were obtained from hospital discharge ICD-9 or ICD-10 codes (see Appendix). Infant death data were obtained from linked death records and hospital discharge status indicating death.
      Infant year of birth, race/ethnicity, age at term, pre-pregnancy weight and height (used to calculate BMI), education, payer for delivery, enrollment in the Women, Infants, and Children Supplemental Nutrition Program (WIC), smoked during pregnancy, and previous preterm birth were obtained from birth certificate records. Hypertension disorder (including preeclampsia/‌eclampsia), diabetes, infection during pregnancy, drug use, and alcohol use were obtained from hospital discharge ICD-9 or ICD-10 codes.
      Maternal characteristics, clinical factors, and infant factors were compared using chi-square statistics comparing people with sleep apnea or insomnia to people without a sleep disorder. Next, unadjusted logistic regression with a Poisson distribution was used to calculate relative risks (RRs) and 95% CIs for each infant adverse outcome using infants without a recorded sleep disorder as the referent population. Then, logistic regression including infant year of birth, race/ethnicity, age at term, BMI, education, payer for delivery, enrollment in WIC, smoked during pregnancy, previous preterm birth, hypertension disorder, diabetes, infection during pregnancy, drug use, alcohol use, gestational age at delivery, and birthweight for gestational age were used to create propensity scores for women with sleep apnea or insomnia.
      Propensity score matching is a method to create a control group that is as identical to the experimental group as possible, to increase the likelihood that differences between the groups are due to the phenomenon in question. For instance, if people with a sleep disorder are more likely to have a preterm birth, but they are also more likely to have hypertension and diabetes (risk factors for preterm birth), we cannot assume the risk of preterm birth is due to the sleep disorder. However, using a control group without a sleep disorder that has an equal number of people with hypertension and diabetes, we can determine whether the risk of preterm birth is due to the sleep disorder. A referent population of women without a sleep disorder was randomly selected at a 1:1 ratio using exact matching of propensity scores without replacement. Although there was no replacement when selecting propensity matched controls for sleep apnea or insomnia, the entire population of women without a sleep disorder was available for each disorder (apnea or insomnia) being analyzed. Women without an exact propensity score matched control were not included in the analysis (n = 1001 people with insomnia; n = 1014 people with sleep apnea). Logistic regression was used to calculate ORs and their 95% CIs for each adverse infant outcome.
      All analyses were performed using Statistical Analysis Software version 9.4 (Cary, NC). Proc logistic was used to calculate propensity scores and ORs, proc genmod was used to calculate relative risks. Methods and protocols for the study were approved by the Committee for the Protection of Human Subjects within the Health and Human Services Agency of the State of California.

      Results

      In this study sample, records identified 3371 individuals who were diagnosed with sleep apnea and 3213 who were diagnosed with insomnia. The majority of these individuals were Hispanic, Black, Asian, or Other race and ethnicity, and between ages 18 and 34 at delivery. Over 50% of individuals had more than 12 years of education and the majority had private health insurance for delivery (Table 1). Individuals with a sleep apnea or insomnia diagnosis differed on many maternal characteristics, obstetric factors, and infant factors relative to those without a sleep disorder diagnosis. For example, those diagnosed with sleep apnea tended to be older (>34 years 39.8% vs. 20.1%), and a larger proportion were obese (70.2% vs. 21.4%), had a hypertension disorder (38.2% vs. 9.0%), had diabetes (34.9% vs. 11.3%), had a mental health diagnosis (45.7% vs. 6.5%), or had an infant large for gestational age (16.1% vs. 9.1%). Of those with sleep apnea, 69.9% (n = 2357) had a propensity score matched control. Individuals diagnosed with insomnia tended to be older (> 34 years 28.7% vs. 20.1%); a larger proportion were obese (24.9% vs. 21.4%), had obtained 12 years or more education (62.1% vs. 54.2%), smoked during pregnancy (13.8% vs. 3.0%), or had a mental health diagnosis (69.2% vs. 6.5%). Of the women with insomnia, 68.8% (n = 2212) had a propensity score matched control.
      Table 1Maternal characteristics, obstetric factors, and infant factors among women without a recorded sleep disorder diagnosis vs. women with a sleep apnea or insomnia diagnosis
      No sleep disorderSleep apneaInsomnia
      n (%)n (%)p-value
      vs. no sleep disorder.
      n (%)p-value
      vs. no sleep disorder.
      Sample2,952,66033713213
      Infant year of birth
       2011436,877 (14.8)248 (7.4)<.0001237 (7.4)<.0001
       2012438,812 (14.9)423 (12.6).0002360 (11.2)<.0001
       2013426,397 (14.4)416 (12.3).0005474 (14.8).6157
       2014433,289 (14.7)449 (13.3).0263481 (15.0).6357
       2015417,852 (14.2)563 (16.7)<.0001599 (17.4)<.0001
       2016409,555 (13.9)535 (15.9).0008564 (17.6)<.0001
       2017389,878 (13.2)737 (21.9)<.0001538 (16.7)<.0001
      Race and ethnicity
       White not Hispanic782.541 (26.5)1018 (30.2)<.00011379 (42.9)<.0001
       Hispanic1,447,581 (49.0)1303 (38.7)<.00011089 (33.9)<.0001
       Black144,887 (4.9)374 (11.1)<.0001249 (7.8)<.0001
       Asian432,667 (14.7)355 (10.5)<.0001225 (7.0)<.0001
       Other144,984 (4.9)321 (9.5)<.0001271 (8.4)<.0001
      Maternal age at term
       <18 years50,003 (1.7)16 (0.5)<.000129 (0.9).0005
       18-34 years2,307,765 (78.2)2015 (59.8)<.00012263 (70.4)<.0001
       >34 years594,781 (20.1)1340 (39.8)<.0001921 (28.7)<.0001
       Missing111 (0.0)0 (0.0).72180 (0.0).7282
      Body mass index
       Underweight112,311 (3.8)23 (0.7)<.0001111 (3.5).3013
       Normal weight1,344,875 (45.6)352 (10.4)<.00011389 (43.2).0084
       Overweight741,117 (25.1)502 (14.9)<.0001769 (23.9).1276
       Obese631,692 (21.4)2366 (70.2)<.0001832 (25.9)<.0001
       Missing122,665 (4.2)128 (3.8).2988112 (3.5).0577
      Maternal education
       <12 years505,985 (17.1)270 (8.0)<.0001327 (10.2)<.0001
       12 years721,774 (24.4)750 (22.3).0030744 (23.2).0893
       >12 years1,600,365 (54.2)2136 (63.4)<.00011996 (62.1)<.0001
       Missing124,536 (4.2)215 (6.4)<.0001146 (4.5).3578
      Payment for delivery
       Private1,406,381 (47.6)2242 (66.5)<.00011922 (59.8)<.0001
       Medi-Cal
      California's Medicaid.
      1,358,235 (46.0)1041 (30.9)<.00011163 (36.2)<.0001
       Other90,389 (3.1)72 (2.1).001899 (3.1).9477
      Mother enrolled in WIC1,500,063 (50.8)1535 (45.5)<.00011404 (43.7)<.0001
      Smoked during pregnancy88,557 (3.0)278 (8.3)<.0001442 (13.8)<.0001
      Previous preterm birth30,203 (1.0)92 (2.7)<.000185 (2.7)<.0001
      Hypertension disorder267,051 (9.0)1292 (38.2)<.0001615 (19.1)<.0001
      Diabetes332,364 (11.3)1176 (34.9)<.0001482 (15.0)<.0001
      Infection during pregnancy306,888 (10.4)687 (20.4)<.0001822 (25.6)<.0001
      Drug/alcohol abuse59,030 (2.0)201 (6.0)<.0001488 (15.2)<.0001
      Mental health diagnosis19,2778 (6.5)1539 (45.7)<.00012223 (69.2)<.0001
      Gestational age at delivery (weeks)
       22-287844 (0.3)37 (1.1)<.000124 (0.8)<.0001
       29-3112,898 (0.4)57 (1.7)<.000150 (1.6)<.0001
       32-36164,841 (5.6)416 (12.3)<.0001349 (10.9)<.0001
       37-38717,424 (24.3)980 (29.1)<.0001822 (25.6).0894
       39-422,048,622 (69.4)1881 (55.8)<.00011968 (61.3)<.0001
       43-441031 (0.0)0 (0.0).27790 (0.0).2894
      Birthweight for gestational age
      SGA is < 10th percentile, AGA is 10th to 90th percentile, and LGA is > 90th percentile. Calculations are made based on gestational age and sex, per the reference Talge et al., 2014.13
       SGA251,788 (8.5)234 (6.9).0010322 (10.0).0024
       AGA2,432,987 (82.4)2594 (77.0)<.00012585 (80.5).0038
       LGA268,211 (9.1)543 (16.1)<.0001310 (9.7).2657
       Missing696 (0.0)0 (0.0).37270 (0.0).3841
      WIC, Women Infants and Children's Program; SGA, small for gestational age; AGA, appropriate for gestational age; LGA, large for gestational age.
      a vs. no sleep disorder.
      b California's Medicaid.
      c SGA is < 10th percentile, AGA is 10th to 90th percentile, and LGA is > 90th percentile. Calculations are made based on gestational age and sex, per the reference Talge et al., 2014.
      • Talge NM
      • Mudd LM
      • Sikorskii A
      • Basso O.
      United States birth weight reference corrected for implausible gestational age estimates.
      Infants born to individuals with a diagnosis code for sleep apnea had a higher rate of many adverse outcomes than infants born to individuals without a recorded sleep disorder (Table 2). These infants were more likely to have any adverse outcome (RR 1.2, 95% CI 1.2-1.3), 1-minute Apgar score <7 (RR 2.6, 95% CI 2.4-2.9), and 5-minute Apgar score <7 (3.5, 95% CI 2.9-4.3). They were also at 2.5-fold higher risk for a NICU stay on birth admission, 3.3-fold higher risk for having respiratory distress syndrome, 2.3-fold higher risk of hypoglycemia, and 2.0-fold higher risk of dying prior to age 3 months. Regarding utilization of hospital services, infants born to individuals with a diagnosis code for sleep apnea were more likely to have a long hospital stay and experience an emergency room visit prior to 3 months of age (RRs 1.6, 95% CI 1.5-1.7 and 1.2, 95% CI 1.1-1.3, respectively). However, once the sample was propensity score matched based on maternal characteristics, obstetric factors, gestational age, and birthweight, many of the associations were no longer statistically significant. In this regard, infants born to an individual with a diagnosis code of sleep apnea were more likely to have any adverse outcome, 1-minute Apgar scores <7, a NICU stay, and an ER visit compared to infants born to an individual without a recorded sleep disorder (Table 2).
      Table 2Infant outcomes for women with ICD-9/10 code for sleep apnea during pregnancy
      Whole populationMatched sample
      Sleep apnea during pregnancyNo sleep disorder during pregnancySleep apnea during pregnancyNo sleep disorder during pregnancy
      n (%)n (%)RR (95% CI)n (%)n (%)OR (95% CI)
      Sample33712,952,66023572357
      Complications
      Any adverse outcome
       No1358 (40.3)1,553,904 (52.0)Reference1095 (46.5)1176 (49.9)Reference
       Yes2013 (59.7)1,418,756 (48.1)1.2 (1.2, 1.3)1262 (53.5)1181 (50.1)1.1 (1.0, 1.3)
      1-minute Apgar
      Numbers do not add up to 100% because Apgar scores were missing for some infants.
       <7430 (12.8)144,497 (4.9)2.6 (2.4, 2.9)226 (9.6)148 (6.3)1.6 (1.3, 2.0)
       ≥72936 (87.1)2,799,961 (94.8)Reference2129 (90.3)2202 (93.4)Reference
      5-minute Apgar
      Numbers do not add up to 100% because Apgar scores were missing for some infants.
       <7102 (3.0)25,328 (0.9)3.5 (2.9, 4.3)49 (2.1)34 (1.4)1.4 (0.9, 2.2)
       ≥73264 (96.8)2,918,295 (98.8)Reference2307 (97.9)2315 (98.2)Reference
      Infant NICU stay on birth admission
       No2907 (86.2)2,791,512 (94.5)Reference2158 (91.6)2208 (93.7)Reference
       Yes464 (13.8)161,148 (5.5)2.5 (2.3, 2.8)199 (8.4)149 (6.3)1.4 (1.1, 1.7)
      Respiratory distress syndrome
       No3215 (95.4)2,911,080 (98.6)Reference2320 (98.4)2327 (98.7)Reference
       Yes156 (4.6)41,580 (1.4)3.3 (2.8, 3.8)37 (1.6)30 (1.3)1.2 (0.8, 2.0)
      Hypoglycemia
       No3233 (95.9)2,900,268 (98.2)Reference2294 (97.3)2296 (97.4)Reference
       Yes138 (4.1)52,392 (1.8)2.3 (2.0, 2.7)63 (2.7)61 (2.6)1.0 (0.8, 1.5)
      Infant death
       No3355 (99.5)2,945,637 (99.8)Reference2352 (99.8)2350 (99.7)Reference
       Yes16 (0.5)7023 (0.2)2.0 (1.2, 3.3)5 (0.2)7 (0.3)0.7 (0.2, 2.3)
        < 3 months13 (0.4)5586 (0.2)2.0 (1.2, 3.5)
      Not displayed when n < 5.
      Not displayed when n < 5.
      Not calculated when n < 5.
      Utilization
      Long birth stay
       No2783 (82.6)2,629,812 (89.1)Reference2087 (88.5)2078 (88.2)Reference
       Yes588 (17.4)322,848 (10.9)1.6 (1.5, 1.7)270 (11.5)279 (11.8)1.0 (0.8, 1.2)
      ER visit
       No2071 (61.4)1,970,343 (66.7)Reference1487 (63.1)1566 (66.4)Reference
       Yes1300 (38.6)982,317 (33.3)1.2 (1.1, 1.2)870 (36.9)791 (33.6)1.2 (1.0, 1.3)
        <3 months513 (15.2)380,215 (12.9)1.2 (1.1, 1.3)339 (14.4)317 (13.5)1.1 (1.0, 1.3)
      Hospital admission
       No2985 (88.6)2,672,001 (90.5)Reference2144 (91.0)2118 (89.9)Reference
       Yes386 (11.5)280,659 (9.5)1.2 (1.1, 1.3)213 (9.0)239 (10.1)0.9 (0.7, 1.1)
        <3 months282 (8.4)193,889 (6.6)1.3 (1.1, 1.4)156 (6.6)169 (7.2)0.9 (0.7, 1.1)
      Bold indicates p < .05.
      a Not displayed when n < 5.
      b Not calculated when n < 5.
      c Numbers do not add up to 100% because Apgar scores were missing for some infants.
      Infants born to individuals with a diagnosis code for insomnia also had a higher rate of many adverse infant birth outcomes than those without a recorded sleep disorder (Table 3). These infants were more likely to have any adverse outcome (RR 1.2, 95% CI 1.2-1.3) and 1 and 5-minute Apgar scores <7 (RRs 2.0, 95% CI 1.8-2.2 and 2.8, 95% CI 2.2-3.5, respectively). These infants were at 2.2-fold higher risk of having a NICU stay, 2.8-fold higher risk of having respiratory distress syndrome, 2.3-fold higher risk of having hypoglycemia, 2.0-fold higher risk of death before 3 months of age, 1.6-fold higher risk of a long birth stay, and 1.3-fold higher risk visiting the emergency room prior to 3-months of age. Again, once the sample was propensity score matched based on maternal characteristics, obstetric factors, gestational age, and birthweight, most associations were no longer statistically significant with the exception of any adverse outcome (OR 1.2, 95% CI 1.1-1.3) and risk of emergency room visit prior to 3 months of age and in the first year of life. Infants born to an individual with a diagnosis code of insomnia had higher odds of an emergency room visit in the first 3 months and first year of life compared to infants born to individuals without a record sleep disorder (ORs 1.2, 95% CI 1.1-1.4 and 1.4, 95% CI 1.2-1.7; Table 3).
      Table 3Infant outcomes for women with ICD-9/10 code for insomnia during pregnancy
      Whole populationMatched sample
      Insomnia during pregnancyNo sleep disorder during pregnancyInsomnia during pregnancyNo sleep disorder during pregnancy
      n (%)n (%)RR (95% CI)n (%)n (%)OR (95% CI)
      Sample32132,952,66022122212
      Complications
      Any adverse outcome
       No1327 (41.3)1,553,904 (52.0)Reference1040 (47.0)1135 (51.3)Reference
       Yes1886 (58.7)1,418,756 (48.1)1.2 (1.2, 1.3)1172 (53.0)1077 (48.7)1.2 (1.1, 1.3)
      1-minute Apgar
      Numbers do not add up to 100% because Apgar scores were missing for some infants.
       < 7312 (9.7)144,497 (4.9)2.0 (1.8, 2.2)158 (7.1)146 (6.6)1.1 (0.9, 1.4)
       ≥ 72885 (89.8)2,799,961 (94.8)Reference2049 (92.6)2058 (93.0)Reference
      5-minute Apgar
      Numbers do not add up to 100% because Apgar scores were missing for some infants.
       < 777 (2.4)25,328 (0.9)2.8 (2.2, 3.5)2178 (98.5)2184 (98.7)1.3 (0.8, 2.4)
       ≥ 73121 (97.1)2,918,295 (98.8)Reference28 (1.3)21 (1.0)Reference
      Infant NICU stay on birth admission
       No2825 (87.9)2,791,512 (94.5)Reference2068 (93.5)2074 (93.8)Reference
       Yes388 (12.1)161,148 (5.5)2.2 (2.0, 2.4)144 (6.5)138 (6.2)1.0 (0.8, 1.3)
      Respiratory distress syndrome
       No3085 (96.0)2,911,080 (98.6)Reference2178 (98.5)2184 (98.7)Reference
       Yes128 (4.0)41,580 (1.4)2.8 (2.4, 3.4)34 (1.5)28 (1.3)1.2 (0.7, 2.0)
      Hypoglycemia
       No3082 (95.9)2,900,268 (98.2)Reference2151 (97.2)2160 (97.7)Reference
       Yes131 (4.1)52,392 (1.8)2.3 (1.9, 2.7)61 (2.8)52 (2.4)1.2 (0.8, 1.7)
      Infant death
       No3197 (99.5)2,945,637 (99.8)Reference2209 (99.9)2207 (99.8)Reference
       Yes16 (0.5)7023 (0.2)2.1 (1.3, 3.4)
      not displayed when n < 5.
      5 (0.2)
      not calculated when n < 5.
        < 3 months12 (0.4)5586 (0.2)2.0 (1.1, 3.5)
      not displayed when n < 5.
      not displayed when n < 5.
      not calculated when n < 5.
      Utilization
      Long birth stay
       No2650 (82.5)2,629,812 (89.1)Reference1958 (88.5)1970 (89.1)Reference
       Yes563 (17.5)322,848 (10.9)1.6 (1.5, 1.7)254 (11.5)242 (10.9)1.1 (0.9, 1.3)
      ER visit
       No1982 (61.7)1,970,343 (66.7)Reference1390 (62.8)1497 (67.7)Reference
       Yes1231 (38.3)982,317 (33.3)1.2 (1.1, 1.2)822 (37.2)715 (32.3)1.2 (1.1, 1.4)
        < 3 months517 (16.1)380,215 (12.9)1.3 (1.2, 1.4)341 (15.4)264 (11.9)1.4 (1.2, 1.7)
      Hospital admission
       No2890 (90.0)2,672,001 (90.5)Reference2004 (90.6)2010 (90.9)Reference
       Yes323 (10.1)280,659 (9.5)1.1 (0.9, 1.2)208 (9.4)202 (9.1)1.0 (0.8, 1.3)
        < 3 months221 (6.9)193,889 (6.6)1.1 (0.9, 1.2)138 (6.2)143 (6.5)1.0 (0.8, 1.2)
      Bold indicates p < .05.
      a not displayed when n < 5.
      b not calculated when n < 5.
      c Numbers do not add up to 100% because Apgar scores were missing for some infants.

      Discussion

      In a sample derived from nearly 3 million live births, we found that relative to infants born to individuals without a sleep disorder diagnosis, infants born to mothers with a diagnosis of sleep apnea or insomnia had significantly higher odds of any adverse outcome. With respect to sleep apnea, our findings are consistent with other studies showing that maternal sleep apnea is associated with increased risk of low Apgar scores
      • Liu LN
      • Su G
      • Wang SL
      • Zhu BQ.
      The prevalence of obstructive sleep apnea and its association with pregnancy-related health outcomes: a systematic review and meta-analysis.
      and NICU admission.
      • Liu LN
      • Su G
      • Wang SL
      • Zhu BQ.
      The prevalence of obstructive sleep apnea and its association with pregnancy-related health outcomes: a systematic review and meta-analysis.
      ,
      • Bourjeily G
      • Danilack VA
      • Bublitz MH
      • Muri J
      • Rosene-Montella K
      • Lipkind H.
      Maternal obstructive sleep apnea and neonatal birth outcomes in a population based sample.
      We did not replicate previous findings suggesting a relationship between sleep apnea and longer hospital stay,
      • Bourjeily G
      • Danilack VA
      • Bublitz MH
      • Muri J
      • Rosene-Montella K
      • Lipkind H.
      Maternal obstructive sleep apnea and neonatal birth outcomes in a population based sample.
      and our finding that infants born to mothers with a sleep apnea diagnosis were at increased risk of an emergency room visit is a new contribution to the literature. Research on possible mechanisms of the relation between maternal prenatal sleep apnea and poorer birth and infant outcomes associations is small but growing, implicating systemic inflammation and late or prolonged fetal heart rate decelerations.
      • Pitts DS
      • Treadwell MC
      • O'Brien LM
      Fetal heart rate decelerations in women with sleep-disordered breathing.
      ,
      • Alonso-Fernandez A
      • Quetglas CR
      • Mochales AH
      • et al.
      Influence of obstructive sleep apnea on systemic inflammation in pregnancy.
      Taken together with previous research suggesting that sleep apnea is associated with increased risk of adverse birth outcomes, such as preterm birth,
      • Felder JN
      • Baer RJ
      • Rand L
      • Jelliffe-Pawlowski LL
      • Prather AA.
      Sleep disorder diagnosis during pregnancy and risk of preterm birth.
      these study findings underscore the importance of utilizing available interventions for treating sleep apnea. Continuous positive airway pressure (CPAP) therapy is the preferred treatment for addressing sleep apnea in the general population and is effective in reducing some of the medical risks associated with sleep apnea.
      • Buchner NJ
      • Quack I
      • Stegbauer J
      • Woznowski M
      • Kaufmann A
      • Rump LC.
      Treatment of obstructive sleep apnea reduces arterial stiffness.
      • Buchner NJ
      • Sanner BM
      • Borgel J
      • Rump LC.
      Continuous positive airway pressure treatment of mild to moderate obstructive sleep apnea reduces cardiovascular risk.
      • Haentjens P
      • Van Meerhaeghe A
      • Moscariello A
      • et al.
      The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome—evidence from a meta-analysis of placebo-controlled randomized trials.
      Surprisingly, little is known about the benefits of CPAP therapy in pregnancy.
      • Truong KK
      • Guilleminault C.
      Sleep disordered breathing in pregnant women: maternal and fetal risk, treatment considerations, and future perspectives.
      However, given the health benefits conferred by CPAP therapy in nonpregnant samples, it is the hope that CPAP therapy will similarly reduce the negative health consequences of sleep apnea in pregnancy.
      • Dominguez JE
      • Street L
      • Louis J.
      Management of obstructive sleep apnea in pregnancy.
      Research on associations between insomnia diagnosis during pregnancy and adverse infant outcomes is sparse, with the exception of a meta-analysis documenting associations between insomnia diagnosis during pregnancy and risk for infant that is large for gestational age.
      • Lu Q
      • Zhang X
      • Wang Y
      • et al.
      Sleep disturbances during pregnancy and adverse maternal and fetal outcomes: a systematic review and meta-analysis.
      A population-based study found that individuals treated with Zolpidem, a hypnotic medication commonly prescribed to treat insomnia, were more likely to have children born preterm, with low birth weight, and with congenital abnormalities than individuals who were not prescribed Zolpidem.
      • Wang LH
      • Lin HC
      • Lin CC
      • Chen YH
      • Lin HC.
      Increased risk of adverse pregnancy outcomes in women receiving zolpidem during pregnancy.
      Unfortunately, such studies cannot disentangle whether these associations are due to the insomnia or the active effects of the drug, which is known to cross into the placenta.
      • Juric S
      • Newport DJ
      • Ritchie JC
      • Galanti M
      • Stowe ZN.
      Zolpidem (Ambien) in pregnancy: placental passage and outcome.
      Thus, our finding that infants born to mothers with an insomnia diagnosis were at increased risk of only emergency room visit but no other analyzed infant outcomes, is important and novel. At the same time, insomnia during pregnancy is associated with other adverse birth and maternal outcomes, such as preterm birth and depression,
      • Felder JN
      • Baer RJ
      • Rand L
      • Jelliffe-Pawlowski LL
      • Prather AA.
      Sleep disorder diagnosis during pregnancy and risk of preterm birth.
      ,
      • Tomfohr LM
      • Buliga E
      • Letourneau NL
      • Campbell TS
      • Giesbrecht GF.
      Trajectories of sleep quality and associations with mood during the perinatal period.
      and thus important to assess and intervene upon. Several randomized clinical trials support the positive benefits of cognitive behavioral therapy for insomnia (CBTI), which is recommended as first line treatment for insomnia in nonpregnant samples,
      • Qaseem A
      • Kansagara D
      • Forciea MA
      • Cooke M
      • Denberg TD
      Clinical guidelines committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians.
      and for significantly reducing insomnia symptoms in pregnant individuals.
      • Felder JN
      • Epel ES
      • Neuhaus J
      • Krystal AD
      • Prather AA.
      Efficacy of digital cognitive behavioral therapy for the treatment of insomnia symptoms among pregnant women: a randomized clinical trial.
      • Kalmbach DA
      • Cheng P
      • O'Brien LM
      • et al.
      A randomized controlled trial of digital cognitive behavior therapy for insomnia in pregnant women.
      • Manber R
      • Bei B
      • Simpson N
      • et al.
      Cognitive behavioral therapy for prenatal insomnia: a randomized controlled trial.
      For example, Felder and colleagues demonstrated that 6 weekly sessions of CBTI, delivered digitally, resulted in twice the reduction in insomnia symptoms 10 weeks later than usual care.
      • Felder JN
      • Epel ES
      • Neuhaus J
      • Krystal AD
      • Prather AA.
      Efficacy of digital cognitive behavioral therapy for the treatment of insomnia symptoms among pregnant women: a randomized clinical trial.
      It is currently unknown whether CBTI is associated with improved birth outcomes.
      In our initial crude analyses, both sleep apnea and insomnia were associated with most of the analyzed infant outcomes. The majority of these associations were attenuated after matching on maternal characteristics, obstetric factors, gestational age, and birthweight. This suggests that these associations may be due to other characteristics and comorbidities, though we are not able to identify statistically which characteristics drove the initial higher rates of adverse infant outcomes.
      The mechanisms underlying the associations between sleep apnea and insomnia and adverse infant outcomes have yet to be fully elucidated. Sleep apnea, which is marked by recurrent total or partial collapse of the upper airway and results in frequent nocturnal arousals and hypoxemia, is also associated with elevated inflammation, oxidative stress, and endothelial dysfunction.
      • Izci-Balserak B
      • Pien GW.
      Sleep-disordered breathing and pregnancy: potential mechanisms and evidence for maternal and fetal morbidity.
      Similarly, a meta-analytic review of the sleep literature demonstrated a significant link between insomnia symptoms and elevated levels of pro-inflammatory mediators (eg, interleukin-6).
      • Irwin MR
      • Olmstead R
      • Carroll JE.
      Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation.
      Dysregulation of inflammatory processes has been proposed as an important pathway in understanding adverse birth outcomes, as well as the role of sleep in pregnancy complications.
      • Bastek JA
      • Weber AL
      • McShea MA
      • Ryan ME
      • Elovitz MA.
      Prenatal inflammation is associated with adverse neonatal outcomes.
      • Kalagiri RR
      • Carder T
      • Choudhury S
      • et al.
      Inflammation in complicated pregnancy and its outcome.
      • Okun ML
      • Roberts JM
      • Marsland AL
      • Hall M.
      How disturbed sleep may be a risk factor for adverse pregnancy outcomes a hypothesis.
      Research prospectively monitoring biological processes implicated in adverse birth outcomes among individuals with and without sleep disorders is warranted.
      There are several strengths of this study that extend the current literature. The use of a large population-based sample provided a sufficient number of cases to test our study hypotheses, which is often challenging in smaller studies. Further, the use of ICD-9 and 10 codes highlights the questions that can be tackled using available medical record data. That said, there are several inherent limitations to using medical record data that should be noted. For example, because this study relied solely on medical records, it remains unclear how routinely sleep disorders were queried by providers. In our sample <0.1% of individuals had an ICD-9 or ICD-10 code of either sleep apnea or insomnia, which is significantly lower than would be expected based on self-report prevalence data. For example, the rates of objectively-defined sleep disordered breathing are approximately 4% in early pregnancy and 8% in mid pregnancy,
      • Facco FL
      • Parker CB
      • Reddy UM
      • et al.
      Association between sleep-disordered breathing and hypertensive disorders of pregnancy and gestational diabetes mellitus.
      and the rates of insomnia disorder are 20% at the end of the third trimester.
      • Quin N
      • Lee JJ
      • Pinnington DM
      • Newman L
      • Manber R
      • Bei B.
      Differentiating perinatal insomnia disorder and sleep disruption: a longitudinal study from pregnancy to 2 years postpartum.
      Reasons for these low numbers may include providers tending not to assess sleep concerns during prenatal care and patients omitting sleep complaints. Indeed, survey data indicate that only about one-third of pregnant individuals discuss sleep with their health care providers.
      • Felder JN
      • Hartman AR
      • Epel ES
      • Prather AA.
      Pregnant patient perceptions of provider detection and treatment of Insomnia.
      Consequently, the findings presented here may reflect more severe cases of insomnia and sleep apnea, and may not represent the population of individuals with diagnosed sleep apnea or insomnia during pregnancy generally. Future research is needed to determine whether severity of insomnia and sleep apnea is associated with infant outcomes. Previous survey data suggest that prenatal insomnia is likely undertreated,
      • Felder JN
      • Hartman AR
      • Epel ES
      • Prather AA.
      Pregnant patient perceptions of provider detection and treatment of Insomnia.
      and treatment rates for prenatal sleep apnea are unknown. A second limitation is that treatment for sleep disorders is not available in this dataset. Thus, it is possible that a portion of individuals with a sleep apnea diagnosis received treatment, which may attenuate associations with adverse infant outcomes. Another limitation is that because we relied on hospital discharge records, we cannot know for certain whether the sleep disorders were diagnosed for the first time during pregnancy or whether the diagnosis preceded pregnancy. This information will be important for clarifying the impact of timing and chronicity of sleep disorders on infant outcomes and identifying key opportunities for intervention.
      Sleep apnea and insomnia may be windows into the overall health of pregnant individuals and offer low-stigma targets for assessment of risk of adverse infant outcomes. Given the growing evidence of the health consequences of sleep apnea and insomnia, there is an increasing need for clinicians to assess and address sleep disorders in pregnancy and for researchers to test whether targeting sleep apnea and insomnia reduces these adverse infant outcomes.

      Declaration of conflict of interest

      The authors report no conflicts of interest.

      Funding

      This work was supported by the UCSF California Preterm Birth Initiative. Dr. Prather's contribution was supported by a grant from NHLBI ( R01HL142051 ). Dr. Felder's contribution was supported by a grant from NCCIH ( K23AT009896 ). The funders had no role in the study design; the collection, analysis and interpretation of data; the writing of the report; the decision to submit the article for publication.

      Author contribution

      JF, AP, RB, LR, KR, and LJP conceived of the study. RB carried out the analyses. JF wrote the initial draft of the manuscript and all authors contributed to editorial changes and approved the final manuscript.

      Appendix. Supplementary materials

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