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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, USADepartment of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, California, USA
Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, California, USAUCSF California Preterm Birth Initiative, University of California, San Francisco, San Francisco, California, USADepartment of Pediatrics, University of California, San Diego, San Diego, California, USA
Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, California, USAUCSF California Preterm Birth Initiative, University of California, San Francisco, San Francisco, California, USA
UCSF California Preterm Birth Initiative, University of California, San Francisco, San Francisco, California, USADepartment of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, California, USA
Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, California, USACenter for Health and Community, University of California, San Francisco, San Francisco, California, USA
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.
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
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.
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
; 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)
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.
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).
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
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
SGA
251,788 (8.5)
234 (6.9)
.0010
322 (10.0)
.0024
AGA
2,432,987 (82.4)
2594 (77.0)
<.0001
2585 (80.5)
.0038
LGA
268,211 (9.1)
543 (16.1)
<.0001
310 (9.7)
.2657
Missing
696 (0.0)
0 (0.0)
.3727
0 (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.
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
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
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
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.
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.
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.
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.
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.
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.
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.
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,
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,
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.
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.
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.
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).
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.
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,
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.
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,
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.
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.
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.
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