Characteristics of the participants according to the apnea–hypopnea index at baseline are shown in Table 1. In early pregnancy, older age, higher BMI, larger neck circumference, non-Hispanic black race–ethnicity, smoking, and chronic hypertension were all associated with increased apnea–hypopnea index. Similar findings were seen with the midpregnancy apnea–hypopnea index (Appendix 5, available online at http://links.lww.com/AOG/A905).
Gestational diabetes mellitus occurred in 134 of 3,245 women without pregestational diabetes (4.1%). The median gestational age in weeks at the time of GDM testing was 27 with an interquartile range of 25–28. Of the patients with GDM, 55% (n=74) were diet-controlled; 36% (n=48) required treatment with insulin, an oral hypoglycemic, or both; and in 9% of patients (n=12), information on therapy modality was not available.
The adjusted OR for hypertensive disorders of pregnancy (preeclampsia and antepartum gestational hypertension) when sleep-disordered breathing was present compared with absent in early pregnancy did not reach statistical significance (adjusted OR 1.46, 95% CI 0.91–2.32), but in midpregnancy, the adjusted analysis was statistically significant (adjusted OR 1.73, 95% CI 1.19–2.52). Statistically significant linear trends were observed between increasing apnea–hypopnea index and the rate of all hypertensive disorders in unadjusted analyses (early and midpregnancy) and remained significant for midpregnancy apnea–hypopnea index in the adjusted analyses (P<.001).
We examined the timing between the sleep study and the diagnosis of a hypertensive disorder. Hypertensive complications were diagnosed between 45 and 229 days after the early pregnancy sleep study and from 44 days before to 113 days after the midpregnancy sleep study. Only 4.1% of hypertension diagnoses were made before the midpregnancy sleep-disordered breathing assessment; 91.7% of hypertension diagnoses were made more than 2 weeks after the midpregnancy assessment.
Both race–ethnicity and smoking were considered for covariate adjustment to the analyses presented in Tables 2 and 3. Neither met the criteria for inclusion as a confounder. Specifically, adding either variable to a univariate model with sleep-disordered breathing (apnea–hypopnea index 5 or greater) for hypertensive disorder of pregnancy and for GDM modified the crude ORs by 0.0–2.6% and 0.4–4.1%, respectively. Adding either variable to the multivariate models shown in the tables modified the adjusted ORs by 0.0–1.4% and 0.3–1.1%, respectively.
Given the clear relationship between sleep-disordered breathing and BMI, we also ran analyses with BMI as a continuous variable and considered the interaction between apnea–hypopnea index and BMI. Adjusting for BMI as a continuous variable (linear and quadratic terms) did not alter the direction, magnitude, or statistical significance of effects (data not shown). For both hypertensive disorders and GDM, the interaction of BMI and sleep-disordered breathing was nonsignificant (early pregnancy: P=.90 and P=.31, respectively; and midpregnancy: P=.61 and P=.95, respectively).
Furthermore, we considered that weight gain from early to midpregnancy could be an intermediate variable in the causal pathway between apnea–hypopnea index and pregnancy outcomes. However, the direction, magnitude, and significance of effects were similar to those in Tables 2 and 3 when we excluded weight gain as a covariate in the midpregnancy models (Appendices 6 and 7, available online at http://links.lww.com/AOG/A905).
In this prospective analysis of objectively assessed sleep-disordered breathing in pregnancy, the prevalence of sleep-disordered breathing was 3.6% and 8.3% in early pregnancy and midpregnancy, respectively. Nearly all participants in this cohort identified as sleep-disordered breathing-positive (apnea–hypopnea index 5 or greater) had a nocturnal respiratory pattern consistent with OSA. There was an independent association between sleep-disordered breathing and preeclampsia, hypertensive disorders of pregnancy, and GDM after adjustment for age, BMI, chronic hypertension, and pregnancy-related weight gain. Increasing exposure–response relationships were observed between apnea–hypopnea index and pregnancy-related hypertension and GDM.
Before this report, the largest studies evaluating sleep-disordered breathing and pregnancy-related hypertension have been retrospective or cross-sectional and limited by the quality of sleep-disordered breathing exposure and pregnancy outcome assessment.26 Data from smaller prospective cohorts, using objective assessments of sleep-disordered breathing, have yielded conflicting results.16–18 Louis et al16 reported on a cohort of 175 obese women and demonstrated that women with sleep-disordered breathing (apnea–hypopnea index 5 or greater) were more likely to develop preeclampsia (adjusted OR 3.5, 95% CI 1.3–9.9). However, two other small studies failed to demonstrate a positive association between sleep-disordered breathing and pregnancy-related hypertension.17,18 In our large prospective study, in which sleep-disordered breathing was diagnosed using objective criteria and confounding variables carefully considered, we found an association between sleep-disordered breathing and preeclampsia and pregnancy-related hypertension. In adjusted analyses, an early pregnancy apnea–hypopnea index of 5 or greater was associated with preeclampsia. In midpregnancy, an apnea–hypopnea index of 5 or greater was associated with the development of preeclampsia and the composite of preeclampsia and antepartum gestational hypertension. In regard to our midpregnancy apnea–hypopnea index data, because rapid weight gain and extravascular fluid retention may result in an increase in apnea–hypopnea index, we additionally adjusted for weight gain between visits in the midpregnancy analyses. We also examined the timing of the midpregnancy sleep assessment in relation to hypertension diagnosis and found that 91.7% of diagnoses were made more than 2 weeks after the midpregnancy sleep test. In summary, the associations and dose–response relationships observed in this study among apnea–hypopnea index, preeclampsia, and pregnancy-related hypertension could potentially signify a causal link between sleep-disordered breathing exposure in pregnancy and the subsequent development of hypertensive disorders of pregnancy.
Our data regarding the association between sleep-disordered breathing and GDM are robust. By excluding women with pregestational diabetes and defining GDM, we optimized case ascertainment. We observed increasing apnea–hypopnea index with increasing incidence of GDM in both early and midpregnancy, independent of important covariates. The early pregnancy apnea–hypopnea index data (6–15 weeks of gestation) predated the GTT testing by more than 1 week in more than 96% of our cohort.
A major strength of this study is the prospective design in which the apnea–hypopnea index results were blinded to the care providers, investigators, and participants. This limited the possibility of ascertainment bias. Our sleep-disordered breathing ascertainment was optimized using an independent and blinded central reading center. We were able to control for important confounding factors including BMI and weight gain, and we evaluated the interaction between apnea–hypopnea index and BMI. We did observe a lower than expected rate of sleep-disordered breathing in early pregnancy (early pregnancy 3.6% observed compared with 5% expected, midpregnancy 8.3% compared with 10%), but despite the lower rates, we detected statistically significant differences in our primary outcome. The observed differences were substantially greater than what we powered to detect. Nonetheless, given the observational and voluntary nature of the study and moderate adjusted ORs (particularly for association with hypertensive disorders), the possibility of residual confounding resulting from selection bias and unmeasured or unknown confounders cannot be definitively excluded. Finally, we recognize the limitations of utilizing a level 3 home sleep apnea test for measuring apnea–hypopnea index. Although a full in-laboratory polysomnogram is considered the gold standard for the objective measurement of sleep-related breathing disorders, it is often not feasible to use a full polysomnogram for large sleep-related studies given the cost and limited availability of sleep laboratory space as well as difficulties recruiting a larger number of participants in research requiring such in-laboratory monitoring. Data indicate that unattended home sleep testing can reliably detect sleep-disordered breathing at substantively lower cost compared with in-laboratory polysomnogram.27 Furthermore, most insurers now routinely require home sleep tests as the first-line diagnostic modality for the majority of patients with suspected sleep-disordered breathing and without certain comorbidities.28,29 Unattended home sleep testing may modestly underestimate the apnea–hypopnea index as a result of this overestimation of sleep time.30 However, studies were scored after editing movement and artifact, reducing the effect of wake time on the apnea–hypopnea index estimates.
Although we found an association with sleep-disordered breathing preceding the development of both pregnancy-related hypertensive disorders and GDM, we cannot conclude that universal screening for and treatment of sleep-disordered breathing in pregnancy would reduce the risks of these adverse outcomes. The most widely prescribed treatment for sleep-disordered breathing is CPAP during sleep. The benefit of treatment with CPAP has been consistently demonstrated when excessive daytime sleepiness and sleep quality are used as endpoints.31,32 However, even in nonpregnant populations, data conflict regarding whether treatment of sleep-disordered breathing can reduce the risk of developing hypertension or diabetes.33–35 This is especially true for milder forms of sleep-disordered breathing (apnea–hypopnea index less than 30), which our study confirms represents the vast majority of sleep-disordered breathing cases in young pregnant women. Pregnancy is an ideal scenario in which to better understand the role of CPAP as a preventive strategy for reducing cardiometabolic morbidity because the timeframe needed to measure outcomes after initiating therapy is significantly contracted. To date, studies examining the effect of CPAP treatment on pregnancy have been small and limited in the scope of endpoints.36–42
In summary, in this prospective analysis of objectively assessed sleep-disordered breathing in pregnancy, the prevalence of sleep-disordered breathing was 3.6% in early pregnancy and increased to 8.3% in midpregnancy. The majority of sleep-disordered breathing cases identified were mild. Our data demonstrate that even modest elevations of apnea–hypopnea index in pregnancy are associated with an increased risk of developing hypertensive disorders and an increased incidence of GDM. These findings are important because sleep-disordered breathing is a risk factor that is amenable to therapeutic intervention. The underlying mechanistic pathways linking sleep-disordered breathing and adverse pregnancy outcomes are likely multifactorial. Sleep-disordered breathing is linked to oxidative stress, autonomic dysfunction, inflammation, endothelial damage, and altered hormonal regulation of energy expenditure.11 These same biologic pathways have been associated with adverse pregnancy outcomes.12 Further research should help to establish whether screening for and treating sleep-disordered breathing in pregnancy can mitigate the risk and consequences of hypertensive disorders of pregnancy and GDM.
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