Sleep apnea in pregnancy may increase the risk for brain and behavioral changes associated with autism


Sleep apnea in pregnancy may increase the risk for brain and behavioral changes associated with autism, especially in males, according to a study in rats by Amanda Vanderplow, Michael Cahill, and colleagues at the University of Wisconsin-Madison, and publishing February 3rd in the open-access journal PLOS Biology.

The findings support evidence in humans of a link between sleep apnea and neurodevelopmental disorders, and provide a potential mechanism to explain the link.

During episodes of sleep apnea, breathing is partially or completely interrupted, often hundreds of timers per night, causing intermittent hypoxia, or decreased blood oxygenation. The incidence of sleep apnea during pregnancy is on the rise, in line with the obesity epidemic, and occurs in about 15% of uncomplicated pregnancies and more than 60% of high-risk pregnancies by the third trimester. Sleep apnea during pregnancy is known to have detrimental effects on the newborn, but the impacts on neurodevelopment have not been well studied.

To investigate such impacts, the authors subjected pregnant rats to intermittent low oxygen levels during times of rest, during the second half of their gestational period. The treatment induced hypoxia in the mothers, but (as expected) not in the fetuses. Behavioral abnormalities in the offspring were observed beginning shortly after birth, including altered distress vocalization patterns in both males and females.

Maternal hypoxia also impaired cognitive and social function in male, but not female, offspring, both of which persisted into adulthood. Effects included reduction in working memory and longer-term memory storage, and reduced interest in socially novel situations.

These behavioral changes were accompanied by significant abnormalities in the density and morphology of dendritic spines, the outgrowths on neurons that receive and integrate signals from other neurons.

In adolescents of both sexes, but much more so in males, the density of dendritic spines was elevated compared to age-matched control animals, an increase due mainly to lack of spine “pruning,” or reduction, a process that begins in childhood and is critical for normal brain development. How maternal hypoxia induced these changes in fetuses not themselves experiencing hypoxia remains unclear.

The authors found that affected offspring had excessive activity of a cell signaling pathway known as the mTOR pathway, a feature identified in the cortex of humans with autism, and that treatment with rapamycin, an mTOR inhibitor, partially mitigated the behavioral effects of maternal hypoxia in the offspring.

“To our knowledge, this is the first direct demonstration of the effects of maternal intermittent hypoxia during gestation on the cognitive and behavioral phenotypes of offspring,” Cahill says.

“Our data provide clear evidence that maternal sleep apnea may be an important risk factor for the development of neurodevelopmental disorders, particularly in male offspring.”

Cahill adds, “Based on clinical correlations, maternal sleep apnea during pregnancy has been theorized to potentially increase risk for autism diagnosis in her offspring; however, functional studies are lacking. Here we show that sleep apnea during gestation produces neuronal and behavioral phenotypes in rodent offspring that closely resemble autism, and demonstrate the efficacy of a pharmacological approach in fully reversing the observed behavioral impairments.”

Sleep quality worsens during pregnancy [1,2], and poor sleep in pregnancy is associated with adverse outcomes of pre-term birth [3], longer labor and delivery time [4,5], and postpartum depressive symptoms [1].

Sleep disordered breathing (SDB)—a spectrum of disorders characterized by interruptions in airflow due to obstruction of the upper airway that leads to fragmented sleep and diminished sleep quality—can disrupt sleep in expectant mothers. Indeed, the physical changes that accompany pregnancy may predispose women to experience SDB [6], and risk for SDB increases as pregnancy advances.

Snoring, a mild form of SDB, increases from 7% of women in the first trimester of pregnancy to up to 48% in the week prior to birth [7]. Obstructive sleep apnea (OSA), a more serious form of SDB, increases from 4–6% of pregnant women in their first trimester to up to 9–20% of women in their third trimester [8,9] and is also associated with adverse maternal health outcomes [10].

While maternal SDB in pregnancy is known to be associated with multiple maternal obstetric complications, such as hypertensive disorders, diabetes, and abnormal fetal growth [9,10,11,12,13], there is limited knowledge about possible associations between SDB in pregnancy and maternal depression. Depression is a common health complication in pregnancy and is associated with adverse maternal, fetal, and child health outcomes [5,14]. A recent meta-analysis identified the prevalence of major depressive disorder as 11.9% during the perinatal period [15].

Previous studies have reported cross-sectional associations between SDB and depressive symptoms in the third trimester [16,17], with recent evidence that the association is also present in early pregnancy [18]. Mellor et al. [19] noted an association between SDB as measured by the Berlin Questionnaire [20] and depressive symptoms between 12 and 39 weeks of pregnancy; however, this association did not withstand adjustment for covariates such as body mass index (BMI).

In non-pregnant adults, development of SDB precedes the onset of depression [21], and OSA is associated with higher depression severity. In addition, treatment of OSA with continuous positive airway pressure (CPAP) has been shown to reduce depressive symptom severity [22,23].

Taken together, past research suggests that SDB precedes depression onset in non-pregnant adults, and emerging evidence demonstrates an association between SDB and perinatal depression.

However, the longitudinal association between SDB and depression in pregnancy has not yet been elucidated. Understanding the temporal association between SDB and depression across gestation is important because mood and sleep are dynamic processes that change along with the physiologic demands of pregnancy.

Therefore, the aim of this study was to explore the temporal relationship among subjective (self-reported) and objective (in-home sleep study) measures of SDB and self-reported depression across pregnancy. We hypothesized that pregnant women with SDB would be more likely to experience symptoms of depression, and that greater SDB severity would be associated with greater depression severity.

As women with SDB symptomatology early in pregnancy would presumably have longer exposure to disturbed sleep throughout the remainder of pregnancy, we also hypothesized that symptoms of SDB in early pregnancy would predict more depressive symptoms in the third trimester.

reference link :,maternal%20health%20outcomes%20%5B10%5D.

More information: Vanderplow AM, Kermath BA, Bernhardt CR, Gums KT, Seablom EN, Radcliff AB, et al. (2022) A feature of maternal sleep apnea during gestation causes autism-relevant neuronal and behavioral phenotypes in offspring. PLoS Biol 20(2): e3001502.


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