In recent years, researchers have assembled a growing body of evidence indicating that activation of the maternal immune system during pregnancy raises the risk of neurodevelopmental deficits in offspring. It has been hypothesized that this risk, in at least some children, may be a causal factor in developmental delays affecting cognition and learning, as well as in heightened risk for psychiatric illnesses including schizophrenia and autism spectrum disorder (ASD).

The mother’s immune system can be activated in response to a wide range of factors, from stress to viral infection to obesity. One little-explored factor is sleep apnea (SA), a condition that affects 15% of pregnant women, typically during the final trimester, and as many as 60% of women with high-risk pregnancies. Sleep apnea is characterized by recurrent, brief cessation of breathing (partial or complete) during sleep, often hundreds of times each night. Most people with SA are unaware of its occurrence, including many women who experience it for the first time late in pregnancy.

SA causes swings in blood oxygen levels, leading to a condition called intermittent hypoxia. Hypoxia can induce “profound inflammation which causes most of the morbidities associated with SA,” according to a research team led by 2019 and 2015 BBRF Young Investigator Michael E. Cahill, Ph.D., of the University of Wisconsin-Madison. Known morbidities related to SA in humans include high blood pressure, heart disease, obesity, and diabetes.

Dr. Cahill and colleagues developed the first rat model of maternal SA during pregnancy in order to study its possible relationship with neural abnormalities in offspring, as well as impacts (if any) on offspring behavior across the lifespan.

Developing the animal model is important, since it is deemed unethical to allow a pregnancy to proceed in a human mother with SA without medical intervention.

In the rat model of SA, animals in late pregnancy experienced intermittent hypoxia by providing them over 8 hours of sleep with 4-minute cycles consisting of 2 minutes of air at a concentration of 10.5% oxygen followed by 2 minutes of air at normal oxygen concentration of 21%. The placenta largely protects the fetus from the direct effects of maternal hypoxia. Thus, intermittent hypoxia in the mother does not cause hypoxia in the fetus. But the real question is whether the activation of the mother’s immune system caused by hypoxia during pregnancy will impact how the fetus develops—in the womb but also after birth.

Results of the team’s experiments were dramatic. They found that intermittent hypoxia in the mother during pregnancy is a “potent inducer of cortical hyperconnectivity and hyperfunction in the offspring.” This, they said, led to “far-ranging behavioral aberrations that span communicative, cognitive, and social domains” in the offspring. Also, importantly, the team found that “the magnitude and breadth of these alternations are consistently more severe in male than female offspring.”

Regarding the behavioral changes in offspring, the researchers explained that these included communications between mothers and pups right after birth, but also, in adolescent and even adult offspring, cognitive and executive function impairment, altered social behavior, and increased grooming behavior (a kind of repetitive behavior). Except for the abnormal postnatal vocalizations, which were seen in males and females, all the other abnormalities were seen only in male offspring.

The neural abnormalities seen in male offspring centered on excessive synapse numbers and hyperactive cortical signaling, particularly in a signaling pathway called the mTOR pathway. “These findings have implications for neuropsychiatric disorders typified by superfluous synapse maintenance that are believed to result, at least in part, from largely unknown insults to the maternal environment” during pregnancy, the researchers noted.

While they did not want specifically to link the observed abnormalities with those hypothesized to cause, for example, ASD or schizophrenia, they were willing to say, at this point in their research, that “our data provide clear evidence that maternal SA may be an important risk factor for the development of neurodevelopmental disorders, particularly in male offspring.”

In a fascinating coda to their study, the team administered an FDA-approved drug called rapamycin to male offspring with the observed neural and behavioral abnormalities. Rapamycin is known to target the mTOR pathway and in this instance appeared to dampen hyperactive signaling in the pathway. The result was a reversal of the behavioral abnormalities in the affected rats. While not suggesting, based on this evidence, that the drug might be a potential treatment for ASD in humans, the team did say that their results in rats help to “advance a growing narrative regarding the pharmacological potential of targeting mTOR signaling in certain brain-based disorders.”

They called for further experiments to determine the precise relation between maternal inflammation and the intermittent hypoxia associated with sleep apnea, and for consideration of a large-scale assessment of SA’s possible contributory or causal role in a range of psychiatric illnesses in people.