Understanding the Importance of Maternal-Fetal Circadian Synchrony

Eric Herzog, PhD

It has been reported that pregnant women experience less sleep, increased wakefulness, and excessive daytime sleepiness compared with non-pregnant populations, with 80% of women reporting poor sleep throughout pregnancy. Previous research has shown that poor sleep during pregnancy is associated with an increased risk of adverse maternal and fetal health outcomes including preeclampsia, gestational diabetes mellitus, caesarean delivery, and preterm birth as well as general tiredness, fatigue, and cognitive impairment.

Over the years, there has been an increased interest in studying circadian rhythms, found in gene expression and hormones, and their impact on birth outcomes in pregnant women. To be useful, these daily rhythms in cells must be synchronized within the body and to the local light-dark cycle. Eric Herzog, PhD, a chronobiologist and professor of biology and neuroscience at Washington University, has been at the forefront of this research, with specific interest in the molecules, cells, and circuits underlying daily rhythms in physiology and behavior.

At the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, Herzog presented a lecture on maternal-fetal circadian synchrony and birth outcomes, highlighting work laboratory work done with colleagues of his. Following his presentation, Herzog sat down with NeurologyLive® to discuss the importance of circadian communication during pregnancy, the conversations between pregnant patients and clinicians, and the factors that play into good birth outcomes. In addition, he spoke on the impact of hormones and how the timing of administering glucocorticoids can have a major effect on the effectiveness of the treatment. Furthermore, he gave thoughts on addressing poor sleep and the ways clinicians can work with patients to ultimately improve birth outcomes prior to conception.

NeurologyLive: Can you provide an overview of your presentation and why this was a topic of interest?

Eric Herzog, PhD: My lab studies circadian rhythms, and we're interested in one of the applications of our studies as to what causes preterm birth. In the United States, there's an average of about 10% of women who deliver preterm meaning, before 37 weeks. That puts the pregnancy and the offspring at risk, and for society, it can be very expensive, because preterm birth is associated with lots of long term health consequences. What we've been asking is whether sleep during pregnancy is associated with pregnancy outcomes.

How important is circadian rhythm during pregnancy? What are some of the downstream effects of disrupted rhythm?

Our studies were in both mice and in people. In people, we have an association where we find that more irregular sleep for the mom during pregnancy, whether it be the first or second trimester, is associated with an increased risk for preterm birth. What I showed here [at SLEEP 2024] was that that circadian rhythms develop in utero in mice, and we can monitor, for example, clock gene expression. We have 20,000 or so genes in our genome. Of those, a dozen or so are dedicated to daily rhythms in physiology and behavior. And we can monitor those genes in real time in mice and watch them turn on and turn off in the fetus in utero imaging through the mom's belly. What we noticed was that those rhythms start early in development, about when cells are starting to differentiate, and as the baby is developing in utero, those rhythms eventually synchronize to the mother. We found that when that synchrony is disrupted, the delivery and the fetuses are compromised.

How much is sleep and maintaining circadian rhythm stressed during and before pregnancy?

One of the really interesting things we found was that women have a natural change in their daily schedules that happens in a healthy pregnancy, and appreciating what's normal is important for understanding when things are not normal or at risk. One of the things that we found was that women and mice actually shift their schedules earlier during their first trimester, and then that gradually resolves just before they deliver. That normal pattern, if disrupted, seems to be interfering with normal development and gating in delivery of parturition. In terms of interventions, we started to think about, “well, these things that we're seeing in women who delivered preterm are there when they arrive in the clinic early in their pregnancy.” This provides us with an opportunity to intervene early with their daily schedules to try and improve their daily sleep schedules, improve their access to light, and to start to consider ways that we might be able to rescue a woman who's at risk with relatively friendly advice to pregnant moms.

Do sleep disorders play a factor into how a woman may sleep during pregnancy and whether tailored approaches should be involved?

One of the most striking findings we have is that irregular sleep onset—day to day variability, when you go to bed, when you wake up—anything over about an hour and a half in terms of the standard deviation of your daily wake up and go to bed times was the greatest risk factor [in poor outcomes], more than short sleep duration and other measures of sleep. And so, for example, there's a lot of literature on obstructive sleep apnea being a risk factor for mom's cardiovascular health, mom's risk for preeclampsia and subsequent consequences on the baby. Here, we're really talking about a different category of women, where we're talking about things that are often associated with socioeconomic status. Irregular sleep is often associated with things like shift work; somebody who has to take two busses to get to work, and so your schedule is not your own. We don't know the sources of the variability in the women. In our study, there were 1260 of the women who delivered, and we were interested in the causes of the sleep abnormalities. I wouldn't call them disorders because, in fact, this is highly prevalent in our population right now, with over 10% of women delivering preterm. Over 28% of the women in our study would qualify as having irregular sleep. We think that those things together really mean that we're addressing something, a societal problem.

How do we manage hormonal changes to ensure good birth outcomes?

First and foremost, thinking about when we make measurements is an important variable in whether that thing (estrogen) is really pathologically high or low. For example, cortisol surges just before we wake up, and then goes down for the rest of the day. If you find high levels of cortisol in the morning, that's normal. If you find high levels of cortisol in the evening, that's probably pathological. Second, we think that some of those hormones may be the important cue from mom to baby to tell the baby what time of day it is. Two hormones, melatonin and cortisol, have been implicated in maternal to fetal circadian communication, communicating what time of day it is to the fetus so that the fetus is born at the right time and developing in the right ways. We don't yet know for sure which signals are most important for synchronization of the fetus to the mom, but we know that clinically, lots of physicians are delivering dexamethasone, a synthetic glucocorticoid, to help a baby that's at risk for prematurity to develop its lungs more rapidly. What we're learning is that those treatments may actually be shifting the circadian system in the fetus and thus giving it at the wrong time of day and in the wrong dose may be actually counterproductive.

Are people in this field commonly aware of this research and the involvement of circadian rhythm?

I think the term circadian is pretty well understood by physicians today. Circadian medicine, the practice of thinking about daily rhythms and physiology changing with time of day, is less common. It's more common for specific areas of medicine. Cardiologists and pulmonologists have adopted circadian medicine pretty readily, but it's less well adopted, for example, in neurology. Here, we're saying glucocorticoids can be more productive when delivered at the appropriate time of day, just before waking or around waking, but could be counterproductive around us. Those are things that we need to be thinking about more in a clinical setting.

How much does race/socioeconomic background play a factor into birth outcomes?

Fantastic question. It's really important to for all of us to accept that race is not a biological factor, it's a societal construct. Where folks have been looking for genetic risks for preterm birth—there have been some hints—but what we're finding is that socioeconomic status and adversity, for example, being born Black, and the treatment that you experience as being born Black, those things have long been associated with preterm birth. We're seeing that it's mediated at least by 30% through irregular sleep. Those folks who are of lower socioeconomic status are at greater risk for preterm birth because they have irregular sleep.

Transcript edited for clarity.