Miscarriage risk increases each week alcohol is used in early pregnancy

August 10, 2020

Science Daily/Vanderbilt University Medical Center

Each week a woman consumes alcohol during the first five to 10 weeks of pregnancy is associated with an incremental 8% increase in risk of miscarriage, according to a study by Vanderbilt University Medical Center (VUMC) researchers.

The findings, published in the American Journal of Obstetrics and Gynecology, examine the timing, amount and type of alcohol use during pregnancy and how these factors relate to miscarriage risk before 20 weeks' gestation.

Impact of alcohol use rises through the ninth week of pregnancy, and risk accrues regardless of whether a woman reported having fewer than one drink or more than four drinks each week. Risk is also independent of the type of alcohol consumed and whether the woman had episodes of binge drinking.

Though most women change their alcohol use after a positive pregnancy test, consuming alcohol before recognizing a pregnancy is common among both those with a planned or unintended pregnancy. Half of the 5,353 women included in the analysis reported alcohol use around conception and during the first weeks of pregnancy.

The median gestational age for stopping alcohol use was 29 days. Although 41% of women who changed their use did so within three days of a positive pregnancy test, those who stopped consumption near their missed period had a 37% greater risk of miscarriage compared to women who did not use alcohol.

"Abstaining from alcohol around conception or during pregnancy has long been advised for many reasons, including preventing fetal alcohol syndrome. Nonetheless, modest levels of consumption are often seen as likely to be safe," said Katherine Hartmann, MD, PhD, vice president for Research Integration at VUMC and principal investigator for the Right from the Start cohort, from which participants were enrolled in the study.

"For this reason, our findings are alarming. Levels of use that women, and some care providers, may believe are responsible are harmful, and no amount can be suggested as safe regarding pregnancy loss."

According to the researchers, one in six recognized pregnancies ends in miscarriage, which brings great emotional cost and leaves unanswered questions about why the miscarriage occurred.

Biologically, little is known about how alcohol causes harm during early pregnancy, but it may increase miscarriage risk by modifying hormone patterns, altering the quality of implantation, increasing oxidative stress or impairing key pathways.

Because alcohol use is most common in the first weeks -- when the embryo develops most rapidly and lays down the pattern for organ development -- understanding how timing relates to risk matters.

Risk did not peak in patterns related to alcohol use in specific phases of embryonic development, and there was no evidence that a cumulative "dose" of alcohol contributed to level of risk.

The study recruited women planning a pregnancy or in early pregnancy from eight metropolitan areas in Tennessee, North Carolina and Texas. Participants were interviewed during the first trimester about their alcohol use in a four-month window.

"Combining the facts that the cohort is large, comes from diverse communities, captures data early in pregnancy and applies more advanced analytic techniques than prior studies, we're confident we've raised important concerns," said Alex Sundermann, MD, PhD, the study's first author and recent graduate of the Vanderbilt Medical Scientist Training Program.

To avoid increased risk of miscarriage, the researchers emphasize the importance of using home pregnancy tests, which can reliably detect pregnancy before a missed period, and ceasing alcohol use when planning a pregnancy or when pregnancy is possible.

https://www.sciencedaily.com/releases/2020/08/200810102430.htm

Consuming alcohol leads to epigenetic changes in brain memory centers

October 23, 2019

Science Daily/University of Pennsylvania School of Medicine

New research revealed a surprising pathway that shows alcohol byproducts travel to the brain to promote addiction memory. They show how acetate travels to the brain's learning system and directly alters proteins the regulate DNA function, impacting how some genes are expressed and ultimately affecting how mice behave when given environmental cues to consume alcohol.

Triggers in everyday life such as running into a former drinking buddy, walking by a once-familiar bar, and attending social gatherings can all cause recovering alcoholics to "fall off the wagon." About 40 to 60 percent of people who have gone through treatment for substance abuse will experience some kind of relapse, according to the National Institute on Drug Abuse. But what drives the biology behind these cravings has remained largely unknown.

Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania, have shown, in mouse models, how acetate -- a byproduct of the alcohol breakdown produced mostly in the liver -- travels to the brain's learning system and directly alters proteins that regulate DNA function. This impacts how some genes are expressed and ultimately affects how mice behave when given environmental cues to consume alcohol. Their findings were published today in Nature.

"It was a huge surprise to us that metabolized alcohol is directly used by the body to add chemicals called acetyl groups to the proteins that package DNA, called histones," said the study's senior author Shelley Berger, PhD, the Daniel S. Och University Professor in the departments Cell and Developmental Biology and Biology, and director of the Penn Epigenetics Institute. "To our knowledge, this data provides the first empirical evidence indicating that a portion of acetate derived from alcohol metabolism directly influences epigenetic regulation in the brain."

It has been known that a major source of acetate in the body comes from the breakdown of alcohol in the liver, which leads to rapidly increased blood acetate. In this study, the team, co-led by Philipp Mews, PhD, a former graduate student in the Berger lab who is now a postdoctoral fellow at Mount Sinai, and Gabor Egervari, MD, PhD, a postdoctoral fellow in Berger's lab, sought to determine whether acetate from alcohol breakdown contributes to rapid histone acetylation in the brain. They did so by using stable-isotope labeling of alcohol to show that alcohol metabolism does, in fact, contribute to this process by directly depositing acetyl groups onto histones via an enzyme called ACSS2.

Authors said that "ACSS2, 'fuels' a whole machinery of gene regulators 'on site' in the nucleus of nerve cells to turn on key memory genes that are important for learning. In fact, Berger and colleagues published findings on ACSS2 in a 2017 Nature paper. In that paper and previous work, the researchers found that ACSS2 is needed to form spatial memories.

In the current study, to better understand how the alcohol-induced changes in gene expression ultimately effect behavior, Berger and her team employed a behavioral test. Mice were exposed to "neutral" stimuli and alcohol reward in distinct compartments, distinguished by environmental cues. After this conditioning period, the researchers measured the preference of the mice by allowing them free access to either compartment, and recording the time spent in both the neutral and alcohol-paired chamber. They found that, as expected, mice with normal ACSS2 activity spent more time in the alcohol compartment following the training period.

To test the importance of ACSS2 in this behavior, researchers reduced the protein level of ACSS2 in a brain region important for learning and memory, and observed that, with lowered ACSS2, there was no preference shown for the alcohol-paired compartment.

"This indicates to us that that alcohol-related memory formation requires ACSS2," Egervari said. "Our molecular and behavioral data, when taken together, establish ACSS2 as a possible intervention target in alcohol use disorder -- in which memory of alcohol-associated environmental cues is a primary driver of craving and relapse even after protracted periods of abstinence."

Importantly, these findings suggest that other external or peripheral sources of physiological acetate -- primarily the gut microbiome -- may similarly affect central histone acetylation and brain function, which may either control or foster other metabolic syndromes.

In addition to investigating the impact of alcohol consumption on brain changes in adults, the team also looked into the effects of consumption in pregnant mice and thus the impact of alcohol on brain cells in developing mice. In utero, alcohol causes impaired neurodevelopmental gene expression and can elicit numerous alcohol-associated postnatal disease symptoms such as small head size, low body weight, and hyperactivity. And while the number of those affected by fetal alcohol spectrum disorders (FASDs) -- which includes fetal alcohol syndrome -- is unknown, the Centers for Disease Control and Prevention suggests that the full range of FASDs in the United States and some Western European countries could be as high as one to five percent of the population.

In this arm of the study, researchers found that, upon consumption of alcohol, acetate is delivered through the placenta and into the developing fetus. The fetal brains of these mice showed that alcohol exposure on the level of "binge drinking" in the pregnant female resulted in deposition of alcohol-derived acetyl-groups onto histones in fetal brains in early neural development in the mice.

Much like the primary results of the study being useful for the potential treatment of alcohol-use disorder, these results could have implications for understanding and combating fetal alcohol syndrome.

https://www.sciencedaily.com/releases/2019/10/191023132254.htm