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Metabolic pregnancy clock

Understanding the biological clock of pregnancy

Stanford scientists have built a detailed picture of the biological clock of pregnancy, tracking thousands of metabolic markers throughout gestation.

Stanford scientists are building an increasingly detailed picture of the metabolic clock of human pregnancy, a step toward developing simple blood tests to pinpoint the progress of gestation for individual mothers-to-be.

In a study published recently in Cell, the researchers charted levels of almost 10,000 metabolic signals -- most of the metabolites that scientists can measure at one time -- in the blood of pregnant women on a week-by-week basis throughout gestation.

The research showed that more than half of these markers shift during a healthy pregnancy. Additionally, the researchers identified two small sets of metabolic signals that could act as the basis for blood tests; these metabolites precisely predict the gestational age of a pregnancy, and also whether a woman is close to delivery.

Mapping out a normal pregnancy

Metabolites are small molecules that play several roles: they can act as signals between and within cells, and also are cellular fuel and byproducts of cellular processes. By tracking metabolite levels, scientists can determine what cells are actually doing in real time, said Michael Snyder, MD, PhD, professor of genetics.

"Genetics lays out the score for the symphony: Here's what the orchestra should play," said Snyder, who is a co-senior author of the study. "Metabolomics is what's actually being played."

The idea for this study was to map out, in great detail, how a normal pregnancy looks, said Mads Melbye, MD, PhD, professor of medicine, who shares senior authorship of the paper with Snyder. "That will allow us to compare with pregnancies that are problematic in one way or another so that we can, hopefully, improve conditions for complicated pregnancies," he said.

Breaking new ground

The study included 38 women who gave frequent blood samples from early pregnancy until after delivering their babies. All women had healthy pregnancies that went past 37 weeks' gestation, meaning the babies were not born prematurely. The researchers used liquid chromatography mass spectrometry, a technique for simultaneously measuring thousands of small molecules in blood, to assess 9,651 metabolic signals in each blood sample. The metabolites measured included many steroid hormones, various types of lipid (fatty and fat-like) molecules, and molecules associated with metabolism of amino acids, caffeine, fatty acids, phospholipids and bile acids.

A total of 4,995 metabolites changed significantly in pregnancy and/or the postpartum period, the research found. Of these, Melbye said, 95% had never previously been associated with pregnancy, showing just how much new ground there was to break.

A small subset of metabolic signals -- including four steroid hormones and one lipid molecule -- precisely tracked the timing of pregnancy, with their levels predicting the gestational age of the baby more effectively than a first-trimester ultrasound, the research found. Other groups of two to three metabolites were able to predict if a woman was within two, four or eight weeks of delivering her baby.

Laying the groundwork for blood tests

These finding lay the groundwork for potential blood tests to predict a pregnant woman's due date, said Liang Liang, PhD, the study's first author. Such tests would be particularly helpful in less-developed countries where women may have to travel for a few days to reach the medical facility where they plan to give birth.

"The current clinical gold-standard to determine gestational age is based on first-trimester ultrasound," Liang said. "For the developing world, it's not easily accessible, and even in the U.S., about 900,000 pregnant women every year miss their first-trimester clinical visit."

What's more, Liang added, even when women get a first-trimester ultrasound, current medical technology can't usually predict whether they may deliver early or have a pregnancy that goes past their due date.

Studies in larger groups of women are needed to confirm the findings, as well as to compare healthy pregnancies with those that develop complications. Liang hopes her future work will help illuminate the biology of pregnancy-related conditions that have long-term effects on women's health, such as pre- or postpartum depression and gestational diabetes.

"My long-term goal is really to help women's health," she said. "I hope women can be healthy and enjoy their pregnancy, have healthy babies, and also have healthier bodies after pregnancy."

The research dovetails with previous Stanford efforts to characterize immune-system shifts, changes in the body's bacterial communities, and changes in gene expression during pregnancy. The study is also part of a larger Stanford effort to identify metabolic signals of health and disease in infancy and childhood.

"We are trying to understand metabolic health as early in life as possible," Snyder said. "We think our findings will have huge implications for the health of both the mom and the fetus."

Photo by Rattanasak

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