Female sheep that were undernourished around the time of conception carried their unborn lambs for a shorter time than their fully-nourished peers according to a new study that may help doctors understand human preterm pregnancies. This research appears in the 25 April issue of the journal, Science, published by the American Association for the Advancement of Science.
Preterm births are a significant health problem, their frequency is on the rise and the cause of 60% of these abbreviated human pregnancies remains unknown.
"If you could reduce preterm birth by some small percentage, you could improve the long-term health and lives of many people," said Frank Bloomfield, a neonatologist and study author from the University of Auckland in Auckland, New Zealand and the University of Toronto in Toronto, Canada.
"Preliminary evidence suggests that severe maternal undernutrition or stress early in human pregnancy may result in preterm birth. However, there is little experimental evidence to support this," write the authors from New Zealand, Australia and Canada who present data showing that the preterm birth of lambs is related to their mothers' nutrition at the time of conception.
The authors decreased the food ration for a group of sheep 60 days before conception and maintained this reduced diet for the first 30 days of the pregnancy. The normal length of a sheep pregnancy only varies by a few days which means time-sensitive developmental deviations can be easily observed. Lambs from undernourished mothers were born significantly earlier than lambs from mothers on full-feed. Fetal hormone levels, critical to a final stage of maturation and necessary for birthing process, followed markedly different patterns based on the nutrition of the mother at conception.
"There could be down-the-road implications for what prospective moms should be eating if these findings are applicable to human pregnancy," said Bloomfield who explained that preterm babies born after less than 30 weeks in the womb are at major risk for both cerebral palsy and learning difficulties. Their brains are not adequately developed and this puts them at risk for brain injury.
"We're looking for the aspect of the mother's nutrition that triggers this message to the fetus," said Bloomfield "It could be a nutrient, a micronutrient, or something else. We don't know."
During the period of feed reduction that sandwiched conception, the wooly moms-to-be dropped 15% of their body weight. However, fetal nutrient requirements are extremely small during the first thirty days, and thus maternal undernutrition is unlikely to have limited nutrient availability for fetal growth, the authors wrote.
"There must be some signal coming from the undernourished mother that tells the fetus to be born earlier," Bloomfield explained.
"Our research is aimed at fetal growth and development. We are interested in how and why undernourishment around conception connects to hormonal changes that shorten gestation time," said Bloomfield who broadened the scope of the conversation. "We are looking at what influences the permanent changes the fetus makes based on changes in the uterine environment. This is called fetal programming."
Now that the researchers have connected undernutrition and shortened pregnancies, they are looking for the precise time point and conditions that may cause an undernourished mother to signal alterations in the timeline of her pregnancy.
Moving from the cause of the signal to the proposed result of the signal requires the addition of hormones to the story. The signal from mother to fetus around the time of conception appears to impact levels of the hormones cortisol and adrenocorticotrophin (ACTH), late in the pregnancy. Cortisol, produced in the adrenal glands of many species including sheep and humans, matures fetal organs and prepares the fetus for life outside the womb. In all species studied, there is a surge in circulating fetal cortisol concentrations before birth.
Near the end of the pregnancy, the researchers documented elevated ACTH levels in the fetuses of all the sheep that were under nourished around the time of conception. About half of these ewes gave birth early and the authors attribute this to a precocious surge in fetal cortisol linked to maternal undernourishment around the time of conception.
As for the undernourished ewes that did not give birth early, the authors hypothesize that the fetal hormone production glands called the hypothalamic-pituitary-adrenal axis (HPAA) did not mature to a threshold level required to initiate the simultaneous rise in ACTH and cortisol thought to cause preterm birth.
The coauthors on the Bloomfield paper are Melanie Campbell and John Challis from the University of Toronto; Mark Oliver, Paul Hawkins, Peter Gluckman and Jane Harding from the University of Auckland; and David Phillips from Monash University.
Funding for this research was primarily provided by the Health Research Council of New Zealand. Additional funders included the Canadian Institutes for Health Research, the Royal Australasian College of Physicians, and the National Health and Medical Research Council in Australia.
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