New evidence on this crucial window of time -- much of it from animal studies -- surfaced at this year's meeting of the Society for the Study of Reproduction in Pittsburgh.
Researchers found during this period, the effects of nutrition, such as a high-fat diet and vitamin B and folate deficiencies, as well as diseases such as diabetes, could trigger epigenetic changes that manifest in offspring as obesity, insulin resistance, and cardiovascular disease.
"All of our work suggests there should be a three- to four-month preconception period that's included in good maternal health," said Kelle H. Moley, MD, of Washington University School of Medicine in St. Louis, who presented one of the studies.
"Early dietary changes or early nutritional changes in the mom can effect epigenetic modifications," Dr. Moley said. "These are persistent in offspring and can be passed down across generations."
The researchers said that they became interested in this period after finding evidence of higher rates of genetic imprinting disorders in babies conceived via in-vitro fertilization.
"This opened the door to ideas that changes early in development could have long-term effects," Dr. Moley said.
"An unfertilized egg and early embryos are very sensitive to their environments," said Kevin Sinclair, PhD, of the University of Nottingham in England, also an author of one of the studies.
Dr. Moley has been studying how diabetes affects production of a mother's egg cells, potentially leading to mitochondrial metabolic dysfunction.
"We've been tackling the question of why, even though we control blood sugar during pregnancy, we still have three- to four-fold greater numbers of birth defects than control patients," she said.
Looking at diabetic and nondiabetic mice, she found an alteration in mitochondrial ultrastructure in the egg cells of the diabetic mice. And the higher the glucose levels of those mice, the higher the incidence of mitochondrial abnormalities and energy deficiencies.
She said the alterations may be responsible for growth abnormalities in the offspring.
Dr. Sinclair's work focused on the effects of vitamin deficiency leading up to conception. He looked at sheep that were fed a normal diet or a diet deficient in vitamin B12 and folate.
The offspring of those on the vitamin-deficient diet were more likely to become obese, experience insulin resistance, and have high blood pressure.
The effects were most pronounced in male offspring, Dr. Sinclair said. He saw similar results in a mouse model.
A third study, by Tom Fleming, PhD, of the University of Southampton in England, looked at the effects of a low-protein diet just before conception and during the early days of fetal development in a mouse model.
Throughout the rest of their pregnancy, the mice were fed a normal diet.
The researchers found that this was associated with cardiovascular problems, particularly hypertension and arterial disease, as well as other metabolic disorders in the offspring.
Again, there was evidence of a stronger effect in male mice.
What's happening during this short period of time? Dr. Fleming said the tiny ball of cells that makes up the fetus is "sensing" its maternal nutritional environment.
If nutrients are scarce, the embryo will make decisions about how best to get nutrients from its mother, potentially overcompensating.
In a fourth study, researchers have been edging closer to a human model by looking at primates. Kjersti M. Aagaard-Tillery, MD, PhD, of Baylor College in Houston, Texas, and colleagues studied macaques given a 35% high-fat diet.
Some of the animals became obese as a result of the diet, while others did not. But of those who became pregnant, all gave birth to offspring that developed non-alcoholic fatty liver disease and hypertriglyceridemia.
Dr. Aagaard-Tillery said the finding may have something to do with DNA methylation, another sign of epigenetic changes.
"It is clear that changes to diet, glucose levels in the mother, and vitamin intake, prior to ovulation and conception can have long-term effects on fetal growth and adolescent and adult disease," Dr. Moley said.
However, she said women should restrain their worry at this point, because the researchers aren't certain about the timing surrounding these events.
"[Egg cells] are constantly being turned over," she said. "The key is to maintain adequate metabolic control for about three months prior to attempts at conception."
Shuk-mei Ho, PhD, of the University of Cincinnati, who also presented data on the subject, said that similar effects in fathers should be noted as well.
"The contribution of paternal influences is very important," Dr. Ho said. "The transmission of epigenetic information could also be passed along through the paternal lineage."
|Drs. Sinclair and Fleming were supported by grants from the NICHD Cooperative Program on Female Health and Egg Quality.|
Zalman S. Agus, MD Emeritus Professor
University of Pennsylvania School of Medicine
Society for the Study of ReproductionSource Reference: Moley KH "Too much of a sweet thing -- Maternal diabetes and oocyte quality" SSR 2009; Abstract 2.
Society for the Study of ReproductionSource Reference: Sinclair KD "Developmental origins of health and disease: B vitamins and DNA methylation programming in the oocyte and pre-implantation embryo" SSR 2009; Abstract 3.
Society for the Study of ReproductionSource Reference: Fleming TP, et al "Maternal dietary effects on rodent egg/embryo developmental potential and long-term health" SSR 2009; Abstract 4.